This study aimed to elucidate the role of collagen type XI alpha 1(COL11A1)-positive cancer-associated fibroblasts(CAFs)in modifying the tumor microenvironment of colon cancer(CC)and facilitating immune evasion throug...This study aimed to elucidate the role of collagen type XI alpha 1(COL11A1)-positive cancer-associated fibroblasts(CAFs)in modifying the tumor microenvironment of colon cancer(CC)and facilitating immune evasion through interactions with myeloid-derived suppressor cells(MDSCs).Using single-cell transcriptomic sequencing,we analyzed the interplay between COL11A1-positive CAFs and MDSCs in the CC microenvironment,focusing on how COL11A1 impacts MDSC differentiation and activation.The results demonstrate that COL11A1 expression in fibroblasts significantly enhances matrix metalloproteinase(MMP)3 and MMP13 expression,leading to paracrine induction of MDSC differentiation and activation,which promotes immune evasion and tumor growth.Additionally,we observed that COL11A1 knockout(COL11A1KO)suppresses tumor growth and hinders immune evasion.These findings underscore the essential role of COL11A1-positive CAFs in establishing an immunosuppressive tumor microenvironment conducive to CC progression.By elucidating the molecular pathway through which COL11A1 influences MDSC activity,this research suggests new therapeutic avenues for targeting the tumor microenvironment in CC,particularly through modulating COL11A1 expression in CAFs.展开更多
Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in man...Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.展开更多
Objectives:Bladder Cancer(BC)is one of the most commonly diagnosed malignancies worldwide,with high rates of mortality and morbidity.It can be classified as non-muscle invasive bladder cancer(NMIBC)or muscle-invasive ...Objectives:Bladder Cancer(BC)is one of the most commonly diagnosed malignancies worldwide,with high rates of mortality and morbidity.It can be classified as non-muscle invasive bladder cancer(NMIBC)or muscle-invasive bladder cancer(MIBC),with radical cystectomy being the treatment for MIBC,which significantly reduces quality of life.MicroRNAs(miRs)act as critical genetic regulators,with both oncogenic and tumor-suppressive roles.MiR-10a is described as a tumor suppressor in various neoplasms,but its role in BC is controversial.This study aims to assess the activity of miR-10a in cellular invasion and proliferation in two distinct BC cell lines.Methods:The study used high-grade T24 and low-grade RT4 bladder cell lines.Cells were transfected with miR-10a mimic or a non-targeting control.Transfection efficiency was validated by qPCR.Cell proliferation was cultured for 10–14 days.Cell migration and invasion were evaluated using Matrigel.All assays were conducted in triplicate.Results:The T24 cells transfected with miR-10a presented decreased cellular proliferation and invasion compared to the Scramble(p=0.0481 and p<0.0001,respectively).In the RT4 cell line,there was only a significant reduction in cellular proliferation after miR-10a transfection(p=0.0029).Conclusions:Our findings suggest that miR-10a has a tumoral suppressor role in BC,demonstrating higher efficacy in high-grade cells.展开更多
BACKGROUND Liver hepatocellular carcinoma(LIHC)is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment(TME)and immune evasion.Regulatory T cells(Tregs)play a critical role in tumor ...BACKGROUND Liver hepatocellular carcinoma(LIHC)is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment(TME)and immune evasion.Regulatory T cells(Tregs)play a critical role in tumor progression.Suppressor of cytokine signaling 2(SOCS2),a key immune regulator,may modulate Treg activity and impact LIHC growth and metastasis.AIM To explore how the SOCS2 affects Treg activity in LIHC and its impact on tumor growth and metastasis.METHODS LIHC transcriptome data from The Cancer Genome Atlas database were analyzed using Gene Set Enrichment Analysis,Estimation of Stromal and Immune Cells in Malignant Tumors Using Expression Data,and Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts to evaluate immune pathways and Treg infiltration.Key prognostic genes were identified using Weighted Gene Coexpression Network Analysis and machine learning.In vitro,co-culture experiments,migration assays,apoptosis detection,and enzyme-linked immunosorbent assay were conducted.In vivo,tumor growth,metastasis,and apoptosis were assessed using subcutaneous and lung metastasis mouse models with hematoxylin and eosin staining,Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling,and immunohistochemistry analyses.RESULTS SOCS2 overexpression inhibited Treg cell activity,reducing LIHC cell migration and invasion while increasing apoptosis.In vivo,SOCS2 suppressed tumor growth and metastasis,confirming its therapeutic potential.CONCLUSION SOCS2 modulates CD4+T function in the TME,contributing to LIHC progression.Targeting SOCS2 presents a potential therapeutic strategy for treating LIHC.展开更多
Osteosarcoma is a bone malignancy characterized by strong invasiveness and rapid disease progression.The tumor microenvironment of osteosarcoma contains various types of immune cells,including myeloid-derived suppress...Osteosarcoma is a bone malignancy characterized by strong invasiveness and rapid disease progression.The tumor microenvironment of osteosarcoma contains various types of immune cells,including myeloid-derived suppressor cells,macrophages,T cells,and B cells.Imbalances of these immune cells can promote the proliferation and metastasis of osteosarcoma.Recent studies have indicated a substantial increase in the levels of myeloid-derived suppressor cells,an immune cell associated with immunosuppressive and pro-cancer effects,in the peripheral blood of patients with osteosarcoma.Moreover,the levels of the pro-inflammatory cytokine interleukin 18 are positively correlated with those of myeloid-derived suppressor cells in the peripheral blood of animal models of osteosarcoma.In this review,we explore the function of myeloid-derived suppressor cells in osteosarcoma based on the clinical diagnoses of patients with osteosarcoma and discuss future therapeutic approaches for targeting osteosarcoma.Targeting myeloid-derived suppressor cells represents a promising approach to improving the prognosis and survival rates of patients with osteosarcoma.展开更多
Objective： To detect the aberrant methylation patterns in the CpG islands of p16 and p15 tumor suppressor genes, and to analyze its correlation with pancreatic carcinogenesis and with clinicopathological characterist...Objective： To detect the aberrant methylation patterns in the CpG islands of p16 and p15 tumor suppressor genes, and to analyze its correlation with pancreatic carcinogenesis and with clinicopathological characteristics of patients with pancreatic cancer （PC）. Methods： The methylation-specific polymerase chain reaction （MSP） method was used to monitor methylation patterns in the CpG islands of p15 and p16 genes from 29 cases of PC and 3 cases of chronic pancreatitis （CP） paraffin-embedded tissue, as well as 2 cases of normal liver tissues and 12 cases of normal blood samples. Results： p15 and p16 genes were detected to show unmethylation patterns and no amplification using methylation-specific primers in control group. The aberrant methylation rates of p16 in carcinoma tissue and adjacent noncarcinoma tissue were 37.9% （11 of 29 cases） and 34.5% （10 of 29 cases） respectively. Of the 11 aberrant methylated samples, 5 showed complete methylation and 6 hemimethylation. The methylation rates of p15 gene in carcinoma tissue and adjacent noncarcinoma tissue were 27.5% （8/29） and 24.4% （7/29） respectively. Of the 8 aberrant methylated samples, 3 showed complete methylation and 5 hemimethylation. In 6 PC samples, aberrant methylation in CpG islands of both p15 and p16 genes existed simultaneously. The aberrant methylation patterns in CpG islands of p15 and p16 genes had no close correlation with the clinicopathological characteristics （age, sex, smoking, volume of primary tumor, differentiation, clinical stage and histological classification） of the patients with PC （P〉0.05）. Conclusion： The aberrant methylation in CpG islands of p15 and p16 genes could be regarded as an early molecular event in PC and had no close correlation with the clinicopathological characteristics of the patients with PC.展开更多
A gene homologous to the human Putative tumor suppressor gone QM, designated OSQM1, was isolated from rice (Oryza sativa L.) genomic DNA library using through homology screening. It contained 4 exons and 3 introns, en...A gene homologous to the human Putative tumor suppressor gone QM, designated OSQM1, was isolated from rice (Oryza sativa L.) genomic DNA library using through homology screening. It contained 4 exons and 3 introns, encoding a protein of 219 amino acids with 46 basic amino acids, leading to a high isoelectric point of 11.02. Homology search showed that this gene existed in eukaryotes and highly conserved throughout eukaryotes, suggesting an essential role of this gene. Northern Not analysis showed that it was expressed in various rice organs, but at lower level in developing flower and callus tissue than in other vegetative organs. Its expression levels in roots and leaves were influenced by different environmental factors.展开更多
AIMS To examine the prevalance of p53 mutations in hepatocellular carcinoma (HCC) from Chongqing area and the relationship between the p53 mutations and clinicopathological features of HCC,as well as the risk factors....AIMS To examine the prevalance of p53 mutations in hepatocellular carcinoma (HCC) from Chongqing area and the relationship between the p53 mutations and clinicopathological features of HCC,as well as the risk factors. METHODS The overexpression and point mutations of tumor suppressor gene p53 in 38 cases of HCC were detected by a sensitive antigen retrieval fluid (ARF) immunohistochemical method and polymerase chain re- action(PCR)-restriction fragment length polymorphism (RFLP),and single strand conformation polymorphism (SSCP)-silver staining analysis. RESULTS The results showed that 16 of 38 HCCs had positive p53 protein (42.1%),7 HCCs had p53 mutation at 249 (18.4 % ) and 2 HCCS had point muta- tion within exon 7 other than 249. Among 9 cases of HCC with mutations,8 cases demonstrated positive p53 protein,its coincidental rate was 88.9%. The overexpression and mutations of p53 were significantly related to the differentiation and metastasis of HCCs. The frequency of p53 mutations was consistent with high prevalence of HBV and a moderate aflatoxin B1 (AFB1) exposure in our area. CONCLUSIONS The results suggest that AFB1 acts synergistically with HBV in the generation of p53 mutations. Furthermore,dietary exposure to AFB1 may mainly contribute to the tumor specific mutation at codon 249,while HBV may account for other scattered mutations in HCC.展开更多
AIM To analyse cumulative loss of heterozygosity (LOH) of chromosomal regions and tumor suppressor genes in hepatocellular carcinomas (HCCs) from 20 southern African blacks. METHODS p53, RB1, BRCA1, BRCA2, WT1 and E c...AIM To analyse cumulative loss of heterozygosity (LOH) of chromosomal regions and tumor suppressor genes in hepatocellular carcinomas (HCCs) from 20 southern African blacks. METHODS p53, RB1, BRCA1, BRCA2, WT1 and E cadherin genes were analysed for LOH, and p53 gene was also analysed for the codon 249 mutation, in tumor and adjacent non tumorous liver tissues using molecular techniques and 10 polymorphic microsatellite markers. RESULTS p53 codon 249 mutation was found in 25% of the subjects, as was expected, because many patients were from Mozambique, a country with high aflatoxin B 1 exposure. LOH was found at the RB1, BRCA2 and WT1 loci in 20%(4/*!20) of the HCCs, supporting a possible role of these genes in HCC. No LOH was evident in any of the remaining genes. Reports of mutations of p53 and RB1 genes in combination, described in other populations, were not confirmed in this study. Change in microsatellite repeat number was noted at 9/*!10 microsatellite loci in different HCCs, and changes at two or more loci were detected in 15%(3/*!20) of subjects. CONCLUSION We propose that microsatellite/genomic instability may play a role in the pathogenesis of a subset of HCCs in black Africans.展开更多
Growing evidence suggests that myeloid-derived suppressor cells （MDSCs）,which have been named ＂immature myeloid cells＂ or ＂myeloid suppressor cells＂ （MSCs）,play a critical role during the progression of cancer...Growing evidence suggests that myeloid-derived suppressor cells （MDSCs）,which have been named ＂immature myeloid cells＂ or ＂myeloid suppressor cells＂ （MSCs）,play a critical role during the progression of cancer in tumor-bearing mice and cancer patients.As their name implies,these cells are derived from bone marrow and have a tremendous potential to suppress immune responses.Recent studies indicated that these cells also have a crucial role in tumor progression.MDSCs can directly incorporate into tumor endothelium.They secret many pro-angiogenic factors as well.In addition,they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases （MMPs）,chemoattractants and creating a pre-metastatic environment.Increasing evidence supports the idea that cancer stem cells （CSCs） are responsible for tumorigenesis,resistance to therapies,invasion and metastasis.Here,we hypothesize that CSCs may ＂hijack＂ MDSCs for use as alternative niche cells,leading to the maintenance of stemness and enhanced chemo-and radio-therapy resistance.The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis.Therefore,the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.展开更多
AIM： To investigate the frequency and clinical signifi- cance of the myeloid-derived suppressor cells （MDSC） in human colorectal carcinoma （CRC）. METHODS： Samples of peripheral blood and tumor tis- sue from 49 C...AIM： To investigate the frequency and clinical signifi- cance of the myeloid-derived suppressor cells （MDSC） in human colorectal carcinoma （CRC）. METHODS： Samples of peripheral blood and tumor tis- sue from 49 CRC patients were analyzed. Mononuclear cells were isolated by FicolI-Hypaque density gradient centrifugation and were subjected to a flow cytometry- based immunophenotypic analysis. RESULTS： A considerable increase in the percentage of CD33＋HLA-DR MDSCs was observed in the periph- eral blood （1.89% ：1= 0.75%） and tumor tissues （2.99%±1.29%） of CRC patients as compared with that in theperipheral blood of healthy controls （0.54%±0.35%）. This expanded CD33＋HLA-DR subset exhibited imma- ture myeloid cell markers, but not lineage markers, and showed up-regulation of CD18/CD11b expression as compared with the MDSCs from healthy donors. Fur- ther studies showed that the MDSC proportion in CRC peripheral blood was correlated with nodal metastasis （P = 0.023）, whereas that in tumor tissues was cor- related with nodal/distant metastasis （P = 0.016/P = 0.047） and tumor stage （P = 0.028）, suggesting the involvement of MDSCs in CRC tumor development. CONCLUSION： Characterization of MDSCs in CRC sug- gests the clinical significance of circulating and tumor- infiltrating MDSCs and may provide new insights into the CRC immunotherapy targeting MDSCs.展开更多
AIM: To evaluate the genetic and epigenetic inactivation mechanism of the RASSF1A tumor suppressor gene at 3p21.3 in extrahepatic cholangiocarcinoma. METHODS: RT-PCR was used to investigate the transcriptional express...AIM: To evaluate the genetic and epigenetic inactivation mechanism of the RASSF1A tumor suppressor gene at 3p21.3 in extrahepatic cholangiocarcinoma. METHODS: RT-PCR was used to investigate the transcriptional expressing and re-expression of RASSFIA. RASSFIA mutation was analyzed with SSCP and selective sequencing. PCR was performed to detect the loss of heterozygosity (LOH) at the region of chromosome 3p21.3. Genomic DNA were modificated bisulfite and the frequency of methylation of CpG islands in RASSFIA promoter were evaluated by methylation specific PCR (MS-PCR). RESULTS: In all 48 samples and one cell lines of extrahepatic cholangiocarcinoma, the RASSFIA mutation is rare (6.12%, 3/49), 33 samples (68.75%) and QBC-939 cell lines (X2= 14.270, P= 0.001<0.01) showed RASSFIA express inactivation with LOH at microsatellite loci D3S4604. Among these 33 samples and QBC-939, 28 of 33 (84.85%) tumor samples and 1 cell lines were methylated for majority of 16 CpGs, the average frequency is 73.42%. CONCLUSION: The data we present suggest that RASSFIA which we have been searching for at 3p21.3 may be one of the key tumor suppressor gene and play an important role in the pathogenesis of extrahepatic cholangiocarcinoma, and the promoter methylation and allelic loss are the major mechanism for inactivation of RASSFIA.展开更多
A few signaling pathways are driving the growth of hepatocellular carcinoma.Each of these pathways possesses negative regulators.These enzymes,which normally suppress unchecked cell proliferation,are circumvented in t...A few signaling pathways are driving the growth of hepatocellular carcinoma.Each of these pathways possesses negative regulators.These enzymes,which normally suppress unchecked cell proliferation,are circumvented in the oncogenic process,either the overactivity of oncogenes is sufficient to annihilate the activity of tumor suppressors or tumor suppressors have been rendered ineffective.The loss of several key tumor suppressors has been described in hepatocellular carcinoma.Here,we systematically review the evidence implicating tumor suppressors in the development of hepatocellular carcinoma.展开更多
AIM To explore the effect of miR-382 on esophageal squamous cell carcinoma (ESCC) in vitro and its possible molecular mechanism. METHODS Eca 109 cells derived from human ESCC and Het-1A cells derived from human normal...AIM To explore the effect of miR-382 on esophageal squamous cell carcinoma (ESCC) in vitro and its possible molecular mechanism. METHODS Eca 109 cells derived from human ESCC and Het-1A cells derived from human normal esophageal epithelium were used. Lentivirus-mediated miR-382 was overexpressed in Eca109 cells. The effect of miR-382 on cell proliferation was evaluated by MTT and colony formation assay. For cell cycle analysis, cells were fixed and stained for 30 min with propidium iodide (PI) staining buffer containing 10 mg/mL PI and 100 mg/mL RNase A, and analyzed by BD FACSCalibur (TM) flow cytometer. For cell apoptosis assay, cells were stained with an Annexin V-FITC/PI Apoptosis Detection Kit according to the manufacturer's instructions and analyzed by a dual-laser flow cytometer. Cell invasion and migration abilities were determined through use of transwell chambers, non-coated or pre-coated with matrigel. Levels of proteins related to cell growth and migration were examined by western blotting. RESULTS Endogenous miR-382 was down-regulated in Eca109 cells compared with Het-1A. Introduction of miR-382 not only significantly inhibited proliferation and colony formation, but also arrested cell cycle at the G2/M phase, as well as promoted apoptosis and autophagy in Eca109 cells. Migration, invasion and epithelial-mesenchymal transition of Eca109 cells were suppressed by overexpressing miR-382. Western blotting results showed that miR-382 inhibited the phosphorylation of mTOR and 4E-BP1. CONCLUSION miR-382 functions as a tumor suppressor against ESCC development and metastasis, and could be considered as a potential drug source for the treatment of ESCC patients.展开更多
Esophageal squamous cell carcinoma(ESCC)is a prevalent and fatal cancer in China and other Asian countries.Epigenetic silencing of key tumor suppressor genes(TSGs)is critical to ESCC initiation and progression.Recentl...Esophageal squamous cell carcinoma(ESCC)is a prevalent and fatal cancer in China and other Asian countries.Epigenetic silencing of key tumor suppressor genes(TSGs)is critical to ESCC initiation and progression.Recently,many novel TSGs silenced by promoter methylation have been identified in ESCC,and these genes further serve as potential tumor markers for high-risk group stratification,early detection,and prognosis prediction.This review summarizes recent discoveries on aberrant promoter methylation of TSGs in ESCC,providing better understanding of the role of disrupted epigenetic regulation in tumorigenesis and insight into diagnostic and prognostic biomarkers for this malignancy.展开更多
AIM:To investigate the function and mechanism of mi R-133a in gastric cancer(GC)and its relationship with clinicopathological characteristics of GC.METHODS:A total of 105 GC patients who underwent surgical resection a...AIM:To investigate the function and mechanism of mi R-133a in gastric cancer(GC)and its relationship with clinicopathological characteristics of GC.METHODS:A total of 105 GC patients who underwent surgical resection as primary treatment were selected for this study.Real-time quantitative reverse transcriptase polymerase chain(q RT-PCR)was used to examine the expression levels of mi R-133a in human GC and adjacent non-tumor tissues,as well as in GC cell lines(SGC-7901,BGC-823,MGC-803,and AGS)and a human gastric mucosal epithelial cell line(GES-1).The biological role of mi RNA(mi R)-133a was assessed in the GC cell lines using MTT,apoptosis,migration and invasion,and colony formation assays,and xenograft tumorigenesis.q RT-PCR and western blot analyses were used to evaluate the potential target gene expression of mi R-133a.Pearson’s correlation was calculated to evaluate the correlation between mi R-133a and insulinlike growth factor 1 receptor(IGF1R)expression.The regulation of IGF1R by mi R-133a was verified using the luciferase reporter assay.RESULTS:In 80%of the 105 GC patients,the mean expression of mi R-133a was significantly downregulated in tumor tissues compared with adjacent normal tissues(1.215±0.1477 vs 3.093±0.4104,P<0.0001).Downregulation of mi R-133a was significantly correlated with the degree of differentiation(P=0.01),local invasion(P=0.001)and TNM stage(P=0.02)in GC patients.Compared with a control construct,forced expression of mi R-133a in GC cell lines inhibited proliferation(0.4787±0.0219 vs 0.7050±0.0147,P=0.0013 in SGC-7901 cells;and 0.5448±0.0085vs 0.7270±0.0084,P=0.001 in MGC-803 cells);migration(0.6333±0.0233 vs 1.037±0.0584,P=0.003 in SGC-7901 cells;0.6126±0.0311 vs 1.024±0.0456,P=0.0017 in MGC-803 cells);and invasion(0.613±0.0399 vs 1.033±0.0278,P=0.0013 in SGC-7901 cells;0.7433±0.0221 vs 1.017±0.0311,P=0.002 in MGC-803 cells).It also induced apoptosis(18.19%±0.2483%vs 5.887%±0.3837%,P<0.0001 in SGC-7901 cells;22.69%±0.7846%vs9.347%±0.3012%,P<0.0001 in MGC-803 cells).Furthermore,mi R-133a inhibited tumor growth and xenograft tumorigenesis of SGC-7901 cells in vivo.In addition,we identified IGF1R as a regulatory target of mi R-133a in GC.CONCLUSION:This study suggests that mi R-133a is downregulated in GC and functions as a tumor suppressor in vitro and in vivo partly by repressing IGF1R.展开更多
BACKGROUND： Myeloid-derived suppressor cells （MDSCs） are heterogeneous cell types that suppress T-cell responses in cancer patients and animal models, some MDSC subpopulations are increased in patients with pancrea...BACKGROUND： Myeloid-derived suppressor cells （MDSCs） are heterogeneous cell types that suppress T-cell responses in cancer patients and animal models, some MDSC subpopulations are increased in patients with pancreatic cancer. The present study was to investigate a specific subset of MDSCs in patients with pancreatic cancer and the mechanism of MDSCs increase in these patients. METHODS： Myeloid cells from whole blood were collected from 37 patients with pancreatic cancer, 17 with cholangiocarcinoma, and 47 healthy controls. Four pancreatic cancer cell lines were co- cultured with normal peripheral blood mononudear cells （PBMCs） to test the effect of tumor cells on the conversion of PBMCs to MDSCs. Levels of granulocyte-macrophage colony-stimulating factor （GM-CSF） and arginase activity in the plasma of cancer patients were analyzed by enzyme-linked immunosorbent assay. RESULTS： CD14＋/CD11b＋/HLA-DR MDSCs were increased in patients with pancreatic or bile duct cancer compared with those in healthy controls, and this increase was correlated with clinical cancer stage. Pancreatic cancer cell lines induced PBMCs to MDSCs in a dose-dependent manner. GM-CSF and arginase activity levels were significantly increased in the se rum of patients with pancreatic cancer. CONCLUSIONS： MDSCs were tumor related： tumor cells induced PBMCs to MDSCs in a dose-dependent manner and circulating CD14＋/CD11b＋/HLA-DR- MDSCs in pancreatic cancer patients were positively correlated with tumor burden. MDSCs might be useful markers for pancreatic cancer detection and progression.展开更多
The tumor suppressor PTEN controls a variety of biological processes including cell proliferation, growth, migration, and death. As a master cellular regulator, PTEN itself is also subjected to deliberated regulation ...The tumor suppressor PTEN controls a variety of biological processes including cell proliferation, growth, migration, and death. As a master cellular regulator, PTEN itself is also subjected to deliberated regulation to ensure its proper function. Defects in PTEN regulation have a profound impact on carcinogenesis. In this review, we briefly discuss recent advances concerning PTEN regulation and how such knowledge facilitates our understanding and further exploration of PTEN biology. The carboxyl-tail of PTEN, which appears to be associated with multiple types of posttranslational regulation, will be under detailed scrutiny. Further, a comparative analysis of PTEN and p53 suggests while p53 needs to be activated to suppress tumorigenesis （a dormant gatekeeper）, PTEN is probably a constitutive surveillant against cancer development, thus a default gatekeeper.展开更多
Insulin-like growth factor binding-protein-7 （IGFBP7） was obtained from our previous colonic adenocarcinoma （CRC） and normal mucosa suppression subtraction hybridization （SSH） cDNA libraries. By RT-PCR and immun...Insulin-like growth factor binding-protein-7 （IGFBP7） was obtained from our previous colonic adenocarcinoma （CRC） and normal mucosa suppression subtraction hybridization （SSH） cDNA libraries. By RT-PCR and immunohistochemistry, we found that IGFBP7 was overexpressed in CRC tissue compared to normal tissue. However, our in vitro experiments performed in 10 CRC cell lines showed that IGFBP7 expressed only in SW480 and Caco2 cell lines, which implied an underlying reversible regulatory mechanism. Using methylation-specific PCR （MSP） and bisulfite sodium PCR （BSP）, we found that its expression was associated with DNA hypomethylation of exonl. This was further supported by the in vitro study which showed restored IGFBP7 expression after demethylation agent 5-aza-2＇-deoxycytidine treatment. Correlation analysis between IGFBP7 expression and prognosis indicated that overexpression of IGFBP7 in CRC tissue correlated with favourable survival. Investigation of the functional role of IGFBP7 through transfection studies showed that IGFBP7 protein could inhibit growth rate, decrease colony formation activity, and induce apoptosis in RKO and SW620 cells, suggesting it a potential tumor suppressor protein in colorectal carcinogenesis. In conclusion, our study clearly demonstrated that IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis and its expression is associated with DNA hypomethylation of exon 1.展开更多
Objective Rheumatoid arthritis(RA)progression is associated with the balance of T-regulatory(Treg)and T-helper 17(Th17)cells,while the role of microRNAs(miRs)in regulating Treg/Th17 cell balance has not been clarified...Objective Rheumatoid arthritis(RA)progression is associated with the balance of T-regulatory(Treg)and T-helper 17(Th17)cells,while the role of microRNAs(miRs)in regulating Treg/Th17 cell balance has not been clarified.This study aimed to assess whether moxibustion could regulate Treg/Th17 cell balance by modulating the miR-221/suppressor of cytokine signaling 3(SOCS3)axis in the RA mouse model.Methods A mouse model of collagen-induced arthritis(CIA)was established in male DBA/1J mice.Twenty-two days after CIA induction,the mice received daily treatment with moxibustion for 12 times.Pathological scores were assessed according to the levels of synovial hyperplasia.The expression levels of cytokines interleukin(IL)-1β,IL-6,tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ),IL-17 and IL-10 were analyzed in serum by enzyme-linked immunosorbent assay.The cluster of differentiation 4(CD4+)splenocytes was analyzed by fluorescence-activated cell sorting.The expression levels of RA-related miRs and target genes were subsequently detected,and the target of miR-221 was confirmed by the dual-luciferase reporter assay.Results It was revealed that moxibustion treatment decreased the pathological scores and downregulated the expression levels of IL-1β,IL-6,TNF-α,IFN-γand IL-17,while upregulated the expression level of IL-10.The Treg/Th17 cell balance was regulated by moxibustion treatment.The expression level of miR-221 was suppressed by moxibustion treatment.Furthermore,SOCS3 was found as the direct target of miR-221,which mediated the function of moxibustion by regulating the Treg/Th17 cell balance.Conclusion Moxibustion therapy regulated the Treg/Th17 cell balance by modulating the miR-221/SOCS3 axis in the RA mouse model.展开更多
文摘This study aimed to elucidate the role of collagen type XI alpha 1(COL11A1)-positive cancer-associated fibroblasts(CAFs)in modifying the tumor microenvironment of colon cancer(CC)and facilitating immune evasion through interactions with myeloid-derived suppressor cells(MDSCs).Using single-cell transcriptomic sequencing,we analyzed the interplay between COL11A1-positive CAFs and MDSCs in the CC microenvironment,focusing on how COL11A1 impacts MDSC differentiation and activation.The results demonstrate that COL11A1 expression in fibroblasts significantly enhances matrix metalloproteinase(MMP)3 and MMP13 expression,leading to paracrine induction of MDSC differentiation and activation,which promotes immune evasion and tumor growth.Additionally,we observed that COL11A1 knockout(COL11A1KO)suppresses tumor growth and hinders immune evasion.These findings underscore the essential role of COL11A1-positive CAFs in establishing an immunosuppressive tumor microenvironment conducive to CC progression.By elucidating the molecular pathway through which COL11A1 influences MDSC activity,this research suggests new therapeutic avenues for targeting the tumor microenvironment in CC,particularly through modulating COL11A1 expression in CAFs.
文摘Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.
基金supported by grants from the São Paulo Research Foundation(FAPESP)to ThaináRodrigues(2021/04603-8).
文摘Objectives:Bladder Cancer(BC)is one of the most commonly diagnosed malignancies worldwide,with high rates of mortality and morbidity.It can be classified as non-muscle invasive bladder cancer(NMIBC)or muscle-invasive bladder cancer(MIBC),with radical cystectomy being the treatment for MIBC,which significantly reduces quality of life.MicroRNAs(miRs)act as critical genetic regulators,with both oncogenic and tumor-suppressive roles.MiR-10a is described as a tumor suppressor in various neoplasms,but its role in BC is controversial.This study aims to assess the activity of miR-10a in cellular invasion and proliferation in two distinct BC cell lines.Methods:The study used high-grade T24 and low-grade RT4 bladder cell lines.Cells were transfected with miR-10a mimic or a non-targeting control.Transfection efficiency was validated by qPCR.Cell proliferation was cultured for 10–14 days.Cell migration and invasion were evaluated using Matrigel.All assays were conducted in triplicate.Results:The T24 cells transfected with miR-10a presented decreased cellular proliferation and invasion compared to the Scramble(p=0.0481 and p<0.0001,respectively).In the RT4 cell line,there was only a significant reduction in cellular proliferation after miR-10a transfection(p=0.0029).Conclusions:Our findings suggest that miR-10a has a tumoral suppressor role in BC,demonstrating higher efficacy in high-grade cells.
基金Supported by Wu Jieping Medical Foundation,No.320.6750.2021-06-30Guangdong Basic and Applied Basic Research Foundation,No.2019A1515110120National Natural Science Foundation of China,No.82002974。
文摘BACKGROUND Liver hepatocellular carcinoma(LIHC)is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment(TME)and immune evasion.Regulatory T cells(Tregs)play a critical role in tumor progression.Suppressor of cytokine signaling 2(SOCS2),a key immune regulator,may modulate Treg activity and impact LIHC growth and metastasis.AIM To explore how the SOCS2 affects Treg activity in LIHC and its impact on tumor growth and metastasis.METHODS LIHC transcriptome data from The Cancer Genome Atlas database were analyzed using Gene Set Enrichment Analysis,Estimation of Stromal and Immune Cells in Malignant Tumors Using Expression Data,and Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts to evaluate immune pathways and Treg infiltration.Key prognostic genes were identified using Weighted Gene Coexpression Network Analysis and machine learning.In vitro,co-culture experiments,migration assays,apoptosis detection,and enzyme-linked immunosorbent assay were conducted.In vivo,tumor growth,metastasis,and apoptosis were assessed using subcutaneous and lung metastasis mouse models with hematoxylin and eosin staining,Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling,and immunohistochemistry analyses.RESULTS SOCS2 overexpression inhibited Treg cell activity,reducing LIHC cell migration and invasion while increasing apoptosis.In vivo,SOCS2 suppressed tumor growth and metastasis,confirming its therapeutic potential.CONCLUSION SOCS2 modulates CD4+T function in the TME,contributing to LIHC progression.Targeting SOCS2 presents a potential therapeutic strategy for treating LIHC.
基金supported by the National Research Foundation of Korea(NRF)funded by the Ministry of Education(2021R1A2C3003414,2021R1A6A1A03038890,2022R1I1A1A01053839,RS-2023-00246963)the Korea government(MSIT)(RS-2024-00344635)the Korea Basic Science Institute(National Research Facilities and Equipment Center,No.2021R1A6C101A564).
文摘Osteosarcoma is a bone malignancy characterized by strong invasiveness and rapid disease progression.The tumor microenvironment of osteosarcoma contains various types of immune cells,including myeloid-derived suppressor cells,macrophages,T cells,and B cells.Imbalances of these immune cells can promote the proliferation and metastasis of osteosarcoma.Recent studies have indicated a substantial increase in the levels of myeloid-derived suppressor cells,an immune cell associated with immunosuppressive and pro-cancer effects,in the peripheral blood of patients with osteosarcoma.Moreover,the levels of the pro-inflammatory cytokine interleukin 18 are positively correlated with those of myeloid-derived suppressor cells in the peripheral blood of animal models of osteosarcoma.In this review,we explore the function of myeloid-derived suppressor cells in osteosarcoma based on the clinical diagnoses of patients with osteosarcoma and discuss future therapeutic approaches for targeting osteosarcoma.Targeting myeloid-derived suppressor cells represents a promising approach to improving the prognosis and survival rates of patients with osteosarcoma.
文摘Objective： To detect the aberrant methylation patterns in the CpG islands of p16 and p15 tumor suppressor genes, and to analyze its correlation with pancreatic carcinogenesis and with clinicopathological characteristics of patients with pancreatic cancer （PC）. Methods： The methylation-specific polymerase chain reaction （MSP） method was used to monitor methylation patterns in the CpG islands of p15 and p16 genes from 29 cases of PC and 3 cases of chronic pancreatitis （CP） paraffin-embedded tissue, as well as 2 cases of normal liver tissues and 12 cases of normal blood samples. Results： p15 and p16 genes were detected to show unmethylation patterns and no amplification using methylation-specific primers in control group. The aberrant methylation rates of p16 in carcinoma tissue and adjacent noncarcinoma tissue were 37.9% （11 of 29 cases） and 34.5% （10 of 29 cases） respectively. Of the 11 aberrant methylated samples, 5 showed complete methylation and 6 hemimethylation. The methylation rates of p15 gene in carcinoma tissue and adjacent noncarcinoma tissue were 27.5% （8/29） and 24.4% （7/29） respectively. Of the 8 aberrant methylated samples, 3 showed complete methylation and 5 hemimethylation. In 6 PC samples, aberrant methylation in CpG islands of both p15 and p16 genes existed simultaneously. The aberrant methylation patterns in CpG islands of p15 and p16 genes had no close correlation with the clinicopathological characteristics （age, sex, smoking, volume of primary tumor, differentiation, clinical stage and histological classification） of the patients with PC （P〉0.05）. Conclusion： The aberrant methylation in CpG islands of p15 and p16 genes could be regarded as an early molecular event in PC and had no close correlation with the clinicopathological characteristics of the patients with PC.
文摘A gene homologous to the human Putative tumor suppressor gone QM, designated OSQM1, was isolated from rice (Oryza sativa L.) genomic DNA library using through homology screening. It contained 4 exons and 3 introns, encoding a protein of 219 amino acids with 46 basic amino acids, leading to a high isoelectric point of 11.02. Homology search showed that this gene existed in eukaryotes and highly conserved throughout eukaryotes, suggesting an essential role of this gene. Northern Not analysis showed that it was expressed in various rice organs, but at lower level in developing flower and callus tissue than in other vegetative organs. Its expression levels in roots and leaves were influenced by different environmental factors.
文摘AIMS To examine the prevalance of p53 mutations in hepatocellular carcinoma (HCC) from Chongqing area and the relationship between the p53 mutations and clinicopathological features of HCC,as well as the risk factors. METHODS The overexpression and point mutations of tumor suppressor gene p53 in 38 cases of HCC were detected by a sensitive antigen retrieval fluid (ARF) immunohistochemical method and polymerase chain re- action(PCR)-restriction fragment length polymorphism (RFLP),and single strand conformation polymorphism (SSCP)-silver staining analysis. RESULTS The results showed that 16 of 38 HCCs had positive p53 protein (42.1%),7 HCCs had p53 mutation at 249 (18.4 % ) and 2 HCCS had point muta- tion within exon 7 other than 249. Among 9 cases of HCC with mutations,8 cases demonstrated positive p53 protein,its coincidental rate was 88.9%. The overexpression and mutations of p53 were significantly related to the differentiation and metastasis of HCCs. The frequency of p53 mutations was consistent with high prevalence of HBV and a moderate aflatoxin B1 (AFB1) exposure in our area. CONCLUSIONS The results suggest that AFB1 acts synergistically with HBV in the generation of p53 mutations. Furthermore,dietary exposure to AFB1 may mainly contribute to the tumor specific mutation at codon 249,while HBV may account for other scattered mutations in HCC.
文摘AIM To analyse cumulative loss of heterozygosity (LOH) of chromosomal regions and tumor suppressor genes in hepatocellular carcinomas (HCCs) from 20 southern African blacks. METHODS p53, RB1, BRCA1, BRCA2, WT1 and E cadherin genes were analysed for LOH, and p53 gene was also analysed for the codon 249 mutation, in tumor and adjacent non tumorous liver tissues using molecular techniques and 10 polymorphic microsatellite markers. RESULTS p53 codon 249 mutation was found in 25% of the subjects, as was expected, because many patients were from Mozambique, a country with high aflatoxin B 1 exposure. LOH was found at the RB1, BRCA2 and WT1 loci in 20%(4/*!20) of the HCCs, supporting a possible role of these genes in HCC. No LOH was evident in any of the remaining genes. Reports of mutations of p53 and RB1 genes in combination, described in other populations, were not confirmed in this study. Change in microsatellite repeat number was noted at 9/*!10 microsatellite loci in different HCCs, and changes at two or more loci were detected in 15%(3/*!20) of subjects. CONCLUSION We propose that microsatellite/genomic instability may play a role in the pathogenesis of a subset of HCCs in black Africans.
基金supported by the National Basic Research Program of China (973 Program) (No 2010CB529403)the National Natural Science Foundation of China (Nos 30725035 and 30930103)
文摘Growing evidence suggests that myeloid-derived suppressor cells （MDSCs）,which have been named ＂immature myeloid cells＂ or ＂myeloid suppressor cells＂ （MSCs）,play a critical role during the progression of cancer in tumor-bearing mice and cancer patients.As their name implies,these cells are derived from bone marrow and have a tremendous potential to suppress immune responses.Recent studies indicated that these cells also have a crucial role in tumor progression.MDSCs can directly incorporate into tumor endothelium.They secret many pro-angiogenic factors as well.In addition,they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases （MMPs）,chemoattractants and creating a pre-metastatic environment.Increasing evidence supports the idea that cancer stem cells （CSCs） are responsible for tumorigenesis,resistance to therapies,invasion and metastasis.Here,we hypothesize that CSCs may ＂hijack＂ MDSCs for use as alternative niche cells,leading to the maintenance of stemness and enhanced chemo-and radio-therapy resistance.The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis.Therefore,the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.
文摘AIM： To investigate the frequency and clinical signifi- cance of the myeloid-derived suppressor cells （MDSC） in human colorectal carcinoma （CRC）. METHODS： Samples of peripheral blood and tumor tis- sue from 49 CRC patients were analyzed. Mononuclear cells were isolated by FicolI-Hypaque density gradient centrifugation and were subjected to a flow cytometry- based immunophenotypic analysis. RESULTS： A considerable increase in the percentage of CD33＋HLA-DR MDSCs was observed in the periph- eral blood （1.89% ：1= 0.75%） and tumor tissues （2.99%±1.29%） of CRC patients as compared with that in theperipheral blood of healthy controls （0.54%±0.35%）. This expanded CD33＋HLA-DR subset exhibited imma- ture myeloid cell markers, but not lineage markers, and showed up-regulation of CD18/CD11b expression as compared with the MDSCs from healthy donors. Fur- ther studies showed that the MDSC proportion in CRC peripheral blood was correlated with nodal metastasis （P = 0.023）, whereas that in tumor tissues was cor- related with nodal/distant metastasis （P = 0.016/P = 0.047） and tumor stage （P = 0.028）, suggesting the involvement of MDSCs in CRC tumor development. CONCLUSION： Characterization of MDSCs in CRC sug- gests the clinical significance of circulating and tumor- infiltrating MDSCs and may provide new insights into the CRC immunotherapy targeting MDSCs.
基金Supported by the National High Technology Research and Development Program of China (863 Program), No. 2002AA214061
文摘AIM: To evaluate the genetic and epigenetic inactivation mechanism of the RASSF1A tumor suppressor gene at 3p21.3 in extrahepatic cholangiocarcinoma. METHODS: RT-PCR was used to investigate the transcriptional expressing and re-expression of RASSFIA. RASSFIA mutation was analyzed with SSCP and selective sequencing. PCR was performed to detect the loss of heterozygosity (LOH) at the region of chromosome 3p21.3. Genomic DNA were modificated bisulfite and the frequency of methylation of CpG islands in RASSFIA promoter were evaluated by methylation specific PCR (MS-PCR). RESULTS: In all 48 samples and one cell lines of extrahepatic cholangiocarcinoma, the RASSFIA mutation is rare (6.12%, 3/49), 33 samples (68.75%) and QBC-939 cell lines (X2= 14.270, P= 0.001<0.01) showed RASSFIA express inactivation with LOH at microsatellite loci D3S4604. Among these 33 samples and QBC-939, 28 of 33 (84.85%) tumor samples and 1 cell lines were methylated for majority of 16 CpGs, the average frequency is 73.42%. CONCLUSION: The data we present suggest that RASSFIA which we have been searching for at 3p21.3 may be one of the key tumor suppressor gene and play an important role in the pathogenesis of extrahepatic cholangiocarcinoma, and the promoter methylation and allelic loss are the major mechanism for inactivation of RASSFIA.
基金The Stiftung für die Leberkranheiten,the EASLfellowship to JM and the Swiss National Foundation grant#3100-063696 to JFD
文摘A few signaling pathways are driving the growth of hepatocellular carcinoma.Each of these pathways possesses negative regulators.These enzymes,which normally suppress unchecked cell proliferation,are circumvented in the oncogenic process,either the overactivity of oncogenes is sufficient to annihilate the activity of tumor suppressors or tumor suppressors have been rendered ineffective.The loss of several key tumor suppressors has been described in hepatocellular carcinoma.Here,we systematically review the evidence implicating tumor suppressors in the development of hepatocellular carcinoma.
基金Supported by Key Technologies R&D Program of Science and Technology Commission of Henan Province,No.152102310110 to Zhao BSKey Science and Technique Fund of Xinxiang,No.ZG15018 to Zhao BS
文摘AIM To explore the effect of miR-382 on esophageal squamous cell carcinoma (ESCC) in vitro and its possible molecular mechanism. METHODS Eca 109 cells derived from human ESCC and Het-1A cells derived from human normal esophageal epithelium were used. Lentivirus-mediated miR-382 was overexpressed in Eca109 cells. The effect of miR-382 on cell proliferation was evaluated by MTT and colony formation assay. For cell cycle analysis, cells were fixed and stained for 30 min with propidium iodide (PI) staining buffer containing 10 mg/mL PI and 100 mg/mL RNase A, and analyzed by BD FACSCalibur (TM) flow cytometer. For cell apoptosis assay, cells were stained with an Annexin V-FITC/PI Apoptosis Detection Kit according to the manufacturer's instructions and analyzed by a dual-laser flow cytometer. Cell invasion and migration abilities were determined through use of transwell chambers, non-coated or pre-coated with matrigel. Levels of proteins related to cell growth and migration were examined by western blotting. RESULTS Endogenous miR-382 was down-regulated in Eca109 cells compared with Het-1A. Introduction of miR-382 not only significantly inhibited proliferation and colony formation, but also arrested cell cycle at the G2/M phase, as well as promoted apoptosis and autophagy in Eca109 cells. Migration, invasion and epithelial-mesenchymal transition of Eca109 cells were suppressed by overexpressing miR-382. Western blotting results showed that miR-382 inhibited the phosphorylation of mTOR and 4E-BP1. CONCLUSION miR-382 functions as a tumor suppressor against ESCC development and metastasis, and could be considered as a potential drug source for the treatment of ESCC patients.
基金supported by NSFC Joint Research Fund for Hong Kong and Macao Young Scholars(No.30928012)National Natural Science Foundation of China(No.81071634,81172582,and 30801344)Shenzhen Science Fund for Distinguished Young Scholars(No.JC201005270328A)
文摘Esophageal squamous cell carcinoma(ESCC)is a prevalent and fatal cancer in China and other Asian countries.Epigenetic silencing of key tumor suppressor genes(TSGs)is critical to ESCC initiation and progression.Recently,many novel TSGs silenced by promoter methylation have been identified in ESCC,and these genes further serve as potential tumor markers for high-risk group stratification,early detection,and prognosis prediction.This review summarizes recent discoveries on aberrant promoter methylation of TSGs in ESCC,providing better understanding of the role of disrupted epigenetic regulation in tumorigenesis and insight into diagnostic and prognostic biomarkers for this malignancy.
基金Supported by Nanjing Medical University institutional grant,No.11ZLKF06(to SYC and LMT)the Changzhou basic research program of science and technology,No.CJ20122014
文摘AIM:To investigate the function and mechanism of mi R-133a in gastric cancer(GC)and its relationship with clinicopathological characteristics of GC.METHODS:A total of 105 GC patients who underwent surgical resection as primary treatment were selected for this study.Real-time quantitative reverse transcriptase polymerase chain(q RT-PCR)was used to examine the expression levels of mi R-133a in human GC and adjacent non-tumor tissues,as well as in GC cell lines(SGC-7901,BGC-823,MGC-803,and AGS)and a human gastric mucosal epithelial cell line(GES-1).The biological role of mi RNA(mi R)-133a was assessed in the GC cell lines using MTT,apoptosis,migration and invasion,and colony formation assays,and xenograft tumorigenesis.q RT-PCR and western blot analyses were used to evaluate the potential target gene expression of mi R-133a.Pearson’s correlation was calculated to evaluate the correlation between mi R-133a and insulinlike growth factor 1 receptor(IGF1R)expression.The regulation of IGF1R by mi R-133a was verified using the luciferase reporter assay.RESULTS:In 80%of the 105 GC patients,the mean expression of mi R-133a was significantly downregulated in tumor tissues compared with adjacent normal tissues(1.215±0.1477 vs 3.093±0.4104,P<0.0001).Downregulation of mi R-133a was significantly correlated with the degree of differentiation(P=0.01),local invasion(P=0.001)and TNM stage(P=0.02)in GC patients.Compared with a control construct,forced expression of mi R-133a in GC cell lines inhibited proliferation(0.4787±0.0219 vs 0.7050±0.0147,P=0.0013 in SGC-7901 cells;and 0.5448±0.0085vs 0.7270±0.0084,P=0.001 in MGC-803 cells);migration(0.6333±0.0233 vs 1.037±0.0584,P=0.003 in SGC-7901 cells;0.6126±0.0311 vs 1.024±0.0456,P=0.0017 in MGC-803 cells);and invasion(0.613±0.0399 vs 1.033±0.0278,P=0.0013 in SGC-7901 cells;0.7433±0.0221 vs 1.017±0.0311,P=0.002 in MGC-803 cells).It also induced apoptosis(18.19%±0.2483%vs 5.887%±0.3837%,P<0.0001 in SGC-7901 cells;22.69%±0.7846%vs9.347%±0.3012%,P<0.0001 in MGC-803 cells).Furthermore,mi R-133a inhibited tumor growth and xenograft tumorigenesis of SGC-7901 cells in vivo.In addition,we identified IGF1R as a regulatory target of mi R-133a in GC.CONCLUSION:This study suggests that mi R-133a is downregulated in GC and functions as a tumor suppressor in vitro and in vivo partly by repressing IGF1R.
基金supported by grants from the National Natural Science Foundation of China(81071775,81272659,81101621,81160311,81172064,81001068,81272425 and 81101870)National“Eleventh Five-Year”Scientific and Technological Support Projects(2006BAI02A13-402)+1 种基金Key Projects of Science Foundation of Hubei Province(2011CDA030)Research Fund of Young Scholars for the Doctoral Program of Higher Education of China(20110142120014)
文摘BACKGROUND： Myeloid-derived suppressor cells （MDSCs） are heterogeneous cell types that suppress T-cell responses in cancer patients and animal models, some MDSC subpopulations are increased in patients with pancreatic cancer. The present study was to investigate a specific subset of MDSCs in patients with pancreatic cancer and the mechanism of MDSCs increase in these patients. METHODS： Myeloid cells from whole blood were collected from 37 patients with pancreatic cancer, 17 with cholangiocarcinoma, and 47 healthy controls. Four pancreatic cancer cell lines were co- cultured with normal peripheral blood mononudear cells （PBMCs） to test the effect of tumor cells on the conversion of PBMCs to MDSCs. Levels of granulocyte-macrophage colony-stimulating factor （GM-CSF） and arginase activity in the plasma of cancer patients were analyzed by enzyme-linked immunosorbent assay. RESULTS： CD14＋/CD11b＋/HLA-DR MDSCs were increased in patients with pancreatic or bile duct cancer compared with those in healthy controls, and this increase was correlated with clinical cancer stage. Pancreatic cancer cell lines induced PBMCs to MDSCs in a dose-dependent manner. GM-CSF and arginase activity levels were significantly increased in the se rum of patients with pancreatic cancer. CONCLUSIONS： MDSCs were tumor related： tumor cells induced PBMCs to MDSCs in a dose-dependent manner and circulating CD14＋/CD11b＋/HLA-DR- MDSCs in pancreatic cancer patients were positively correlated with tumor burden. MDSCs might be useful markers for pancreatic cancer detection and progression.
文摘The tumor suppressor PTEN controls a variety of biological processes including cell proliferation, growth, migration, and death. As a master cellular regulator, PTEN itself is also subjected to deliberated regulation to ensure its proper function. Defects in PTEN regulation have a profound impact on carcinogenesis. In this review, we briefly discuss recent advances concerning PTEN regulation and how such knowledge facilitates our understanding and further exploration of PTEN biology. The carboxyl-tail of PTEN, which appears to be associated with multiple types of posttranslational regulation, will be under detailed scrutiny. Further, a comparative analysis of PTEN and p53 suggests while p53 needs to be activated to suppress tumorigenesis （a dormant gatekeeper）, PTEN is probably a constitutive surveillant against cancer development, thus a default gatekeeper.
基金Project (Nos. 30200333 and 30570840) supported by the NationalNatural Science Foundation of China
文摘Insulin-like growth factor binding-protein-7 （IGFBP7） was obtained from our previous colonic adenocarcinoma （CRC） and normal mucosa suppression subtraction hybridization （SSH） cDNA libraries. By RT-PCR and immunohistochemistry, we found that IGFBP7 was overexpressed in CRC tissue compared to normal tissue. However, our in vitro experiments performed in 10 CRC cell lines showed that IGFBP7 expressed only in SW480 and Caco2 cell lines, which implied an underlying reversible regulatory mechanism. Using methylation-specific PCR （MSP） and bisulfite sodium PCR （BSP）, we found that its expression was associated with DNA hypomethylation of exonl. This was further supported by the in vitro study which showed restored IGFBP7 expression after demethylation agent 5-aza-2＇-deoxycytidine treatment. Correlation analysis between IGFBP7 expression and prognosis indicated that overexpression of IGFBP7 in CRC tissue correlated with favourable survival. Investigation of the functional role of IGFBP7 through transfection studies showed that IGFBP7 protein could inhibit growth rate, decrease colony formation activity, and induce apoptosis in RKO and SW620 cells, suggesting it a potential tumor suppressor protein in colorectal carcinogenesis. In conclusion, our study clearly demonstrated that IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis and its expression is associated with DNA hypomethylation of exon 1.
基金This study was supported by the National Natural Science Foundation of China(No.81904284)Shanghai Talent Development Fund(No,2020086)Key Discipline Construction Fund of Baoshan Hospital of Integrated Traditional Chinese Medicine and Western Medicine,Shanghai(No.BSYYZDZK-2019-03 and No.BSYYZDZK-2019-04)。
文摘Objective Rheumatoid arthritis(RA)progression is associated with the balance of T-regulatory(Treg)and T-helper 17(Th17)cells,while the role of microRNAs(miRs)in regulating Treg/Th17 cell balance has not been clarified.This study aimed to assess whether moxibustion could regulate Treg/Th17 cell balance by modulating the miR-221/suppressor of cytokine signaling 3(SOCS3)axis in the RA mouse model.Methods A mouse model of collagen-induced arthritis(CIA)was established in male DBA/1J mice.Twenty-two days after CIA induction,the mice received daily treatment with moxibustion for 12 times.Pathological scores were assessed according to the levels of synovial hyperplasia.The expression levels of cytokines interleukin(IL)-1β,IL-6,tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ),IL-17 and IL-10 were analyzed in serum by enzyme-linked immunosorbent assay.The cluster of differentiation 4(CD4+)splenocytes was analyzed by fluorescence-activated cell sorting.The expression levels of RA-related miRs and target genes were subsequently detected,and the target of miR-221 was confirmed by the dual-luciferase reporter assay.Results It was revealed that moxibustion treatment decreased the pathological scores and downregulated the expression levels of IL-1β,IL-6,TNF-α,IFN-γand IL-17,while upregulated the expression level of IL-10.The Treg/Th17 cell balance was regulated by moxibustion treatment.The expression level of miR-221 was suppressed by moxibustion treatment.Furthermore,SOCS3 was found as the direct target of miR-221,which mediated the function of moxibustion by regulating the Treg/Th17 cell balance.Conclusion Moxibustion therapy regulated the Treg/Th17 cell balance by modulating the miR-221/SOCS3 axis in the RA mouse model.
