BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes...BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.展开更多
Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis.However,mechanisms associated with stem cell senescence require further investigation.In this study,we conducted a proteomic a...Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis.However,mechanisms associated with stem cell senescence require further investigation.In this study,we conducted a proteomic analysis of human dental pulp stem cells(HDPSCs)obtained from individuals of various ages.Our findings showed that the expression of NUP62 was decreased in aged HDPSCs.We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo.Conversely,the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs.Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression,we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1.This,in turn,stimulates the transcription of the epigenetic enzyme NSD2.Finally,the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes(HMGA1,HMGA2,and SIRT6).Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.展开更多
BACKGROUND Over the years,the numbers of treatment options for colorectal cancer(CRC)have increased,leading to notable improvements in the overall survival of CRC patients.Although therapy may initially yield positive...BACKGROUND Over the years,the numbers of treatment options for colorectal cancer(CRC)have increased,leading to notable improvements in the overall survival of CRC patients.Although therapy may initially yield positive results,the development of drug resistance can result in treatment failure and cancer recurrence.This resistance is often attributed to the presence of cancer stem cells(CSCs).These CSCs not only contribute to therapeutic resistance but also play crucial roles in the initiation and development of tumor metastasis.AIM To investigate the antitumor effects of SH-4-54,which are mediated by targeting CSCs relative to treatment outcomes.METHODS CSCs were enriched by culturing CRC cells in serum-free medium.Hallmarks of stemness and IL-6/JAK2/STAT3 signaling were detected by Western blotting.Indicators of CSC malignancy,including proliferation,invasion,and tumor formation,were measured.RESULTS In this study,we employed SH-4-54,which exhibits anticancer activity in solid tumors through targeting the SH2 domain of both the signal transducer and activator of transcription(STAT)3 and the STAT5,and evaluated its effects on stemness and chemoresistance in colorectal CSCs.As expected,SH-4-54 treatment inhibited the phosphorylation of STAT3(p-STAT3)and decreased the percentage of ALDH1A1-positive CRC cells.The addition of SH-4-54 dissociated colorectal spheroids and decreased the expression of stemness markers,including ALDH1A1,CD44 and Nanog.SH-4-54 treatment decreased IL-6/JAK2/STAT3 signaling by inhibiting p-STAT3 and thus inhibited spheroid formation by SW480 and LoVo cells.Moreover,SH-4-54 treatment inhibited indicators of malignancy,including cell proliferation,invasion,and tumor formation,in CSCs in vitro and in vivo.Notably,SH-4-54 treatment significantly increased chemosensitivity to oxaplatin.CONCLUSION Taken together,these results indicate that SH-4-54 is a promising molecule that exerts antitumor effects on colorectal CSCs by inhibiting STAT3 signaling.展开更多
BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC ...BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC pathobiology is being increasingly recognized.AIM To investigate the role of OCT4 in pancreatic CSCs and its effect on PC cell prolif-eration,migration,drug sensitivity,and stemness maintenance.METHODS We analyzed OCT4 and CD133 expression in PC tissues and cell lines.BxPC-3 cells were used to assess the effects of OCT4 modulation on cellular behavior.Proliferation,migration,and stemness of BxPC-3 cells were evaluated,and the PI3K/AKT/mTOR pathway was examined to gain mechanistic insights.RESULTS OCT4 and CD133 were significantly overexpressed in PC tissues.OCT4 mo-dulation altered BxPC-3 cell proliferation,invasion,and stemness,with OCT4 overexpression(OV-OCT4)enhancing these properties and OCT4 interference decreasing them.OV-OCT4 activated the PI3K/AKT/mTOR pathway,which correlated with an increase in PC stem cells(PCSC).CONCLUSION OCT4 plays a crucial role in PCSCs by influencing the aggressiveness and drug resistance of PC cells,thus presenting itself as a potential therapeutic target.展开更多
BACKGROUND Tumors characterized by high cellular stemness often have unfavorable clinical outcomes,primarily due to their heightened potential for metastasis and resistance to chemotherapy.Among the model genes,the cl...BACKGROUND Tumors characterized by high cellular stemness often have unfavorable clinical outcomes,primarily due to their heightened potential for metastasis and resistance to chemotherapy.Among the model genes,the clinical relevance and prognostic significance of Niemann-Pick type C2(NPC2)in gastric cancer(GC)remained largely unexplored.AIM To identify stemness-associated genes in GC.METHODS In this study,epithelial cells were categorized as either tumor or normal epithelial cells using the infer copy number variation method.Stemness scores were calculated for both cell types.The hierarchical Weighted Gene Co-expression Network Analysis identified two gene modules with the strongest association with stemness.Prognostically significant stemness-related genes were pinpointed using univariate Cox regression based on The Cancer Genome Atlas dataset.A predictive model related to stemness was constructed using Least Absolute Shrinkage and Selection Operator regression followed by multivariate Cox analysis.RESULTS Functional roles of NPC2 were validated using single-cell and bulk RNA sequencing data.Further experimental validation revealed that elevated NPC2 expression promoted tumor cell stemness,invasiveness,migratory ability,and resistance to standard chemotherapeutic agents.Importantly,high NPC2 expression correlated with poorer overall survival in GC patients.CONCLUSION In summary,the proposed model offers prognostic insights that outperform traditional clinical staging and may inform more tailored therapeutic approaches for gastric cancer management.展开更多
Aims:The aim of this study is to develop a prognostic model for hepatocellular carcinoma(HCC)using stemness-related genes(SRGs),while also pinpointing and validating pivotal genes associated with this process.Methods:...Aims:The aim of this study is to develop a prognostic model for hepatocellular carcinoma(HCC)using stemness-related genes(SRGs),while also pinpointing and validating pivotal genes associated with this process.Methods:Utilizing the TCGA and ICGC database,a prognostic stemness-related scores(SRS)for HCC through a combination of WGCNA and machine learning.Bioinformatics analysis evaluated tumor immune infiltration characteristics and drug sensitivity in different SRS subgroups,identifying the key gene TOMM40L.qRT-PCR and IHC were employed to detect the expression level of TOMM40 L.Kaplan-Meier survival analysis assessed the prognostic value of TOMM40L in HCC.In vitro cell experiments explored the influence of TOMM40L on HCC cell progression and stemness.Results:The prognostic model SRS for HCC was developed and validated,incorporating four SRGs:EIF2B4,CDCA8,TCOF1,and TOMM40L.Distinct variations in tumor immune infiltration profiles and drug sensitivity were noted across different SRS subgroups.Elevated TOMM40L levels are notably detected in malignant tissues in contrast to adjacent tissues,with heightened TOMM40L expression correlating with unfavorable prognostic outcomes.In addition,knockdown of TOMM40L significantly inhibited cell progression and stemness.Conclusion:The newly constructed SRS model is a potential biomarker for assessing HCC prognosis,and the key gene TOMM40L exhibits oncogenic properties.展开更多
Background:The role of 1,25-dihydroxyvitamin D3(1,25-(OH)_(2)D_(3))in cancer prevention and treatment is an emerging topic of interest.However,its effects on the stemness of acute myeloid leukemia(AML)cells are poorly...Background:The role of 1,25-dihydroxyvitamin D3(1,25-(OH)_(2)D_(3))in cancer prevention and treatment is an emerging topic of interest.However,its effects on the stemness of acute myeloid leukemia(AML)cells are poorly understood.Methods:The proliferation and differentiation of AML cells(HL60 and NB4)were investigated by the CCK-8 assay,immunocytochemical staining,and flow cytometry.The abilities of HL60 and NB4 cells to form spheres were examined by the cell sphere formation assay.In addition,the levels of stemness-associated markers(SOX2,Nanog,OCT4,and c-Myc)in HL60 and NB4 cells were measured by western blotting and quantitative real-time polymerase chain reaction.Moreover,we obtainedβ-catenin-interacting protein 1(ICAT)-knockout and ICAT-overexpressing HL-60 cells using gene editing and lentiviral infection techniques and investigated the role of ICAT in modulating the stemness-inhibiting effects of 1,25-(OH)_(2)D_(3)using the aforementioned experimental methods.Finally,we validated our findings in vivo using NOD/SCID mice.Results:1,25-(OH)_(2)D_(3)inhibited the proliferation and stemness of AML cells(HL60 and NB4)and induced their differentiation into monocytes.Additionally,the knockdown of ICAT in HL60 cells attenuated the inhibitory effects of 1,25-(OH)_(2)D_(3)on proliferation and stemness and suppressed the expression of stemness markers.Conversely,overexpression of ICAT enhanced the aforementioned inhibitory effects of 1,25-(OH)_(2)D_(3).Consistently,in NOD/SCID mice,1,25-(OH)_(2)D_(3)suppressed tumor formation by HL-60 cells,and the effects of ICAT knockdown or overexpression on 1,25-(OH)_(2)D_(3) aligned with the in vitro findings.Conclusion:1,25-(OH)_(2)D_(3)inhibits AML cell stemness,possibly through modulation of the ICAT-mediated Wnt/β-catenin signaling pathway.展开更多
Cancer Stem Cells(CSCs)are cancer cells with self-renewal and tumorigenesis abilities.CSCs in tumor tissues are the leading cause of tumor progression,recurrence,and drug resistance.CSCs have distinct metabolic featur...Cancer Stem Cells(CSCs)are cancer cells with self-renewal and tumorigenesis abilities.CSCs in tumor tissues are the leading cause of tumor progression,recurrence,and drug resistance.CSCs have distinct metabolic features that contribute to maintaining their self-renewal and stemness.Phospholipids are essential components of cell membranes and play fundamental roles in cellular activities.CSCs have abnormal phospholipid metabolism,which affects their self-renewal,differentiation,invasion,and drug resistance.Compared with non-CSCs,the phospholipid metabolism of CSCs mainly focused on significantly increased fatty acid(FAs)and phospholipids synthesis,phospho-lipid unsaturation,and lipolysis-fatty acid oxidation(FAO).In brief,FA and phospholipid metabolism in the anabolic and catabolic pathways are strictly regulated in CSCs to maintain self-renewal and stemness activity.In this review,we summarize the alterations in phospholipid metabolism in CSCs and their impacts on the stemness of CSCs,and we put forward the potential applications of targeting phospholipid metabolism for CSCs,to provide directions for the development of drugs targeting the phospholipid metabolism.展开更多
BACKGROUND Gastric cancer(GC)is a type of cancer which causes high cancer-related mortality.Surgical operation and systematic chemical therapies are primary choices for the treatment of GC patients with advanced stage...BACKGROUND Gastric cancer(GC)is a type of cancer which causes high cancer-related mortality.Surgical operation and systematic chemical therapies are primary choices for the treatment of GC patients with advanced stages,however,the 5-year overall survival is only around 30%.AIM To investigate the role of mesenchymal stem cell(MSC)-derived long non-coding RNAs(lncRNA)NKILA in fatty acid oxidation and chemoresistance in GC cells,mediated through the miR-485-5p/STAT3 pathway.METHODS GC cell lines(AGS and MKN45)were co-cultured with human bone marrowderived MSCs were cultured.The MSC identity was confirmed by flow cytometry(CD73,CD90,CD105>95%positive,CD34,CD45 negative).Co-culture of GC cells and MSCs was performed in Transwell plates,where MSCs were placed in the upper chamber and GC cells in the lower chamber for 72 hours.For transfections,pcDNA-NKILA vectors,shSTAT3,and miR-485-5p mimics were utilized.Colony formation,apoptosis assays(Annexin V/PI staining),sphere formation,and flow cytometry were performed to evaluate cell proliferation,stemness,and chemoresistance.qPCR was used to analyze gene expression(Sox2,Oct4,CD133,LIN28,NKILA),and Western blotting assessed protein levels of stemness markers.Luciferase reporter assays were conducted to confirm miR-485-5p/STAT3 interactions,and biotin-labeled RNA pulldown was used to assess RNA-protein binding.Fatty acid oxidation was evaluated using a CPT1 activity assay andβ-oxidation rate detection.ATP levels were measured to assess the energetic status of GC cells.Clinical GC tissue samples were collected from patients at our hospital for validation.RESULTS MSCs were found to enhance the stemness and chemoresistance of GC cells.Co-culturing MKN45 and AGS cells with MSCs significantly increased sphere-forming ability and the expression of key cancer stem cell markers(SOX2,Oct4,LIN28,CD133),indicating that MSCs promote stem-like properties.Flow cytometry confirmed an enrichment of CD44+and CD133+subpopulations in MSC-treated GC cells.Additionally,MSC co-culture reduced chemotherapy-induced apoptosis and enhanced cell proliferation,suggesting a protective role in chemotherapy resistance.MSC-derived lncRNA NKILA further promoted stemness and chemoresistance,enhancing expression of stem cell markers and protecting cells from oxaliplatin and 5-FU-induced apoptosis.MSC co-culture also induced fatty acid oxidation in GC cells,as shown by increased CPT1 activity,β-oxidation rates,and ATP levels.NKILA mediated these effects by upregulating STAT3,which was confirmed to regulate fatty acid oxidation and chemoresistance.NKILA’s interaction with miR-485-5p further promoted STAT3 expression and fatty acid oxidation,reinforcing its role in maintaining stemness and enhancing chemoresistance.CONCLUSION MSCs enhance the stemness and chemoresistance of GC cells by secreting lncRNA NKILA,which promotes fatty acid oxidation through STAT3 activation.NKILA modulates the miR-485-5p/STAT3 axis,thereby increasing energy metabolism and supporting cancer stem cell properties.Targeting NKILA or the miR-485-5p/STAT3 pathway offers potential therapeutic strategies to overcome chemoresistance in GC.展开更多
Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervica...Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervical cancer progression.Methods:The roles of m^(6)A RNA methylation and centromere protein K(CENPK)in cervical cancer were analyzed using bioinformatics analysis.Methylated RNA immunoprecipitation was adopted to detect m^(6)A modification of CENPK mRNA.Human cervical cancer clinical samples,cell lines,and xenografts were used for analyzing gene expression and function.Immunofluorescence staining and the tumorsphere formation,clonogenic,MTT,and EdU assays were performed to determine cell stemness,chemoresistance,migration,invasion,and proliferation in HeLa and SiHa cells,respectively.Western blot analysis,co-immunoprecipitation,chromatin immunoprecipitation,and luciferase reporter,cycloheximide chase,and cell fractionation assays were performed to elucidate the underlying mechanism.Results:Bioinformatics analysis of public cancer datasets revealed firm links between m^(6)A modification patterns and cervical cancer prognosis,especially through ZC3H13-mediated m^(6)A modification of CENPK mRNA.CENPK expression was elevated in cervical cancer,associated with cancer recurrence,and independently predicts poor patient prognosis[hazard ratio=1.413,95%confidence interval=1.078−1.853,P=0.012].Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo(P<0.001).We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK withβ-catenin,which promotedβ-catenin expression and nuclear translocation,facilitated p53 ubiquitination,and led to activation of Wnt/β-catenin signaling,but suppression of the p53 pathway.This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness,DNA damage repair pathways necessary for cisplatin/carboplatin resistance,epithelial-mesenchymal transition involved in metastasis,and DNA replication that drove tumor cell proliferation.Conclusions:CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.展开更多
Cancer cells possess metabolic properties that are different from those of benign cells.p21,encoded by CDKN1A gene,also named p21Cip1/WAF1,was first identified as a cyclin-dependent kinase regulator that suppresses ce...Cancer cells possess metabolic properties that are different from those of benign cells.p21,encoded by CDKN1A gene,also named p21Cip1/WAF1,was first identified as a cyclin-dependent kinase regulator that suppresses cell cycle G1/S phase and retinoblastoma protein phosphorylation.CDKN1A(p21)acts as the downstream target gene of TP53(p53),and its expression is induced by wild-type p53 and it is not associated with mutant p53.p21 has been characterized as a vital regulator that involves multiple cell functions,including G1/S cell cycle progression,cell growth,DNA damage,and cell stemness.In 1994,p21 was found as a tumor suppressor in brain,lung and colon cancer by targeting p53 and was associated with tumorigenesis and metastasis.Notably,p21 plays a significant role in tumor development through p53-dependent and p53-independent pathways.In addition,expression of p21 is closely related to the resting state or terminal differentiation of cells.p21 is also associated with cancer stem cells and acts as a biomarker for such cells.In cancer therapy,given the importance of p21 in regulating the G1/S and G2 check points,it is not surprising that p21 is implicated in response to many cancer treatments and p21 promotes the effect of oncolytic virotherapy.展开更多
Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant ro...Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant role of hepatocytes in regeneration at all levels of liver damage. The most frequent liver cancer is hepatocellular carcinoma(HCC). Historical findings originally led to the idea that the cell of origin of HCC might be a progenitor cell. However, current linage tracing studies put the progenitor hypothesis of HCC origin into question. In agreement with their dominant role in liver regeneration, mature hepatocytes are emerging as the cell of origin of HCC, although, the specific hepatocyte subpopulation of origin is yet to be determined. The relationship between the cancer cell of origin(CCO) and cancer-propagating cells, known as hepatic cancer stem cell(HCSC) is unknown. It has been challenging to identify the definitive phenotypic marker of HCSC, probably due to the existence of different cancer stem cells(CSC) subpopulations with different functions within HCC. There is a dynamic interconversion among different CSCs, and between CSC and non-CSCs. Because of that, CSC-state is currently defined as a description of a highly adaptable and dynamic intrinsic property of tumor cells, instead of a static subpopulation of a tumor. Altered conditions could trigger the gain of stemness, some of them include: EMT-MET, epigenetics, microenvironment and selective stimulus such as chemotherapy. This CSC heterogeneity and dynamism makes them out reach from therapeutic protocols directed to a single target. A further avenue of research in this line will be to uncover mechanisms that trigger this interconversion of cell populations within tumors and target it.展开更多
AIM To find the mechanisms by which special AT-rich sequence-binding protein 2(SATB2) influences colorectal cancer(CRC) metastasis.METHODS Cell growth assay, colony-forming assay, cell adhesion assay and cell migratio...AIM To find the mechanisms by which special AT-rich sequence-binding protein 2(SATB2) influences colorectal cancer(CRC) metastasis.METHODS Cell growth assay, colony-forming assay, cell adhesion assay and cell migration assay were used to evaluate the biological characteristics of CRC cells with gain or loss of SATB2. Sphere formation assay was used to detect the self-renewal ability of CRC cells. The m RNA expression of stem cell markers in CRC cells with upregulated or downregulated SATB2 expression was detected by quantitative real-time polymerase chain reaction. Chromatin immunoprecipitation(Ch IP) was used to verify the binding loci of SATB2 on genomic sequences of stem cell markers. The Cancer Genome Atlas(TCGA) database and our clinical samples wereanalyzed to find the correlation between SATB2 and some key stem cell markers.RESULTS Downregulation of SATB2 led to an aggressive phenotype in SW480 and DLD-1 cells, which was characterized by increased migration and invasion abilities. Overexpression of SATB2 suppressed the migration and invasion abilities in SW480 and SW620 cells. Using sequential sphere formation assay to detect the selfrenewal abilities of CRC cells, we found more secondary sphere formation but not primary sphere formation in SW480 and DLD-1 cells after SATB2 expression was knocked down. Moreover, most markers for stem cells such as CD133, CD44, AXIN2, MEIS2 and NANOG were increased in cells with SATB2 knockdown and decreased in cells with SATB2 overexpression. Ch IP assay showed that SATB2 bound to regulatory elements of CD133, CD44, MEIS2 and AXIN2 genes. Using TCGA database and our clinical samples, we found that SATB2 was correlated with some key stem cell markers including CD44 and CD24 in clinical tissues of CRC patients.CONCLUSION SATB2 can directly bind to the regulatory elements in the genetic loci of several stem cell markers and consequently inhibit the progression of CRC by negatively regulating stemness of CRC cells.展开更多
Objective Jiedu Recipe(JR),a Chinese herbal remedy,has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma(HCC).This work investigated the...Objective Jiedu Recipe(JR),a Chinese herbal remedy,has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma(HCC).This work investigated the mechanism of JR in HCC treatment.Methods The chemical constituents of JR were detected using liquid chromatography-mass spectrometry.The potential anti-HCC mechanism of JR was screened using network pharmacology and messenger ribonucleic acid(mRNA)microarray chip assay,followed by experimental validation in human HCC cells(SMMC-7721 and Huh7)in vitro and a nude mouse subcutaneous transplantation model of HCC in vivo.HCC cell characteristics of proliferation,migration and invasion under hypoxic setting were investigated using thiazolyl blue tetrazolium bromide,wound healing and Transwell assays,respectively.Image-i^(TM)Hypoxia Reagent was added to reveal hypoxic conditions.Stem cell sphere formation assay was used to detect the stemness.Epithelial-mesenchymal transition(EMT)markers like E-cadherin,vimentin andα-smooth muscle actin,and pluripotent transcription factors including nanog homeobox,octamer-binding transcription factor 4,and sex-determining region Y box protein 2 were analyzed using Western blotting and real-time polymerase chain reaction.Western blot was performed to ascertain the anti-HCC effect of JR under hypoxia involving the Wnt/β-catenin pathway.Results According to network pharmacology and mRNA microarray chip analysis,JR may potentially act on hypoxia and inhibit the Wnt/β-catenin pathway.In vitro and in vivo experiments showed that JR significantly decreased hypoxia,and suppressed HCC cell features of proliferation,migration and invasion;furthermore,the hypoxia-induced increases in EMT and stemness marker expression in HCC cells were inhibited by JR.Results based on the co-administration of JR and an agonist(LiCl)or inhibitor(IWR-1-endo)verified that JR suppressed HCC cancer stem-like properties under hypoxia by blocking the Wnt/β-catenin pathway.Conclusion JR exerts potent anti-HCC effects by inhibiting cancer stemness via abating the Wnt/β-catenin pathway under hypoxic conditions.展开更多
Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely unknown.Due to the importance of hy...Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely unknown.Due to the importance of hypoxia and cancer stemness in the development of HCC,the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness.Methods:A physical exercise intervention of swimming(30 min/d,5 d/week,for 4 weeks)was administered to BALB/c nude mice bearing subcutaneous human HCC tumor.The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring,hematoxylin and eosin(HE)staining,and immunohistochemistry(IHC)detection of proliferating cell nuclear antigen(PCNA)and Ki67.The expression of stemness transcription factors,including Nanog homeobox(NANOG),octamer-binding transcription factor 4(OCT-4),v-Myc avian myelocytomatosis viral oncogene homolog(C-MYC)and hypoxia-inducible factor-1a(HIF-1a),was detected using real-time reverse transcription polymerase chain reaction.A hypoxia probe was used to explore the intratumoral hypoxia status.Western blot was used to detect the expression of HIF-1a and proteins related to protein kinase B(Akt)/glycogen synthase kinase-3β(GSK-3β)/β-catenin signaling pathway.The IHC analysis of platelet endothelial cell adhesion molecule-1(CD31),and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion.SMMC-7721 cells were treated with nude mice serum.The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors.The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1a.Further,the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected.Results:Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor.HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention.Swimming potently alleviated the intratumoral hypoxia,attenuated the cancer stemness,and inhibited the Akt/GSK-3β/β-catenin signaling pathway.Additionally,the desmin+/CD31+ratio,rather than the number of CD31+vessels,was significantly increased in swimming-treated mice.In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere,as well as the m RNA expression level of stemness transcription factors.Consistent with the in vivo results,HIF-1a and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group.Conclusion:Swimming alleviated hypoxia and attenuated cancer stemness in HCC,through suppression of the Akt/GSK-3β/β-catenin signaling pathway.The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor.展开更多
Previously regarded as simple fat storage particles,new evidence suggests thatlipid droplets(LDs)are dynamic and functional organelles involved in keycellular processes such as membrane biosynthesis,lipid metabolism,c...Previously regarded as simple fat storage particles,new evidence suggests thatlipid droplets(LDs)are dynamic and functional organelles involved in keycellular processes such as membrane biosynthesis,lipid metabolism,cellsignalling and inflammation.Indeed,an increased LD content is one of the mostapparent features resulting from lipid metabolism reprogramming necessary tosupport the basic functions of cancer cells.LDs have been associated to differentcellular processes involved in cancer progression and aggressiveness,such astumorigenicity,invasion and metastasis,as well as chemoresistance.Interestingly,all of these processes are controlled by a subpopulation of highly aggressivetumoral cells named cancer stem cells(CSCs),suggesting that LDs may befundamental elements for stemness in cancer.Considering the key role of CSCs onchemoresistance and disease relapse,main factors of therapy failure,the design ofnovel therapeutic approaches targeting these cells may be the only chance forlong-term survival in cancer patients.In this sense,their biology and functionalproperties render LDs excellent candidates for target discovery and design ofcombined therapeutic strategies.In this review,we summarise the currentknowledge identifying LDs and CSCs as main contributors to cancer aggressiveness,metastasis and chemoresistance.展开更多
The discovery of cancer stem cells caused a paradigm shift in the concepts of origin and development of colorectal cancer. Several unresolved questions remain in this field though. Are colorectal cancer stem cells the...The discovery of cancer stem cells caused a paradigm shift in the concepts of origin and development of colorectal cancer. Several unresolved questions remain in this field though. Are colorectal cancer stem cells the cause or an effect of the disease? How do cancer stem cells assist in colorectal tumor dissemination to distant organs? What are the molecular or environmental factors affecting the roles of these cells in colorectal cancer? Through this review, we investigate the key findings until now and attempt to elucidate the origins, physical properties, microenvironmental niches, as well as the molecular signaling network that support the existence, self-renewal, plasticity, quiescence, and the overall maintenance of cancer stem cells in colorectal cancer. Increasing data show that the cancer stem cells play a crucial role not only in the establishment of the primary colorectal tumor but also in the distant spread of the disease. Hence, we will also look at the mechanisms adopted by cancer stem cells to influence the development of metastasis and evade therapeutic targeting and its role in the overall disease prognosis. Finally, we will illustrate the importance of understanding the biology of these cells to develop improved clinical strategies to tackle colorectal cancer.展开更多
Glioblastoma(GBM)is the most common,most aggressive and deadliest brain tumor.Recently,remarkable progress has been made towards understanding the cellular and molecular biology of gliomas.GBM tumor initiation,progres...Glioblastoma(GBM)is the most common,most aggressive and deadliest brain tumor.Recently,remarkable progress has been made towards understanding the cellular and molecular biology of gliomas.GBM tumor initiation,progression and relapse as well as resistance to treatments are associated with glioma stem cells(GSCs).GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types,generating a range of distinct cell types within the tumor,leading to cellular heterogeneity.GBM tumors may contain different subsets of GSCs,and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy.GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties,making them more malignant,able to rapidly spread.The impact of SOX transcription factors(TFs)on brain tumors has been extensively studied in the last decade.Almost all SOX genes are expressed in GBM,and their expression levels are associated with patient prognosis and survival.Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation.The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation.Therefore,innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM.Combatting GBM has been a demanding and challenging goal for decades.The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival.Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.展开更多
Cancer stem cells(CSCs)are heterogeneous with self-renewal and differentiation ability.The mRNA expression-based stemness index(mRNAsi)described the similarity between tumor cells and CSCs,which is positively associat...Cancer stem cells(CSCs)are heterogeneous with self-renewal and differentiation ability.The mRNA expression-based stemness index(mRNAsi)described the similarity between tumor cells and CSCs,which is positively associated with the poor prognosis of cancer patients.However,the key prognostic genes related to mRNAsi in hepatocellular carcinoma(HCC)remains unclear.A 9-gene signature related to mRNAsi and HCC prognosis including PSMG3,SNRPD1,DTYMK,PIGU,NME1,TXNL4A,IPO4,PES1,and REXO4 was obtained.High expression of this signature indicates poor prognosis of HCC.PIGU was an independent prognostic factor of HCC,which was significantly associated with progression of HCC.Among them,DTYMK and NME1 enriched in pyrimidine metabolism,SNRPD1 and TXNL4A enriched in spliceosome and PIGU enriched in glycosyl phosphatidylinositol(GPI)-anchor biosynthesis pathways.High levels of IPO4,NME1,PES1,PIGU and SNRPD1 were closely associated with metastasis of HCC,and low levels of IPO4,PIGU and REOX4 were significantly associated with sorafenib resistance of HCC.High expression of the 9-gene signature was negatively correlated with the stromal cell infiltration,and positively correlated with specific immune subtypes-related to angiogenesis,M1/M2 macrophage polarization,and M2 response.The 9-gene signature was negatively correlated with the stroma,and SNRPD1 and TXNL4 were positively correlated with immune infiltrate.NME1 was negatively correlated with tumor purity.Therefore,a 9-gene signature related to mRNAsi and poor prognosis in HCC were identified,which can be used as biomarkers for the diagnosis of HCC and functional mechanism exploration of CSCs in HCC.These genes such as IPO4 and PIGU might drive the transition of tumor cells into CSCs which possibly controls the balance between metastasis and drug resistance in HCC.The challenge on balance between metastasis and drug resistance for tumor therapy was firstly reported by the present study.展开更多
Background:Liver cancer is one of the major causes of cancer-related deaths globally.Cancer cell stem-ness and chemotherapy resistance contribute to the high mortality.Although evidence indicates that the alpha subuni...Background:Liver cancer is one of the major causes of cancer-related deaths globally.Cancer cell stem-ness and chemotherapy resistance contribute to the high mortality.Although evidence indicates that the alpha subunit of protein kinase 2(CK2α)is involved in several human cancers,its function in liver cancer remains unknown.In the present study,we aimed to elucidate the role of CK2αin liver cancer.Methods:We examined the role of CK2αregulation in stemness and chemotherapy resistance capacity of liver cancer cells.MTT assays,tumor sphere formation assays,RT-PCR,flow cytometry,Western blotting assay,clonogenicity assay,matrigel invasion assay and bioinformatics were conducted in this study.Results:CK2αexpression in the liver cancer tissues was notably upregulated compared with that in the corresponding non-tumorous tissues.The overexpression of CK2αpromoted tumor sphere formation,increased the percentage of CD133(+)and side population cells,caused the resistance of liver cancer cells to 5-FU treatment,increased the expression levels of NANOG,OCT4,SOX2,Gli1 and Ptch1,and enhanced the ability of CD133(+)cell clone formation and invasion.Consistently,the downregulation of CK2αhad the opposite effects.CK2αsilencing inhibited the Hedgehog pathway by reducing the expression of Gli1 and Ptch1.Mechanistically,CK2αregulation on liver cancer cell stemness and chemotherapy resistance was found to be involved in the Hedgehog signaling pathway.Conclusions:Our study may bring some new insights into the occurrence of liver cancer.Furthermore,these findings suggest that targeting CK2αmay be a novel therapeutic strategy for patients with liver cancer.展开更多
文摘BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.
基金supported by the National Natural Science Foundation of China(32171347)the Foundation of Leading Talents from Shanghai Health Commission(2022XD038)+1 种基金Training Program for Research Physicians in Innovation,the Funda-mental Research Funds for the Central Universities(YG2023QNA23)Transforma-tion from shanghai hospital development center(SHDC2022CRD002).
文摘Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis.However,mechanisms associated with stem cell senescence require further investigation.In this study,we conducted a proteomic analysis of human dental pulp stem cells(HDPSCs)obtained from individuals of various ages.Our findings showed that the expression of NUP62 was decreased in aged HDPSCs.We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo.Conversely,the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs.Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression,we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1.This,in turn,stimulates the transcription of the epigenetic enzyme NSD2.Finally,the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes(HMGA1,HMGA2,and SIRT6).Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.
文摘BACKGROUND Over the years,the numbers of treatment options for colorectal cancer(CRC)have increased,leading to notable improvements in the overall survival of CRC patients.Although therapy may initially yield positive results,the development of drug resistance can result in treatment failure and cancer recurrence.This resistance is often attributed to the presence of cancer stem cells(CSCs).These CSCs not only contribute to therapeutic resistance but also play crucial roles in the initiation and development of tumor metastasis.AIM To investigate the antitumor effects of SH-4-54,which are mediated by targeting CSCs relative to treatment outcomes.METHODS CSCs were enriched by culturing CRC cells in serum-free medium.Hallmarks of stemness and IL-6/JAK2/STAT3 signaling were detected by Western blotting.Indicators of CSC malignancy,including proliferation,invasion,and tumor formation,were measured.RESULTS In this study,we employed SH-4-54,which exhibits anticancer activity in solid tumors through targeting the SH2 domain of both the signal transducer and activator of transcription(STAT)3 and the STAT5,and evaluated its effects on stemness and chemoresistance in colorectal CSCs.As expected,SH-4-54 treatment inhibited the phosphorylation of STAT3(p-STAT3)and decreased the percentage of ALDH1A1-positive CRC cells.The addition of SH-4-54 dissociated colorectal spheroids and decreased the expression of stemness markers,including ALDH1A1,CD44 and Nanog.SH-4-54 treatment decreased IL-6/JAK2/STAT3 signaling by inhibiting p-STAT3 and thus inhibited spheroid formation by SW480 and LoVo cells.Moreover,SH-4-54 treatment inhibited indicators of malignancy,including cell proliferation,invasion,and tumor formation,in CSCs in vitro and in vivo.Notably,SH-4-54 treatment significantly increased chemosensitivity to oxaplatin.CONCLUSION Taken together,these results indicate that SH-4-54 is a promising molecule that exerts antitumor effects on colorectal CSCs by inhibiting STAT3 signaling.
基金Supported by Inner Mongolia Natural Science Foundation and the 3rd Affiliated of Inner Medical University,No.2021MS08067.
文摘BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC pathobiology is being increasingly recognized.AIM To investigate the role of OCT4 in pancreatic CSCs and its effect on PC cell prolif-eration,migration,drug sensitivity,and stemness maintenance.METHODS We analyzed OCT4 and CD133 expression in PC tissues and cell lines.BxPC-3 cells were used to assess the effects of OCT4 modulation on cellular behavior.Proliferation,migration,and stemness of BxPC-3 cells were evaluated,and the PI3K/AKT/mTOR pathway was examined to gain mechanistic insights.RESULTS OCT4 and CD133 were significantly overexpressed in PC tissues.OCT4 mo-dulation altered BxPC-3 cell proliferation,invasion,and stemness,with OCT4 overexpression(OV-OCT4)enhancing these properties and OCT4 interference decreasing them.OV-OCT4 activated the PI3K/AKT/mTOR pathway,which correlated with an increase in PC stem cells(PCSC).CONCLUSION OCT4 plays a crucial role in PCSCs by influencing the aggressiveness and drug resistance of PC cells,thus presenting itself as a potential therapeutic target.
文摘BACKGROUND Tumors characterized by high cellular stemness often have unfavorable clinical outcomes,primarily due to their heightened potential for metastasis and resistance to chemotherapy.Among the model genes,the clinical relevance and prognostic significance of Niemann-Pick type C2(NPC2)in gastric cancer(GC)remained largely unexplored.AIM To identify stemness-associated genes in GC.METHODS In this study,epithelial cells were categorized as either tumor or normal epithelial cells using the infer copy number variation method.Stemness scores were calculated for both cell types.The hierarchical Weighted Gene Co-expression Network Analysis identified two gene modules with the strongest association with stemness.Prognostically significant stemness-related genes were pinpointed using univariate Cox regression based on The Cancer Genome Atlas dataset.A predictive model related to stemness was constructed using Least Absolute Shrinkage and Selection Operator regression followed by multivariate Cox analysis.RESULTS Functional roles of NPC2 were validated using single-cell and bulk RNA sequencing data.Further experimental validation revealed that elevated NPC2 expression promoted tumor cell stemness,invasiveness,migratory ability,and resistance to standard chemotherapeutic agents.Importantly,high NPC2 expression correlated with poorer overall survival in GC patients.CONCLUSION In summary,the proposed model offers prognostic insights that outperform traditional clinical staging and may inform more tailored therapeutic approaches for gastric cancer management.
基金supported by the National Natural Science Foundation of China(No.82370608)Natural Science Foundation of Anhui Province(No.2208085MH204)+5 种基金Natural Science Foundation of Education Department of Anhui Province(No.2022AH040160)Anhui Provincial Special Fund for Clinical Medical Research Transformation(No.202304295107020040)Suzhou Health Commission“Suzhou Health Young Talent”National Mentor Training Program(No.Qngg2023046)Kunshan Social Development Science and Technology Special Fund(No.KS1719)New Coronavirus Pneumonia Research Project of Kunshan First People’s Hospital(First Batch,No.XGF202018)Kunshan First People’s Hospital Medical and Health Science and Technology Innovation Special Project(No.KETDCX202424).
文摘Aims:The aim of this study is to develop a prognostic model for hepatocellular carcinoma(HCC)using stemness-related genes(SRGs),while also pinpointing and validating pivotal genes associated with this process.Methods:Utilizing the TCGA and ICGC database,a prognostic stemness-related scores(SRS)for HCC through a combination of WGCNA and machine learning.Bioinformatics analysis evaluated tumor immune infiltration characteristics and drug sensitivity in different SRS subgroups,identifying the key gene TOMM40L.qRT-PCR and IHC were employed to detect the expression level of TOMM40 L.Kaplan-Meier survival analysis assessed the prognostic value of TOMM40L in HCC.In vitro cell experiments explored the influence of TOMM40L on HCC cell progression and stemness.Results:The prognostic model SRS for HCC was developed and validated,incorporating four SRGs:EIF2B4,CDCA8,TCOF1,and TOMM40L.Distinct variations in tumor immune infiltration profiles and drug sensitivity were noted across different SRS subgroups.Elevated TOMM40L levels are notably detected in malignant tissues in contrast to adjacent tissues,with heightened TOMM40L expression correlating with unfavorable prognostic outcomes.In addition,knockdown of TOMM40L significantly inhibited cell progression and stemness.Conclusion:The newly constructed SRS model is a potential biomarker for assessing HCC prognosis,and the key gene TOMM40L exhibits oncogenic properties.
基金supported by the Guangdong Basic and Applied Basic Research Foundation(2022B1515230007).
文摘Background:The role of 1,25-dihydroxyvitamin D3(1,25-(OH)_(2)D_(3))in cancer prevention and treatment is an emerging topic of interest.However,its effects on the stemness of acute myeloid leukemia(AML)cells are poorly understood.Methods:The proliferation and differentiation of AML cells(HL60 and NB4)were investigated by the CCK-8 assay,immunocytochemical staining,and flow cytometry.The abilities of HL60 and NB4 cells to form spheres were examined by the cell sphere formation assay.In addition,the levels of stemness-associated markers(SOX2,Nanog,OCT4,and c-Myc)in HL60 and NB4 cells were measured by western blotting and quantitative real-time polymerase chain reaction.Moreover,we obtainedβ-catenin-interacting protein 1(ICAT)-knockout and ICAT-overexpressing HL-60 cells using gene editing and lentiviral infection techniques and investigated the role of ICAT in modulating the stemness-inhibiting effects of 1,25-(OH)_(2)D_(3)using the aforementioned experimental methods.Finally,we validated our findings in vivo using NOD/SCID mice.Results:1,25-(OH)_(2)D_(3)inhibited the proliferation and stemness of AML cells(HL60 and NB4)and induced their differentiation into monocytes.Additionally,the knockdown of ICAT in HL60 cells attenuated the inhibitory effects of 1,25-(OH)_(2)D_(3)on proliferation and stemness and suppressed the expression of stemness markers.Conversely,overexpression of ICAT enhanced the aforementioned inhibitory effects of 1,25-(OH)_(2)D_(3).Consistently,in NOD/SCID mice,1,25-(OH)_(2)D_(3)suppressed tumor formation by HL-60 cells,and the effects of ICAT knockdown or overexpression on 1,25-(OH)_(2)D_(3) aligned with the in vitro findings.Conclusion:1,25-(OH)_(2)D_(3)inhibits AML cell stemness,possibly through modulation of the ICAT-mediated Wnt/β-catenin signaling pathway.
基金supported by grants from National Natural Science Foundation of China(81902784,81771086)by the Fund of Sichuan Provincial Department of science and technology(2024YFFK0393,2022YFS0039)+1 种基金the Research and Develop Program,West China Hospital of Stomatology,Sichuan University(LCYJ2023-DL-2,RD-02-202002)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-004)。
文摘Cancer Stem Cells(CSCs)are cancer cells with self-renewal and tumorigenesis abilities.CSCs in tumor tissues are the leading cause of tumor progression,recurrence,and drug resistance.CSCs have distinct metabolic features that contribute to maintaining their self-renewal and stemness.Phospholipids are essential components of cell membranes and play fundamental roles in cellular activities.CSCs have abnormal phospholipid metabolism,which affects their self-renewal,differentiation,invasion,and drug resistance.Compared with non-CSCs,the phospholipid metabolism of CSCs mainly focused on significantly increased fatty acid(FAs)and phospholipids synthesis,phospho-lipid unsaturation,and lipolysis-fatty acid oxidation(FAO).In brief,FA and phospholipid metabolism in the anabolic and catabolic pathways are strictly regulated in CSCs to maintain self-renewal and stemness activity.In this review,we summarize the alterations in phospholipid metabolism in CSCs and their impacts on the stemness of CSCs,and we put forward the potential applications of targeting phospholipid metabolism for CSCs,to provide directions for the development of drugs targeting the phospholipid metabolism.
文摘BACKGROUND Gastric cancer(GC)is a type of cancer which causes high cancer-related mortality.Surgical operation and systematic chemical therapies are primary choices for the treatment of GC patients with advanced stages,however,the 5-year overall survival is only around 30%.AIM To investigate the role of mesenchymal stem cell(MSC)-derived long non-coding RNAs(lncRNA)NKILA in fatty acid oxidation and chemoresistance in GC cells,mediated through the miR-485-5p/STAT3 pathway.METHODS GC cell lines(AGS and MKN45)were co-cultured with human bone marrowderived MSCs were cultured.The MSC identity was confirmed by flow cytometry(CD73,CD90,CD105>95%positive,CD34,CD45 negative).Co-culture of GC cells and MSCs was performed in Transwell plates,where MSCs were placed in the upper chamber and GC cells in the lower chamber for 72 hours.For transfections,pcDNA-NKILA vectors,shSTAT3,and miR-485-5p mimics were utilized.Colony formation,apoptosis assays(Annexin V/PI staining),sphere formation,and flow cytometry were performed to evaluate cell proliferation,stemness,and chemoresistance.qPCR was used to analyze gene expression(Sox2,Oct4,CD133,LIN28,NKILA),and Western blotting assessed protein levels of stemness markers.Luciferase reporter assays were conducted to confirm miR-485-5p/STAT3 interactions,and biotin-labeled RNA pulldown was used to assess RNA-protein binding.Fatty acid oxidation was evaluated using a CPT1 activity assay andβ-oxidation rate detection.ATP levels were measured to assess the energetic status of GC cells.Clinical GC tissue samples were collected from patients at our hospital for validation.RESULTS MSCs were found to enhance the stemness and chemoresistance of GC cells.Co-culturing MKN45 and AGS cells with MSCs significantly increased sphere-forming ability and the expression of key cancer stem cell markers(SOX2,Oct4,LIN28,CD133),indicating that MSCs promote stem-like properties.Flow cytometry confirmed an enrichment of CD44+and CD133+subpopulations in MSC-treated GC cells.Additionally,MSC co-culture reduced chemotherapy-induced apoptosis and enhanced cell proliferation,suggesting a protective role in chemotherapy resistance.MSC-derived lncRNA NKILA further promoted stemness and chemoresistance,enhancing expression of stem cell markers and protecting cells from oxaliplatin and 5-FU-induced apoptosis.MSC co-culture also induced fatty acid oxidation in GC cells,as shown by increased CPT1 activity,β-oxidation rates,and ATP levels.NKILA mediated these effects by upregulating STAT3,which was confirmed to regulate fatty acid oxidation and chemoresistance.NKILA’s interaction with miR-485-5p further promoted STAT3 expression and fatty acid oxidation,reinforcing its role in maintaining stemness and enhancing chemoresistance.CONCLUSION MSCs enhance the stemness and chemoresistance of GC cells by secreting lncRNA NKILA,which promotes fatty acid oxidation through STAT3 activation.NKILA modulates the miR-485-5p/STAT3 axis,thereby increasing energy metabolism and supporting cancer stem cell properties.Targeting NKILA or the miR-485-5p/STAT3 pathway offers potential therapeutic strategies to overcome chemoresistance in GC.
基金the Joint Funds for the Innovation of Science and Technology Program of Fujian Province,China(2018Y9110)the Natural Science Foundation of Fujian Province,China,(2020J011126)the China Postdoctoral Science Foundation(2021T140468).
文摘Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervical cancer progression.Methods:The roles of m^(6)A RNA methylation and centromere protein K(CENPK)in cervical cancer were analyzed using bioinformatics analysis.Methylated RNA immunoprecipitation was adopted to detect m^(6)A modification of CENPK mRNA.Human cervical cancer clinical samples,cell lines,and xenografts were used for analyzing gene expression and function.Immunofluorescence staining and the tumorsphere formation,clonogenic,MTT,and EdU assays were performed to determine cell stemness,chemoresistance,migration,invasion,and proliferation in HeLa and SiHa cells,respectively.Western blot analysis,co-immunoprecipitation,chromatin immunoprecipitation,and luciferase reporter,cycloheximide chase,and cell fractionation assays were performed to elucidate the underlying mechanism.Results:Bioinformatics analysis of public cancer datasets revealed firm links between m^(6)A modification patterns and cervical cancer prognosis,especially through ZC3H13-mediated m^(6)A modification of CENPK mRNA.CENPK expression was elevated in cervical cancer,associated with cancer recurrence,and independently predicts poor patient prognosis[hazard ratio=1.413,95%confidence interval=1.078−1.853,P=0.012].Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo(P<0.001).We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK withβ-catenin,which promotedβ-catenin expression and nuclear translocation,facilitated p53 ubiquitination,and led to activation of Wnt/β-catenin signaling,but suppression of the p53 pathway.This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness,DNA damage repair pathways necessary for cisplatin/carboplatin resistance,epithelial-mesenchymal transition involved in metastasis,and DNA replication that drove tumor cell proliferation.Conclusions:CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.
基金Supported by the Natural Science Foundation of Zhejiang Province of China,No. LY18C070002 and No.LY16H160056National Natural Science Foundation of China,No.81803069+1 种基金the 521 Talent Project of Zhejiang Sci-Tech UniversityScience Foundation of Zhejiang Sci Tech University,No. 18042291Y。
文摘Cancer cells possess metabolic properties that are different from those of benign cells.p21,encoded by CDKN1A gene,also named p21Cip1/WAF1,was first identified as a cyclin-dependent kinase regulator that suppresses cell cycle G1/S phase and retinoblastoma protein phosphorylation.CDKN1A(p21)acts as the downstream target gene of TP53(p53),and its expression is induced by wild-type p53 and it is not associated with mutant p53.p21 has been characterized as a vital regulator that involves multiple cell functions,including G1/S cell cycle progression,cell growth,DNA damage,and cell stemness.In 1994,p21 was found as a tumor suppressor in brain,lung and colon cancer by targeting p53 and was associated with tumorigenesis and metastasis.Notably,p21 plays a significant role in tumor development through p53-dependent and p53-independent pathways.In addition,expression of p21 is closely related to the resting state or terminal differentiation of cells.p21 is also associated with cancer stem cells and acts as a biomarker for such cells.In cancer therapy,given the importance of p21 in regulating the G1/S and G2 check points,it is not surprising that p21 is implicated in response to many cancer treatments and p21 promotes the effect of oncolytic virotherapy.
文摘Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant role of hepatocytes in regeneration at all levels of liver damage. The most frequent liver cancer is hepatocellular carcinoma(HCC). Historical findings originally led to the idea that the cell of origin of HCC might be a progenitor cell. However, current linage tracing studies put the progenitor hypothesis of HCC origin into question. In agreement with their dominant role in liver regeneration, mature hepatocytes are emerging as the cell of origin of HCC, although, the specific hepatocyte subpopulation of origin is yet to be determined. The relationship between the cancer cell of origin(CCO) and cancer-propagating cells, known as hepatic cancer stem cell(HCSC) is unknown. It has been challenging to identify the definitive phenotypic marker of HCSC, probably due to the existence of different cancer stem cells(CSC) subpopulations with different functions within HCC. There is a dynamic interconversion among different CSCs, and between CSC and non-CSCs. Because of that, CSC-state is currently defined as a description of a highly adaptable and dynamic intrinsic property of tumor cells, instead of a static subpopulation of a tumor. Altered conditions could trigger the gain of stemness, some of them include: EMT-MET, epigenetics, microenvironment and selective stimulus such as chemotherapy. This CSC heterogeneity and dynamism makes them out reach from therapeutic protocols directed to a single target. A further avenue of research in this line will be to uncover mechanisms that trigger this interconversion of cell populations within tumors and target it.
基金Supported by National Natural Science Foundation of China,No.81525020,No.81502033,No.81272300 and No.31570753
文摘AIM To find the mechanisms by which special AT-rich sequence-binding protein 2(SATB2) influences colorectal cancer(CRC) metastasis.METHODS Cell growth assay, colony-forming assay, cell adhesion assay and cell migration assay were used to evaluate the biological characteristics of CRC cells with gain or loss of SATB2. Sphere formation assay was used to detect the self-renewal ability of CRC cells. The m RNA expression of stem cell markers in CRC cells with upregulated or downregulated SATB2 expression was detected by quantitative real-time polymerase chain reaction. Chromatin immunoprecipitation(Ch IP) was used to verify the binding loci of SATB2 on genomic sequences of stem cell markers. The Cancer Genome Atlas(TCGA) database and our clinical samples wereanalyzed to find the correlation between SATB2 and some key stem cell markers.RESULTS Downregulation of SATB2 led to an aggressive phenotype in SW480 and DLD-1 cells, which was characterized by increased migration and invasion abilities. Overexpression of SATB2 suppressed the migration and invasion abilities in SW480 and SW620 cells. Using sequential sphere formation assay to detect the selfrenewal abilities of CRC cells, we found more secondary sphere formation but not primary sphere formation in SW480 and DLD-1 cells after SATB2 expression was knocked down. Moreover, most markers for stem cells such as CD133, CD44, AXIN2, MEIS2 and NANOG were increased in cells with SATB2 knockdown and decreased in cells with SATB2 overexpression. Ch IP assay showed that SATB2 bound to regulatory elements of CD133, CD44, MEIS2 and AXIN2 genes. Using TCGA database and our clinical samples, we found that SATB2 was correlated with some key stem cell markers including CD44 and CD24 in clinical tissues of CRC patients.CONCLUSION SATB2 can directly bind to the regulatory elements in the genetic loci of several stem cell markers and consequently inhibit the progression of CRC by negatively regulating stemness of CRC cells.
基金This study was supported by the National Natural Science Foundation of China(No.81803929 and 82074138)the Natural Science Foundation of Shanghai(No.21ZR1479500).
文摘Objective Jiedu Recipe(JR),a Chinese herbal remedy,has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma(HCC).This work investigated the mechanism of JR in HCC treatment.Methods The chemical constituents of JR were detected using liquid chromatography-mass spectrometry.The potential anti-HCC mechanism of JR was screened using network pharmacology and messenger ribonucleic acid(mRNA)microarray chip assay,followed by experimental validation in human HCC cells(SMMC-7721 and Huh7)in vitro and a nude mouse subcutaneous transplantation model of HCC in vivo.HCC cell characteristics of proliferation,migration and invasion under hypoxic setting were investigated using thiazolyl blue tetrazolium bromide,wound healing and Transwell assays,respectively.Image-i^(TM)Hypoxia Reagent was added to reveal hypoxic conditions.Stem cell sphere formation assay was used to detect the stemness.Epithelial-mesenchymal transition(EMT)markers like E-cadherin,vimentin andα-smooth muscle actin,and pluripotent transcription factors including nanog homeobox,octamer-binding transcription factor 4,and sex-determining region Y box protein 2 were analyzed using Western blotting and real-time polymerase chain reaction.Western blot was performed to ascertain the anti-HCC effect of JR under hypoxia involving the Wnt/β-catenin pathway.Results According to network pharmacology and mRNA microarray chip analysis,JR may potentially act on hypoxia and inhibit the Wnt/β-catenin pathway.In vitro and in vivo experiments showed that JR significantly decreased hypoxia,and suppressed HCC cell features of proliferation,migration and invasion;furthermore,the hypoxia-induced increases in EMT and stemness marker expression in HCC cells were inhibited by JR.Results based on the co-administration of JR and an agonist(LiCl)or inhibitor(IWR-1-endo)verified that JR suppressed HCC cancer stem-like properties under hypoxia by blocking the Wnt/β-catenin pathway.Conclusion JR exerts potent anti-HCC effects by inhibiting cancer stemness via abating the Wnt/β-catenin pathway under hypoxic conditions.
基金supported by the National Natural Science Foundation of China(No.82104977)Youth Start-up Foundation of Changhai Hospital(No.2019QNB05)。
文摘Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely unknown.Due to the importance of hypoxia and cancer stemness in the development of HCC,the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness.Methods:A physical exercise intervention of swimming(30 min/d,5 d/week,for 4 weeks)was administered to BALB/c nude mice bearing subcutaneous human HCC tumor.The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring,hematoxylin and eosin(HE)staining,and immunohistochemistry(IHC)detection of proliferating cell nuclear antigen(PCNA)and Ki67.The expression of stemness transcription factors,including Nanog homeobox(NANOG),octamer-binding transcription factor 4(OCT-4),v-Myc avian myelocytomatosis viral oncogene homolog(C-MYC)and hypoxia-inducible factor-1a(HIF-1a),was detected using real-time reverse transcription polymerase chain reaction.A hypoxia probe was used to explore the intratumoral hypoxia status.Western blot was used to detect the expression of HIF-1a and proteins related to protein kinase B(Akt)/glycogen synthase kinase-3β(GSK-3β)/β-catenin signaling pathway.The IHC analysis of platelet endothelial cell adhesion molecule-1(CD31),and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion.SMMC-7721 cells were treated with nude mice serum.The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors.The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1a.Further,the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected.Results:Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor.HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention.Swimming potently alleviated the intratumoral hypoxia,attenuated the cancer stemness,and inhibited the Akt/GSK-3β/β-catenin signaling pathway.Additionally,the desmin+/CD31+ratio,rather than the number of CD31+vessels,was significantly increased in swimming-treated mice.In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere,as well as the m RNA expression level of stemness transcription factors.Consistent with the in vivo results,HIF-1a and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group.Conclusion:Swimming alleviated hypoxia and attenuated cancer stemness in HCC,through suppression of the Akt/GSK-3β/β-catenin signaling pathway.The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor.
基金Miguel Servet Fellowship,No.CP16/00121FIS(Fondo Investigaciones Sanitarias)grants,No.PI17/00082 and No.PI20/00942,all from Instituto de Salud Carlos Ⅲ and Cofinanced by European Funds(FSE:“El FSE invierte en tu futuro”and FEDER:“Una manera de hacer Europa,”respectively)and the Worldwide Cancer Research Charity together with Fundación Científica Asociación Española contra el Cáncer(FCAECC),No.19-0250.
文摘Previously regarded as simple fat storage particles,new evidence suggests thatlipid droplets(LDs)are dynamic and functional organelles involved in keycellular processes such as membrane biosynthesis,lipid metabolism,cellsignalling and inflammation.Indeed,an increased LD content is one of the mostapparent features resulting from lipid metabolism reprogramming necessary tosupport the basic functions of cancer cells.LDs have been associated to differentcellular processes involved in cancer progression and aggressiveness,such astumorigenicity,invasion and metastasis,as well as chemoresistance.Interestingly,all of these processes are controlled by a subpopulation of highly aggressivetumoral cells named cancer stem cells(CSCs),suggesting that LDs may befundamental elements for stemness in cancer.Considering the key role of CSCs onchemoresistance and disease relapse,main factors of therapy failure,the design ofnovel therapeutic approaches targeting these cells may be the only chance forlong-term survival in cancer patients.In this sense,their biology and functionalproperties render LDs excellent candidates for target discovery and design ofcombined therapeutic strategies.In this review,we summarise the currentknowledge identifying LDs and CSCs as main contributors to cancer aggressiveness,metastasis and chemoresistance.
文摘The discovery of cancer stem cells caused a paradigm shift in the concepts of origin and development of colorectal cancer. Several unresolved questions remain in this field though. Are colorectal cancer stem cells the cause or an effect of the disease? How do cancer stem cells assist in colorectal tumor dissemination to distant organs? What are the molecular or environmental factors affecting the roles of these cells in colorectal cancer? Through this review, we investigate the key findings until now and attempt to elucidate the origins, physical properties, microenvironmental niches, as well as the molecular signaling network that support the existence, self-renewal, plasticity, quiescence, and the overall maintenance of cancer stem cells in colorectal cancer. Increasing data show that the cancer stem cells play a crucial role not only in the establishment of the primary colorectal tumor but also in the distant spread of the disease. Hence, we will also look at the mechanisms adopted by cancer stem cells to influence the development of metastasis and evade therapeutic targeting and its role in the overall disease prognosis. Finally, we will illustrate the importance of understanding the biology of these cells to develop improved clinical strategies to tackle colorectal cancer.
基金Supported by Ministry of Education,Science and Technological Development of the Republic of Serbia,No.451-03-9/2021-14/200042。
文摘Glioblastoma(GBM)is the most common,most aggressive and deadliest brain tumor.Recently,remarkable progress has been made towards understanding the cellular and molecular biology of gliomas.GBM tumor initiation,progression and relapse as well as resistance to treatments are associated with glioma stem cells(GSCs).GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types,generating a range of distinct cell types within the tumor,leading to cellular heterogeneity.GBM tumors may contain different subsets of GSCs,and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy.GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties,making them more malignant,able to rapidly spread.The impact of SOX transcription factors(TFs)on brain tumors has been extensively studied in the last decade.Almost all SOX genes are expressed in GBM,and their expression levels are associated with patient prognosis and survival.Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation.The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation.Therefore,innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM.Combatting GBM has been a demanding and challenging goal for decades.The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival.Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.
基金the Key Research and Development Projects in Sichuan Province(No.2021YFS0188).
文摘Cancer stem cells(CSCs)are heterogeneous with self-renewal and differentiation ability.The mRNA expression-based stemness index(mRNAsi)described the similarity between tumor cells and CSCs,which is positively associated with the poor prognosis of cancer patients.However,the key prognostic genes related to mRNAsi in hepatocellular carcinoma(HCC)remains unclear.A 9-gene signature related to mRNAsi and HCC prognosis including PSMG3,SNRPD1,DTYMK,PIGU,NME1,TXNL4A,IPO4,PES1,and REXO4 was obtained.High expression of this signature indicates poor prognosis of HCC.PIGU was an independent prognostic factor of HCC,which was significantly associated with progression of HCC.Among them,DTYMK and NME1 enriched in pyrimidine metabolism,SNRPD1 and TXNL4A enriched in spliceosome and PIGU enriched in glycosyl phosphatidylinositol(GPI)-anchor biosynthesis pathways.High levels of IPO4,NME1,PES1,PIGU and SNRPD1 were closely associated with metastasis of HCC,and low levels of IPO4,PIGU and REOX4 were significantly associated with sorafenib resistance of HCC.High expression of the 9-gene signature was negatively correlated with the stromal cell infiltration,and positively correlated with specific immune subtypes-related to angiogenesis,M1/M2 macrophage polarization,and M2 response.The 9-gene signature was negatively correlated with the stroma,and SNRPD1 and TXNL4 were positively correlated with immune infiltrate.NME1 was negatively correlated with tumor purity.Therefore,a 9-gene signature related to mRNAsi and poor prognosis in HCC were identified,which can be used as biomarkers for the diagnosis of HCC and functional mechanism exploration of CSCs in HCC.These genes such as IPO4 and PIGU might drive the transition of tumor cells into CSCs which possibly controls the balance between metastasis and drug resistance in HCC.The challenge on balance between metastasis and drug resistance for tumor therapy was firstly reported by the present study.
基金supported by grants from the National Natu-ral Science Foundation of China (81602589 and 81601692)345 Talent Program of Shengjing Hospital
文摘Background:Liver cancer is one of the major causes of cancer-related deaths globally.Cancer cell stem-ness and chemotherapy resistance contribute to the high mortality.Although evidence indicates that the alpha subunit of protein kinase 2(CK2α)is involved in several human cancers,its function in liver cancer remains unknown.In the present study,we aimed to elucidate the role of CK2αin liver cancer.Methods:We examined the role of CK2αregulation in stemness and chemotherapy resistance capacity of liver cancer cells.MTT assays,tumor sphere formation assays,RT-PCR,flow cytometry,Western blotting assay,clonogenicity assay,matrigel invasion assay and bioinformatics were conducted in this study.Results:CK2αexpression in the liver cancer tissues was notably upregulated compared with that in the corresponding non-tumorous tissues.The overexpression of CK2αpromoted tumor sphere formation,increased the percentage of CD133(+)and side population cells,caused the resistance of liver cancer cells to 5-FU treatment,increased the expression levels of NANOG,OCT4,SOX2,Gli1 and Ptch1,and enhanced the ability of CD133(+)cell clone formation and invasion.Consistently,the downregulation of CK2αhad the opposite effects.CK2αsilencing inhibited the Hedgehog pathway by reducing the expression of Gli1 and Ptch1.Mechanistically,CK2αregulation on liver cancer cell stemness and chemotherapy resistance was found to be involved in the Hedgehog signaling pathway.Conclusions:Our study may bring some new insights into the occurrence of liver cancer.Furthermore,these findings suggest that targeting CK2αmay be a novel therapeutic strategy for patients with liver cancer.
