BACKGROUND Gastric cancer(GC)is a widespread malignancy and associated with high rates of morbidity and mortality worldwide.AIM To examine the functional role of long non-coding RNAs small nucleolar RNA host gene 5(SN...BACKGROUND Gastric cancer(GC)is a widespread malignancy and associated with high rates of morbidity and mortality worldwide.AIM To examine the functional role of long non-coding RNAs small nucleolar RNA host gene 5(SNHG5)and its regulation of miR-92a-3p and B-cell translocation gene 2(BTG2)in GC progression.METHODS Quantitative reverse transcription PCR and western blot analysis determined the expression of SNHG5,miR-92a-3p,and BTG2 in GC and adjacent non-neoplastic mucosa.Dual-luciferase assays demonstrated interactions of SNHG5 with miR-92a-3p and BTG2.AGS cells were transfected with SNHG5 overexpression and miR-92a-3p knockdown models.Various assays,including CCK-8,colony formation,scratch wound healing,and Transwell assays,were used to determine cell proliferation and migration.An experimental model of a xenograft mouse was used to determine in vivo tumor growth.At the same time histological changes were evaluated by hematoxylin and eosin staining,with western blot analysis used to evaluate signaling pathway protein expression.RESULTS BTG2 and SNHG5 were downregulated in GC tissues,and miR-92a-3p was upregulated.Overexpression of SNHG5 or knockdown of miR-92a-3p reduced GC cell proliferation and migration,and increased BTG2 expression while decreasing PI3K/AKT signaling activity.The dual-luciferase assays demonstrated direct binding of miR-92a-3p to SNHG5 and BTG2.Tumor volume and weight were significantly reduced in mice transplanted with AGS cells treated with miR-92a-3p inhibitor or SNHG5 overexpression compared with control AGS cells.Hematoxylin and eosin staining revealed that treated tumors exhibited degenerative characteristics,including irregular morphology and nucleolysis.CONCLUSION LncRNA SNHG5 inhibited GC cell growth and migration by modulating the PI3K/AKT pathway via the miR-92a-3p/BTG2 axis.展开更多
BACKGROUND Pancreatic ductal adenocarcinoma(PDAC) is one of the deadliest solid tumors. Identification of diagnostic and therapeutic biomarkers for PDAC is urgently needed. Transducin(β)-like 1 X-linked receptor 1(TB...BACKGROUND Pancreatic ductal adenocarcinoma(PDAC) is one of the deadliest solid tumors. Identification of diagnostic and therapeutic biomarkers for PDAC is urgently needed. Transducin(β)-like 1 X-linked receptor 1(TBL1 XR1) has been linked to the progression of various human cancers. Nevertheless, the function and role of TBL1 XR1 in pancreatic cancers are unclear.AIM To elucidate the function and potential mechanism of TBL1 XR1 in the development of PDAC.METHODS Ninety patients with histologically-confirmed PDAC were included in this study. PDAC tumor samples and cell lines were used to determine the expression of TBL1 XR1. CCK-8 assays and colony formation assays were carried out to assess PDAC cell viability. Flow cytometry was performed to measure the changes in the cell cycle and cell apoptosis. Changes in related protein expression were measured by western blot analysis. Animal analysis was conducted to confirm the impact of TBL1 XR1 in vivo.RESULTS Patients with TBL1 XR1-positive tumors had worse overall survival than those with TBL1 XR1-negative tumors. Moreover, we found that TBL1 XR1 strongly promoted PDAC cell proliferation and inhibited PDAC cell apoptosis. Moreover, knockdown of TBL1 XR1 induced G0/G1 phase arrest. In vivo animal studies confirmed that TBL1 XR1 accelerated tumor cell growth. The results of western blot analysis showed that TBL1 XR1 might play a key role in regulating PDAC cell proliferation and apoptosis via the PI3 K/AKT pathway.CONCLUSION TBL1 XR1 promoted PDAC cell progression and might be an effective diagnostic and therapeutic marker for pancreatic cancer.展开更多
BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations...BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue.Never-theless,the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.AIM To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.METHODS Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk.Subsequently,blood and urine indexes were assessed,along with examination of renal tissue pathology.Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin,periodic acid–Schiff,Masson’s trichrome,and Sirius-red.Additionally,high-glucose culturing was conducted on the RAW 264.7 cell line,treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h.In both in vivo and in vitro settings,quantification of inflammation factor levels was conducted using western blotting,real-time qPCR and ELISA.RESULTS In db/db mice,administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis.Notably,we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin,along with a decrease in expressions of inflammatory cytokine-related factors.Furthermore,myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha,interleukin-6,and interluekin-1βinduced by high glucose in RAW 264.7 cells.Additionally,myricetin modulated the M1-type polarization of the RAW 264.7 cells.Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin.The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.CONCLUSION This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.展开更多
This study examined the role of PI3K/Akt pathway in radiosensitization of DNA damage of cervical carcinoma cells.The 50% inhibition concentration(IC50) of cisplatin and docetaxel in HeLa cells was detected by Mono-nuc...This study examined the role of PI3K/Akt pathway in radiosensitization of DNA damage of cervical carcinoma cells.The 50% inhibition concentration(IC50) of cisplatin and docetaxel in HeLa cells was detected by Mono-nuclear cell direct cytotoxicity assay(MTT) in vitro.HeLa cells were treated by cisplatin/docetaxel of 10 percent of IC20 alone or combined with LY294002 for 24 h,and then radiated by different doses of X-ray.The cell survival ratio was obtained by means of clone formation.One-hit multi-target model was fitted to the cell survival curve to calculate dose quasithreshold(Dq),mean lethal dose(D0),2Gy survival fraction(SF2) and sensitization enhancement ratio(SER).The pAkt and total Akt expression was detected by Western blotting and DNA damage by neutro-comet electrophoresis.The HeLa cells were randomly divided into 7 groups in terms of different treatments:Control;radiation treatment(RT) group;LY294002+RT group;cisplatin+RT group;docetaxel+RT group;LY294002+cisplatin+RT group;LY294002+docetaxel+RT group.The apoptosis ratio of each group was measured by flow cytometry.The results showed that docetaxel and cisplatin significantly enhanced the phosphorylation of Akt in radiation-treated HeLa cells.The Dq,D0 and SF2 in LY294002-contained groups were lower than those in docetaxel or cisplatin+RT group.The SER in the LY294002+docetaxel+RT group was 1.35 times that of the docetaxel+RT group,and that in the LY294002+cisplatin+RT group 1.26 times that of the cisplatin+RT group.The Comet electrophoresis showed that tail distance in the LY294002+cisplatin+RT group or LY294002+docetaxel+RT group was longer than in the cisplatin+RT group or docetaxel+RT group.The apoptosis ratio in the LY294002+cisplatin+RT group or LY294002+docetaxel +RT group was higher than in the cisplatin+RT group or docetaxel+RT group.It was concluded that inhibiting PI3K/Akt pathway can increase the effect of docetaxel and cisplatin on the radiosensitivity of HeLa cells and DNA damage resulted from radiation.展开更多
Chemotherapy can significantly reduce follicle counts in ovarian tissues and damage ovarian stroma,causing endocrine disorder,reproductive dysfunction,and primary ovarian insufficiency(POI).Recent studies have suggest...Chemotherapy can significantly reduce follicle counts in ovarian tissues and damage ovarian stroma,causing endocrine disorder,reproductive dysfunction,and primary ovarian insufficiency(POI).Recent studies have suggested that extracellular vesicles(EVs)secreted from mesenchymal stem cells(MSCs)exert therapeutic effects in various degenerative diseases.In this study,transplantation of EVs from human induced pluripotent stem cell-derived MSCs(iPSC-MSC-EVs)resulted in significant restoration of ovarian follicle numbers,improved granulosa cell proliferation,and inhibition of apoptosis in chemotherapy-damaged granulosa cells,cultured ovaries,and in vivo ovaries in mice.Mechanistically,treatment with i PSC-MSC-EVs resulted in up-regulation of the integrinlinked kinase(ILK)-PI3K/AKT pathway,which is suppressed during chemotherapy,most likely through the transfer of regulatory microRNAs(miRNAs)targeting ILK pathway genes.This work provides a framework for the development of advanced therapeutics to ameliorate ovarian damage and POI in female chemotherapy patients.展开更多
Objective: Exercise, as a common non-drug intervention, is one of several lifestyle choices known to reduce the risk of cancer. Mitochondrial division has been reported to play a key role in the occurrence and transfo...Objective: Exercise, as a common non-drug intervention, is one of several lifestyle choices known to reduce the risk of cancer. Mitochondrial division has been reported to play a key role in the occurrence and transformation of hepatocellular carcinoma(HCC). This study investigated whether exercise could regulate the occurrence and development of HCC through mitosis.Methods: Bioinformatics technology was used to analyze the expression level of dynamin-related protein1(DRP1), a key protein of mitochondrial division. The effects of DRP1 and DRP1 inhibitor(mdivi-1) on the proliferation and migration of liver cancer cells BEL-7402 were observed using cell counting kit-8, plate colony formation, transwell cell migration, and scratch experiments. Enzyme-linked immunosorbent assay, Western blot and real-time polymerase chain reaction were used to detect the expression of DRP1 and its downstream phosphoinositide 3-kinase(PI3 K)/protein kinase B(AKT) pathway. A treadmill exercise intervention was tested in a nude mouse human liver cancer subcutaneous tumor model expressing different levels of DRP1. The size and weight of subcutaneous tumors in mice were detected before and after exercise.Results: The expression of DRP1 in liver cancer tissues was significantly upregulated compared with normal liver tissues(P<0.001). The proliferation rate and the migration of BEL-7402 cells in the DRP1 overexpression group were higher than that in the control group. The mdivi-1 group showed an inhibitory effect on the proliferation and migration of BEL-7402 cells at 50 lmol/L. Aerobic exercise was able to inhibit the expression of DRP1 and decrease the size and weight of subcutaneous tumors. Moreover,the expression of phosphorylated PI3 K(p-PI3 K) and phosphorylated AKT(p-AKT) decreased in the exercise group. However, exercise could not change p-PI3 K and p-AKT levels after knocking down DRP1 or using mdivi-1 on subcutaneous tumor.Conclusion: Aerobic exercise can suppress the development of tumors partially by regulating DRP1 through PI3 K/AKT pathway.展开更多
Objective This study investigated the impact of occupational mercury(Hg) exposure on human gene transcription and expression, and its potential biological mechanisms.Methods Differentially expressed genes related to H...Objective This study investigated the impact of occupational mercury(Hg) exposure on human gene transcription and expression, and its potential biological mechanisms.Methods Differentially expressed genes related to Hg exposure were identified and validated using gene expression microarray analysis and extended validation. Hg-exposed cell models and PTEN lowexpression models were established in vitro using 293T cells. PTEN gene expression was assessed using qRT-PCR, and Western blotting was used to measure PTEN, AKT, and PI3K protein levels. IL-6 expression was determined by ELISA.Results Combined findings from gene expression microarray analysis, bioinformatics, and population expansion validation indicated significant downregulation of the PTEN gene in the high-concentration Hg exposure group. In the Hg-exposed cell model(25 and 10 μmol/L), a significant decrease in PTEN expression was observed, accompanied by a significant increase in PI3K, AKT, and IL-6 expression.Similarly, a low-expression cell model demonstrated that PTEN gene knockdown led to a significant decrease in PTEN protein expression and a substantial increase in PI3K, AKT, and IL-6 levels.Conclusion This is the first study to report that Hg exposure downregulates the PTEN gene, activates the PI3K/AKT regulatory pathway, and increases the expression of inflammatory factors, ultimately resulting in kidney inflammation.展开更多
BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most prevalent malignancies that seriously threaten people’s health worldwide.DEAD-box helicase 51(DDX51)is a member of the DEAD-box(DDX)RNA helicase f...BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most prevalent malignancies that seriously threaten people’s health worldwide.DEAD-box helicase 51(DDX51)is a member of the DEAD-box(DDX)RNA helicase family,and drives or inhibits tumor progression in multiple cancer types.AIM To determine whether DDX51 affects the biological behavior of ESCC.METHODS The expression of DDX51 in ESCC tumor tissues and adjacent normal tissues was detected by Immunohistochemistry(IHC)analyses and quantitative PCR(qPCR).We knocked down DDX51 in ESCC cell lines by using a small interfering RNA(siRNA)transfection.The proliferation,apoptosis,and mobility of DDX51 siRNAtransfected cells were detected.The effect of DDX51 on the phosphoinositide 3-kinase(PI3K)/AKT pathway was investigated by western blot analysis.A mouse xenograft model was established to investigate the effects of DDX51 knockdown on ESCC tumor growth.RESULTS DDX51 exhibited high expression in ESCC tissues compared with normal tissues and represented a poor prognosis in patients with ESCC.Knockdown of DDX51 induced inhibition of ESCC cell proliferation and promoted apoptosis.Moreover,DDX51 siRNA-expressing cells also exhibited lower migration and invasion rates.Investigations into the underlying mechanisms suggested that DDX51 knock down induced inactivation of the PI3K/AKT pathway,including decreased phosphorylation levels of phosphate and tensin homolog,PI3K,AKT,and mammalian target of rapamycin.Rescue experiments demonstrated that the AKT activator insulin-like growth factor 1 could reverse the inhibitory effects of DDX51 on ESCC malignant development.Finally,we injected DDX51 siRNA-transfected TE-1 cells into an animal model,which resulted in slower tumor growth.CONCLUSION Our study suggests for the first time that DDX51 promotes cancer cell proliferation by regulating the PI3K/AKT pathway;thus,DDX51 might be a therapeutic target for ESCC.展开更多
This study examined the role of EMP-1 in tumorigenesis of non-small cell lung carcinoma (NSCLC) and the possible mechanism. Specimens were collected from 28 patients with benign lung diseases and 28 with NSCLC, and im...This study examined the role of EMP-1 in tumorigenesis of non-small cell lung carcinoma (NSCLC) and the possible mechanism. Specimens were collected from 28 patients with benign lung diseases and 28 with NSCLC, and immunohis to chemically detected to evaluate the correlation of EMP-1 expression to the clinical features of NSCLC. Recombinant adenovirus was constructed to over-express EMP-1 and then infect PC9 cells. Cell proliferation was measured by Ki67 staining. Western blotting was performed to examine the effect of EMP-1 on the PI3K/AKT signaling. Moreover, tumor xeno-grafts were established by subcutaneous injection of PC9 cell suspension (about 5×107/mL in 100 μL of PBS) into the right hind limbs of athymic nude mice. The results showed EMP-1 was significantly up-regulated in NSCLC patients as compared with those with benign lung diseases. Over-expression of EMP-1 promoted proliferation of PC9 cells, which coincided with the activation of the PI3K/AKT pathway. EMP-1 promoted the growth of xenografts of PC9 cells in athymic nude mice. It was concluded that EMP-1 expression may contribute to the development and progress of NSCLC by activating PI3K/AKT pathway.展开更多
Lambda-cyhalothrin（LCT）,one of the type II pyrethroids,has been widely used throughout the world.The estrogenic effect of LCT to increase cell proliferation has been well established.However,whether the estrogenic e...Lambda-cyhalothrin（LCT）,one of the type II pyrethroids,has been widely used throughout the world.The estrogenic effect of LCT to increase cell proliferation has been well established.However,whether the estrogenic effect of LCT will influence neurodevelopment has not been investigated.In addition,17β-Estradiol（E2）plays a crucial role in neurodevelopment and induces an increase in synaptic proteins.The post-synaptic density 95（PSD95）protein,which is involved in the development of the structure and function of new spines and localized with estrogen receptor α（ERα）at the post-synaptic density（PSD）,was detected in our study by using hippocampal neuron cell line HT22.We found that LCT up-regulated PSD95 and ERα expression,estrogen receptor（ER）antagonist ICI182,780 and phosphatidylinositol-4;5-bisphosphate 3-kinase（PI3K）inhibitor LY294,002 blocked this effect.In addition,LCT disrupted the promotion effect of E2 on PSD95.To investigate whether the observed changes are caused by ERα-dependent signaling activation,we next detected the effects of LCT on the ERα-mediated PI3K-Protein kinase B（PKB/Akt）-eukaryotic initiation factor（e IF）4E-binding protein 1（4E-BP1）pathway.There existed an activation of Akt and the downstream factor 4E-BP1 after LCT treatment.In addition,LCT could disrupt the activation effect of E2 on the Akt pathway.However,no changes in c AMP response element-binding protein（CREB）activation and PSD95 messenger ribonucleic acid（m RNA）were observed.Our findings demonstrated that LCT could increase the PSD95 protein level via the ERα-dependent Akt pathway,and LCT might disrupt the up-regulation effect of E2 on PSD95 protein expression via this signaling pathway.展开更多
BACKGROUND Helicobacter pylori(H.pylori)colonizes the human gastric mucosa and is implicated in the development of gastric cancer(GC).The tumor microenvironment is characterized by hypoxia,where hypoxia-inducible fact...BACKGROUND Helicobacter pylori(H.pylori)colonizes the human gastric mucosa and is implicated in the development of gastric cancer(GC).The tumor microenvironment is characterized by hypoxia,where hypoxia-inducible factor-1α(HIF-1α)plays a key role as a transcription factor,but the mechanisms underlying H.pylori-induced HIF-1αexpression and carcinogenesis remain unclear.AIM To explore the underlying mechanism of H.pylori-induced HIF-1αexpression in promoting the malignant biological behavior of gastric epithelial cells(GES-1).METHODS The study was conducted with human GES-1 cells in vitro.Relative protein levels of methyltransferase-like protein 14(METTL14),HIF-1α,main proteins of the PI3K/AKT pathway,epithelial-mesenchymal transition(EMT)biomarkers,and invasion indicators were detected by Western blot.Relative mRNA levels of METTL14 and HIF-1αwere detected by quantitative reverse transcription-polymerase chain reaction.mRNA stability was evaluated using actinomycin D,and the interaction between METTL14 and HIF-1αwas confirmed by immunofluorescence staining.Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay,respectively.RESULTS H.pylori promoted HIF-1αexpression and activated the PI3K/AKT pathway.Notably,METTL14 was downregulated in H.pylori-infected gastric mucosal epithelial cells and positively regulated HIF-1αexpression.Functional experiments showed that the overexpression of HIF-1αor knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway,thereby driving a series of malignant transformation,such as EMT and cell proliferation,migration,and invasion.By contrast,the knockdown of HIF-1αor overexpression of METTL14 had an opposite effect.CONCLUSION H.pylori-induced underexpression of METTL14 promotes the translation of HIF-1αand accelerates tumor progression by activating the PI3K/AKT pathway.These results provide novel insights into the carcinogenesis of GC.展开更多
Objectives:Thyroid cancer(THCA)is the most common malignant tumor in endocrine system and the incidence has been increasing worldwide.And the number of patients dying from THCA has also gradually risen because the inc...Objectives:Thyroid cancer(THCA)is the most common malignant tumor in endocrine system and the incidence has been increasing worldwide.And the number of patients dying from THCA has also gradually risen because the incidence continues to increase,so the mechanisms related to effective targets is necessary to improve the survival.This study was to preliminarily investigate the effects of the COL4A2 gene on the regulation of thyroid cancer(THCA)cell proliferation and the associated pathways.Methods:Bioinformatics analysis revealed that COL4A2 was closely associated with cancer development.COL4A2 expression in THCA tissues was analyzed using immunohistochemistry,and survival information was determined via Kaplan-Meier curves.The expression of COL4A2 and AKT pathway-related genes were analyzed using qPCR and western blot analyses.Colony formation as well as CCK-8 assays exhibited the cell proliferation level and cell activity,respectively.Downstream of COL4A2 was identified by Gene set enrichment analysis(GSEA).The effects of the COL4A2 and AKT pathways on THCA tumor growth in vivo were determined using a mouse model.Results:Bioinformatics analysis exhibited that COL4A2 plays a significant role in cancer and that the AKT pathway is downstream of COL4A2.THCA patients with high COL4A2 expression had shorter recurrence-free survival.Upregulation of COL4A2 gene expression in 2 THCA cell lines promoted tumor cell growth and activity.The use of AKT pathway blockers also restrained the growth and activity of the 2 THCA cell lines.The use of AKT pathway blockers reduced tumor volume and mass and prolonged mouse survival.Conclusions:COL4A2 can promote the growth as well as development of THCA through the AKT pathway and COL4A2 could be used as a target for THCA.展开更多
OBJECTIVE To determine the role of the basic helix-loop-helix(b HLH)transcription factor,differentiated embryonic chondrocyte gene 1(DEC1),in the apoptosis induced by 1-methyl-4-phenylpyridiniumion(MPP+)in SH-SY5Y cel...OBJECTIVE To determine the role of the basic helix-loop-helix(b HLH)transcription factor,differentiated embryonic chondrocyte gene 1(DEC1),in the apoptosis induced by 1-methyl-4-phenylpyridiniumion(MPP+)in SH-SY5Y cells.METHODS SH-SY5Y cells were treated with different concentrations of MPP+for 24or 48 h.The cell inhibition and apoptosis were measured by MTT and DAPI staining.DEC1,the apoptosis-related proteins and PI3K/Akt/GSK3β/β-catenin signaling were determined by Western blotting.The expression of DEC1was regulated by overexpression and sh RNA.RESULTS MPP+induces apoptosis along with decreasing of DEC1expression in SH-SY5Y cells.Overexpression or knockdown of DEC1 can alleviate or enhance the cell inhibition induced by MPP+.And overexpression of DEC1 can alleviate the increased cleaved caspase 3/caspase 3 but not alleviate Bax/Bcl-2 induced by MPP+.Meanwhile,MPP+represses PI3Kp110α,p-Akt/Akt,p-GSK-3β/GSK-3βandβ-catenin expression,which is accompanied by decreasing DEC1 expressions.It is confirmed that the activator or inhibitor of PI3K/Akt/GSK-3βpathway can alleviate or enhance the repression of PI3K/Akt/GSK3β/β-catenin signaling cascade induced by MPP+.Further study,we find that overexpression of DEC1 alone can increase PI3Kp110α,p-Akt/Akt,p-GSK-3β/GSK-3β,andβ-catenin expression.More importantly,overexpression of DEC1 significantly alleviates the decreased levels of PI3Kp110α,p-Akt/Akt,p-GSK-3β/GSK-3β,andβ-catenin induced by MPP+.CONCLUSION DEC1 provides neuroprotection from apoptosis induced by MPP+through PI3K/Akt pathway in SH-SY5Y cells.Promisingly,DEC1 is a candidate gene that may provide a novel therapeutic approach for the treatment of Parkinson disease.展开更多
There is evidence to suggest that follicle-stimulating hormone （FSH） can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor （VEGF） expression in cancer cells, alt...There is evidence to suggest that follicle-stimulating hormone （FSH） can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor （VEGF） expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose- and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxlainducible factor-1 （HIF-1α）. Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase （PI3K）/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT （pAKT） protein staining than did benign ovarian cystadenoma samples （p 〈 0.01）. The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursulug effective treatment against this disease.展开更多
Objective:The expression of pyroptosis related factors GSDMD,Caspase-1,NLRP3,IL-1β,IL-18 and PI3K/AKT signaling pathways in ovarian endometriosis was investigated and their correlations analyzed.Methods:A total of 50...Objective:The expression of pyroptosis related factors GSDMD,Caspase-1,NLRP3,IL-1β,IL-18 and PI3K/AKT signaling pathways in ovarian endometriosis was investigated and their correlations analyzed.Methods:A total of 50 patients with endometriosis who underwent ovarian cystectomy in the Department of Gynecology,the First Affiliated Hospital of Bengbu Medical College from January 2022 to January 2023 were enrolled as endometriosis group.In addition,55 patients with normal endometrial tissue who underwent hysteroscopic surgery in the hospital during the same period were selected as the control group,and patients with endometriosis were excluded during the operation.RT-qPCR,Western Blot was used to detect the expression of pyroptosis-related factor and PI3K/AKT signaling pathway mRAN,protein in the above tissues,and the correlation between the expression of the two was analyzed by Pearson correlation test.Results:The expression of pyroptosis-related factors and mRAN of PI3K/AKT signaling pathway in ectopic ovarian cyst tissues was significantly higher than that in the control group,and the difference was statistically significant(P<0.05).Pearson correlation analysis showed that pyroptosis-related factors in ectopic ovarian cysts were positively correlated with the mRNA expression levels of PI3K/AKT signaling pathway(P<0.05).Conclusion:The pyroptosis correlation factors GSDMD,Caspase-1,NLRP3,IL-1β,IL-18 and PI3K/AKT signaling pathways are highly expressed in ovarian endometriosis,and the pyroptosis-related factors are positively correlated with the expression of PI3K/AKT signaling pathway,suggesting that the regulation of endometriosis by activating the PI3K/AKT signaling pathway is likely to be achieved by activating the PI3K/AKT signaling pathway.展开更多
Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and publ...Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.展开更多
Background Gliomas represent the most prevalent primary neoplasm in the adult central nervous system.Despite advancements in therapeutic modalities,such as surgical intervention,radiotherapy,chemotherapy,and tumor tre...Background Gliomas represent the most prevalent primary neoplasm in the adult central nervous system.Despite advancements in therapeutic modalities,such as surgical intervention,radiotherapy,chemotherapy,and tumor treatment,the 5-year survival rate of glioma patients remains low.Therefore,there is an urgent need to develop additional treatment methods.Recent studies have suggested that FAM111B is involved in DNA repair,cell cycle regulation,and apoptosis.FAM111B mutations and overexpression are related to cancer.Methods We found that FAM111B was significantly overexpressed in glioma tissues compared to the adjacent tissues by analyzing data from the TCGA_GBM&LGG and CGGA databases.Moreover,overexpression of FAM111B was associated with shorter overall survival,and disease-specific survival and tended to increase with disease stage progression.Cellular experiments confirmed these results.These results suggest that overexpression of FAM111B promotes the proliferation,migration,and invasion of glioma cells,whereas the knockdown of FAM111B inhibits these activities.We also found that FAM111B regulated glioma cell proliferation,migration,and invasion via the PI3K/AKT pathway.Results FAM111B is capable of enhancing the proliferation,invasion,and migration capabilities of glioma cells and promotes the malignant progression of glioma via the PI3K/Akt signaling pathway.Conclusions This is the first study to demonstrate that FAM111B plays a crucial role in the proliferation,migration,and invasion of glioma cells.The malignant phenotype of FAM111B has also been shown to be closely associated with the PI3K/AKT pathway.FAM111B may be a predictive biomarker and a potential therapeutic target for gliomas.展开更多
SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer(CRC)progression,and it is consistently overexpressed in CRC.It facilitates CRC oncogenesis by mediating downstream signaling ...SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer(CRC)progression,and it is consistently overexpressed in CRC.It facilitates CRC oncogenesis by mediating downstream signaling cascades of receptor tyrosine kinases,including the RAS/ERK,JAK/STAT,and PI3K/AKT pathways,which are clinically associated with poor prognosis.Furthermore,SHP2 orchestrates immunosuppressive signaling networks by impairing cytotoxic T cell infiltration and changing the phenotype of tumor-associated macrophages within the tumor microenvironment(TME).Targeting SHP2 represents a dual therapeutic strategy in CRC:It concurrently regulates RTK signaling and reprograms the immunosuppressive TME.SHP2 inhibitors,administered both as monotherapy and in combination regimens,have advanced into clinical trial phases.Consequently,SHP2 serves as both a molecular target for precision oncology and an immunomodulatory node,positioning it as a high-priority candidate for CRC treatment.展开更多
BACKGROUND Type 2 diabetes mellitus(T2DM)is associated with significant metabolic and renal complications,including diabetic nephropathy(DN).AIM To investigate the role of ribonucleotide reductase regulatory subunit M...BACKGROUND Type 2 diabetes mellitus(T2DM)is associated with significant metabolic and renal complications,including diabetic nephropathy(DN).AIM To investigate the role of ribonucleotide reductase regulatory subunit M2(RRM2)in T2DM and its potential involvement in renal injury through oxidative stress,apoptosis,and ferroptosis.METHODS A cross-sectional study was conducted,comprising 194 patients with T2DM and 120 healthy controls at our hospital between January 2022 and December 2023.The data were analyzed to ascertain the correlation between RRM2 levels and DN onset in patients with T2DM.The apoptosis rate,reactive oxygen species(ROS)levels,oxidative stress,cystine uptake,and ferrous ion(Fe2+)levels were quantified using the HK-2 cell lysates.Reverse transcription quantitative PCR and western blotting were used to assess mRNA and protein expression,respectively.RESULTS Serum RRM2 levels were significantly higher in T2DM patients than in controls(P<0.05)but declined in the macroalbuminuria subgroup.Receiver operating characteristic analysis identified 30 pg/mL as the optimal cut-off(area under the curve=0.958;sensitivity=86%;specificity=95%).RRM2 was negatively correlated with age,diabetes duration,systolic blood pressure,fasting blood glucose,glycosylated hemoglobin,serum creatinine,neutrophil gelatinase-associated lipocalin,kidney injury molecule-1,and malondialdehyde,and positively correlated with estimated glomerular filtration rate,glutathione(GSH),solute carrier family 7 member 11(SLC7A11),and GSH peroxidase 4(GPX4).Logistic regression confirmed RRM2 as an independent protective factor against DN[odds ratio(OR)=0.820,95%confidence interval(95%CI)=0.712-0.945,P=0.006].In vitro,RRM2 overexpression enhanced HK-2 cell proliferation,activated PI3K/Akt signaling,and reduced apoptosis,ROS,oxidative stress,and ferroptosis,accompanied by the restoration of GSH,Nrf2,SLC7A11,and GPX4.These protective effects were abolished by PI3K/Akt inhibition,highlighting RRM2’s renoprotective,pathway-dependent role.CONCLUSION These findings suggest that RRM2 plays a crucial protective role against diabetic renal injury by mitigating oxidative stress,apoptosis,and ferroptosis via PI3K/Akt activation.Serum RRM2 may serve as a novel biomarker for early DN detection,and therapeutic strategies targeting RRM2 may offer potential benefits in preventing diabetic kidney disease progression.展开更多
AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)...AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway in retinal pigment epithelial(RPE)cells in humans subjected to photodamage.METHODS:Human adult RPE cell line-19(ARPE-19)was cultured in vitro and randomly divided into control,damage,overexpression,negative,and PI3K/Akt blocker groups to establish a photodamage model of ARPE-19 cells.The models were subjected to 24h of light exposure,after which the corresponding indices were detected.The cell counting kit-8 assay quantified cell viability,while flow cytometry determined apoptosis rates.The miRNA-21 mimics and miRNA mimic NC were transfected into ARPE-19 cells using a transient transfection technique.Quantitative reverse transcription polymerase chain reaction(SYBR Green)and Western blotting analyzed expression levels of miRNA-21-5p,PTEN,p-PI3K/PI3K,p-mTOR/mTOR,and p-Akt/Akt.Statistical analyses comprised one-way analysis of variance and the Student-Newman-Keuls test for multiple group comparisons.RESULTS:The photodamage group demonstrated reduced cell survival rates than the control group(P<0.01).The overexpression group exhibited higher cell survival rates than the injury group(P<0.01).The negative group showed no difference in viability(P>0.05).The PI3K/Akt blocker group demonstrated lower cell viability,compared with the overexpression group(P<0.01).CONCLUSION:miRNA-21-5p significantly increases ARPE-19 cell survival after photodamage and inhibits lightinduced ARPE-19 cell apoptosis,suggesting that it may play a protective role in RPE by activating the PI3K/Akt/mTOR pathway while downregulating PTEN expression.展开更多
文摘BACKGROUND Gastric cancer(GC)is a widespread malignancy and associated with high rates of morbidity and mortality worldwide.AIM To examine the functional role of long non-coding RNAs small nucleolar RNA host gene 5(SNHG5)and its regulation of miR-92a-3p and B-cell translocation gene 2(BTG2)in GC progression.METHODS Quantitative reverse transcription PCR and western blot analysis determined the expression of SNHG5,miR-92a-3p,and BTG2 in GC and adjacent non-neoplastic mucosa.Dual-luciferase assays demonstrated interactions of SNHG5 with miR-92a-3p and BTG2.AGS cells were transfected with SNHG5 overexpression and miR-92a-3p knockdown models.Various assays,including CCK-8,colony formation,scratch wound healing,and Transwell assays,were used to determine cell proliferation and migration.An experimental model of a xenograft mouse was used to determine in vivo tumor growth.At the same time histological changes were evaluated by hematoxylin and eosin staining,with western blot analysis used to evaluate signaling pathway protein expression.RESULTS BTG2 and SNHG5 were downregulated in GC tissues,and miR-92a-3p was upregulated.Overexpression of SNHG5 or knockdown of miR-92a-3p reduced GC cell proliferation and migration,and increased BTG2 expression while decreasing PI3K/AKT signaling activity.The dual-luciferase assays demonstrated direct binding of miR-92a-3p to SNHG5 and BTG2.Tumor volume and weight were significantly reduced in mice transplanted with AGS cells treated with miR-92a-3p inhibitor or SNHG5 overexpression compared with control AGS cells.Hematoxylin and eosin staining revealed that treated tumors exhibited degenerative characteristics,including irregular morphology and nucleolysis.CONCLUSION LncRNA SNHG5 inhibited GC cell growth and migration by modulating the PI3K/AKT pathway via the miR-92a-3p/BTG2 axis.
文摘BACKGROUND Pancreatic ductal adenocarcinoma(PDAC) is one of the deadliest solid tumors. Identification of diagnostic and therapeutic biomarkers for PDAC is urgently needed. Transducin(β)-like 1 X-linked receptor 1(TBL1 XR1) has been linked to the progression of various human cancers. Nevertheless, the function and role of TBL1 XR1 in pancreatic cancers are unclear.AIM To elucidate the function and potential mechanism of TBL1 XR1 in the development of PDAC.METHODS Ninety patients with histologically-confirmed PDAC were included in this study. PDAC tumor samples and cell lines were used to determine the expression of TBL1 XR1. CCK-8 assays and colony formation assays were carried out to assess PDAC cell viability. Flow cytometry was performed to measure the changes in the cell cycle and cell apoptosis. Changes in related protein expression were measured by western blot analysis. Animal analysis was conducted to confirm the impact of TBL1 XR1 in vivo.RESULTS Patients with TBL1 XR1-positive tumors had worse overall survival than those with TBL1 XR1-negative tumors. Moreover, we found that TBL1 XR1 strongly promoted PDAC cell proliferation and inhibited PDAC cell apoptosis. Moreover, knockdown of TBL1 XR1 induced G0/G1 phase arrest. In vivo animal studies confirmed that TBL1 XR1 accelerated tumor cell growth. The results of western blot analysis showed that TBL1 XR1 might play a key role in regulating PDAC cell proliferation and apoptosis via the PI3 K/AKT pathway.CONCLUSION TBL1 XR1 promoted PDAC cell progression and might be an effective diagnostic and therapeutic marker for pancreatic cancer.
基金Supported by National Natural Science Foundation of China,No.82205025,No.82374355 and No.82174293Subject of Jiangsu Province Hospital of Chinese Medicine,No.Y21023Forth Batch of Construction Program for Inheritance Office of Jiangsu Province Famous TCM Experts,No.[2021]7.
文摘BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue.Never-theless,the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.AIM To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.METHODS Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk.Subsequently,blood and urine indexes were assessed,along with examination of renal tissue pathology.Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin,periodic acid–Schiff,Masson’s trichrome,and Sirius-red.Additionally,high-glucose culturing was conducted on the RAW 264.7 cell line,treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h.In both in vivo and in vitro settings,quantification of inflammation factor levels was conducted using western blotting,real-time qPCR and ELISA.RESULTS In db/db mice,administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis.Notably,we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin,along with a decrease in expressions of inflammatory cytokine-related factors.Furthermore,myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha,interleukin-6,and interluekin-1βinduced by high glucose in RAW 264.7 cells.Additionally,myricetin modulated the M1-type polarization of the RAW 264.7 cells.Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin.The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.CONCLUSION This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.
基金supported by grants from the Hubei Province Natural Sciences Foundation (No.2008cdb133)Science Foundation for The Youth Scholars of Ministry of Education of China (No.200804871034)
文摘This study examined the role of PI3K/Akt pathway in radiosensitization of DNA damage of cervical carcinoma cells.The 50% inhibition concentration(IC50) of cisplatin and docetaxel in HeLa cells was detected by Mono-nuclear cell direct cytotoxicity assay(MTT) in vitro.HeLa cells were treated by cisplatin/docetaxel of 10 percent of IC20 alone or combined with LY294002 for 24 h,and then radiated by different doses of X-ray.The cell survival ratio was obtained by means of clone formation.One-hit multi-target model was fitted to the cell survival curve to calculate dose quasithreshold(Dq),mean lethal dose(D0),2Gy survival fraction(SF2) and sensitization enhancement ratio(SER).The pAkt and total Akt expression was detected by Western blotting and DNA damage by neutro-comet electrophoresis.The HeLa cells were randomly divided into 7 groups in terms of different treatments:Control;radiation treatment(RT) group;LY294002+RT group;cisplatin+RT group;docetaxel+RT group;LY294002+cisplatin+RT group;LY294002+docetaxel+RT group.The apoptosis ratio of each group was measured by flow cytometry.The results showed that docetaxel and cisplatin significantly enhanced the phosphorylation of Akt in radiation-treated HeLa cells.The Dq,D0 and SF2 in LY294002-contained groups were lower than those in docetaxel or cisplatin+RT group.The SER in the LY294002+docetaxel+RT group was 1.35 times that of the docetaxel+RT group,and that in the LY294002+cisplatin+RT group 1.26 times that of the cisplatin+RT group.The Comet electrophoresis showed that tail distance in the LY294002+cisplatin+RT group or LY294002+docetaxel+RT group was longer than in the cisplatin+RT group or docetaxel+RT group.The apoptosis ratio in the LY294002+cisplatin+RT group or LY294002+docetaxel +RT group was higher than in the cisplatin+RT group or docetaxel+RT group.It was concluded that inhibiting PI3K/Akt pathway can increase the effect of docetaxel and cisplatin on the radiosensitivity of HeLa cells and DNA damage resulted from radiation.
基金supported by the CUHK VC Discretionary Fund provided to the Hong Kong Branch of Chinese Academy of Science Center for Excellence in Animal Evolution and Genetics(Acc 8601011)the National Key R&D Program(2021YFC2700500)A-Smart Group to Shandong University and SDIVF R&D Centre Hong Kong,and Research Grants Council General Research Fund(Hong Kong Special Administrative Region Government)(14103418)。
文摘Chemotherapy can significantly reduce follicle counts in ovarian tissues and damage ovarian stroma,causing endocrine disorder,reproductive dysfunction,and primary ovarian insufficiency(POI).Recent studies have suggested that extracellular vesicles(EVs)secreted from mesenchymal stem cells(MSCs)exert therapeutic effects in various degenerative diseases.In this study,transplantation of EVs from human induced pluripotent stem cell-derived MSCs(iPSC-MSC-EVs)resulted in significant restoration of ovarian follicle numbers,improved granulosa cell proliferation,and inhibition of apoptosis in chemotherapy-damaged granulosa cells,cultured ovaries,and in vivo ovaries in mice.Mechanistically,treatment with i PSC-MSC-EVs resulted in up-regulation of the integrinlinked kinase(ILK)-PI3K/AKT pathway,which is suppressed during chemotherapy,most likely through the transfer of regulatory microRNAs(miRNAs)targeting ILK pathway genes.This work provides a framework for the development of advanced therapeutics to ameliorate ovarian damage and POI in female chemotherapy patients.
基金supported by National Natural Science Foundation of China (No. 81503632)Youth Startup Fund of the First Affiliated Hospital of Naval Medical University (No. 2019QNB05)。
文摘Objective: Exercise, as a common non-drug intervention, is one of several lifestyle choices known to reduce the risk of cancer. Mitochondrial division has been reported to play a key role in the occurrence and transformation of hepatocellular carcinoma(HCC). This study investigated whether exercise could regulate the occurrence and development of HCC through mitosis.Methods: Bioinformatics technology was used to analyze the expression level of dynamin-related protein1(DRP1), a key protein of mitochondrial division. The effects of DRP1 and DRP1 inhibitor(mdivi-1) on the proliferation and migration of liver cancer cells BEL-7402 were observed using cell counting kit-8, plate colony formation, transwell cell migration, and scratch experiments. Enzyme-linked immunosorbent assay, Western blot and real-time polymerase chain reaction were used to detect the expression of DRP1 and its downstream phosphoinositide 3-kinase(PI3 K)/protein kinase B(AKT) pathway. A treadmill exercise intervention was tested in a nude mouse human liver cancer subcutaneous tumor model expressing different levels of DRP1. The size and weight of subcutaneous tumors in mice were detected before and after exercise.Results: The expression of DRP1 in liver cancer tissues was significantly upregulated compared with normal liver tissues(P<0.001). The proliferation rate and the migration of BEL-7402 cells in the DRP1 overexpression group were higher than that in the control group. The mdivi-1 group showed an inhibitory effect on the proliferation and migration of BEL-7402 cells at 50 lmol/L. Aerobic exercise was able to inhibit the expression of DRP1 and decrease the size and weight of subcutaneous tumors. Moreover,the expression of phosphorylated PI3 K(p-PI3 K) and phosphorylated AKT(p-AKT) decreased in the exercise group. However, exercise could not change p-PI3 K and p-AKT levels after knocking down DRP1 or using mdivi-1 on subcutaneous tumor.Conclusion: Aerobic exercise can suppress the development of tumors partially by regulating DRP1 through PI3 K/AKT pathway.
基金supported by the Jiangsu Province’s Outstanding Medical Academic Leader Program [CXTDA2017029]the Jiangsu Provincial Key Medical Discipline [ZDXK202249].
文摘Objective This study investigated the impact of occupational mercury(Hg) exposure on human gene transcription and expression, and its potential biological mechanisms.Methods Differentially expressed genes related to Hg exposure were identified and validated using gene expression microarray analysis and extended validation. Hg-exposed cell models and PTEN lowexpression models were established in vitro using 293T cells. PTEN gene expression was assessed using qRT-PCR, and Western blotting was used to measure PTEN, AKT, and PI3K protein levels. IL-6 expression was determined by ELISA.Results Combined findings from gene expression microarray analysis, bioinformatics, and population expansion validation indicated significant downregulation of the PTEN gene in the high-concentration Hg exposure group. In the Hg-exposed cell model(25 and 10 μmol/L), a significant decrease in PTEN expression was observed, accompanied by a significant increase in PI3K, AKT, and IL-6 expression.Similarly, a low-expression cell model demonstrated that PTEN gene knockdown led to a significant decrease in PTEN protein expression and a substantial increase in PI3K, AKT, and IL-6 levels.Conclusion This is the first study to report that Hg exposure downregulates the PTEN gene, activates the PI3K/AKT regulatory pathway, and increases the expression of inflammatory factors, ultimately resulting in kidney inflammation.
基金Supported by the Natural Science Foundation of Shandong Province,No.ZR2020QH194.
文摘BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most prevalent malignancies that seriously threaten people’s health worldwide.DEAD-box helicase 51(DDX51)is a member of the DEAD-box(DDX)RNA helicase family,and drives or inhibits tumor progression in multiple cancer types.AIM To determine whether DDX51 affects the biological behavior of ESCC.METHODS The expression of DDX51 in ESCC tumor tissues and adjacent normal tissues was detected by Immunohistochemistry(IHC)analyses and quantitative PCR(qPCR).We knocked down DDX51 in ESCC cell lines by using a small interfering RNA(siRNA)transfection.The proliferation,apoptosis,and mobility of DDX51 siRNAtransfected cells were detected.The effect of DDX51 on the phosphoinositide 3-kinase(PI3K)/AKT pathway was investigated by western blot analysis.A mouse xenograft model was established to investigate the effects of DDX51 knockdown on ESCC tumor growth.RESULTS DDX51 exhibited high expression in ESCC tissues compared with normal tissues and represented a poor prognosis in patients with ESCC.Knockdown of DDX51 induced inhibition of ESCC cell proliferation and promoted apoptosis.Moreover,DDX51 siRNA-expressing cells also exhibited lower migration and invasion rates.Investigations into the underlying mechanisms suggested that DDX51 knock down induced inactivation of the PI3K/AKT pathway,including decreased phosphorylation levels of phosphate and tensin homolog,PI3K,AKT,and mammalian target of rapamycin.Rescue experiments demonstrated that the AKT activator insulin-like growth factor 1 could reverse the inhibitory effects of DDX51 on ESCC malignant development.Finally,we injected DDX51 siRNA-transfected TE-1 cells into an animal model,which resulted in slower tumor growth.CONCLUSION Our study suggests for the first time that DDX51 promotes cancer cell proliferation by regulating the PI3K/AKT pathway;thus,DDX51 might be a therapeutic target for ESCC.
基金supported by grants from the National Natural Science Foundation of China (Nos.81072431,30872472,30973496 and 30800569)the Innovative Foundation of Huazhong University of Science and Technology (No.2010MS027)+1 种基金the Foundation of "973" Program (No.2009CB521802)by Special Fund for Central University Basic Scientific Research (Nos.2011JC062,2011JC063)
文摘This study examined the role of EMP-1 in tumorigenesis of non-small cell lung carcinoma (NSCLC) and the possible mechanism. Specimens were collected from 28 patients with benign lung diseases and 28 with NSCLC, and immunohis to chemically detected to evaluate the correlation of EMP-1 expression to the clinical features of NSCLC. Recombinant adenovirus was constructed to over-express EMP-1 and then infect PC9 cells. Cell proliferation was measured by Ki67 staining. Western blotting was performed to examine the effect of EMP-1 on the PI3K/AKT signaling. Moreover, tumor xeno-grafts were established by subcutaneous injection of PC9 cell suspension (about 5×107/mL in 100 μL of PBS) into the right hind limbs of athymic nude mice. The results showed EMP-1 was significantly up-regulated in NSCLC patients as compared with those with benign lung diseases. Over-expression of EMP-1 promoted proliferation of PC9 cells, which coincided with the activation of the PI3K/AKT pathway. EMP-1 promoted the growth of xenografts of PC9 cells in athymic nude mice. It was concluded that EMP-1 expression may contribute to the development and progress of NSCLC by activating PI3K/AKT pathway.
基金supported by the National Natural Science Foundation of China(No.H2607-30571585)
文摘Lambda-cyhalothrin（LCT）,one of the type II pyrethroids,has been widely used throughout the world.The estrogenic effect of LCT to increase cell proliferation has been well established.However,whether the estrogenic effect of LCT will influence neurodevelopment has not been investigated.In addition,17β-Estradiol（E2）plays a crucial role in neurodevelopment and induces an increase in synaptic proteins.The post-synaptic density 95（PSD95）protein,which is involved in the development of the structure and function of new spines and localized with estrogen receptor α（ERα）at the post-synaptic density（PSD）,was detected in our study by using hippocampal neuron cell line HT22.We found that LCT up-regulated PSD95 and ERα expression,estrogen receptor（ER）antagonist ICI182,780 and phosphatidylinositol-4;5-bisphosphate 3-kinase（PI3K）inhibitor LY294,002 blocked this effect.In addition,LCT disrupted the promotion effect of E2 on PSD95.To investigate whether the observed changes are caused by ERα-dependent signaling activation,we next detected the effects of LCT on the ERα-mediated PI3K-Protein kinase B（PKB/Akt）-eukaryotic initiation factor（e IF）4E-binding protein 1（4E-BP1）pathway.There existed an activation of Akt and the downstream factor 4E-BP1 after LCT treatment.In addition,LCT could disrupt the activation effect of E2 on the Akt pathway.However,no changes in c AMP response element-binding protein（CREB）activation and PSD95 messenger ribonucleic acid（m RNA）were observed.Our findings demonstrated that LCT could increase the PSD95 protein level via the ERα-dependent Akt pathway,and LCT might disrupt the up-regulation effect of E2 on PSD95 protein expression via this signaling pathway.
基金Supported by The Key Research and Development and Promotion Special Project of Henan Province,No.222102310069National Natural Science Foundation of China,No.82073618.
文摘BACKGROUND Helicobacter pylori(H.pylori)colonizes the human gastric mucosa and is implicated in the development of gastric cancer(GC).The tumor microenvironment is characterized by hypoxia,where hypoxia-inducible factor-1α(HIF-1α)plays a key role as a transcription factor,but the mechanisms underlying H.pylori-induced HIF-1αexpression and carcinogenesis remain unclear.AIM To explore the underlying mechanism of H.pylori-induced HIF-1αexpression in promoting the malignant biological behavior of gastric epithelial cells(GES-1).METHODS The study was conducted with human GES-1 cells in vitro.Relative protein levels of methyltransferase-like protein 14(METTL14),HIF-1α,main proteins of the PI3K/AKT pathway,epithelial-mesenchymal transition(EMT)biomarkers,and invasion indicators were detected by Western blot.Relative mRNA levels of METTL14 and HIF-1αwere detected by quantitative reverse transcription-polymerase chain reaction.mRNA stability was evaluated using actinomycin D,and the interaction between METTL14 and HIF-1αwas confirmed by immunofluorescence staining.Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay,respectively.RESULTS H.pylori promoted HIF-1αexpression and activated the PI3K/AKT pathway.Notably,METTL14 was downregulated in H.pylori-infected gastric mucosal epithelial cells and positively regulated HIF-1αexpression.Functional experiments showed that the overexpression of HIF-1αor knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway,thereby driving a series of malignant transformation,such as EMT and cell proliferation,migration,and invasion.By contrast,the knockdown of HIF-1αor overexpression of METTL14 had an opposite effect.CONCLUSION H.pylori-induced underexpression of METTL14 promotes the translation of HIF-1αand accelerates tumor progression by activating the PI3K/AKT pathway.These results provide novel insights into the carcinogenesis of GC.
文摘Objectives:Thyroid cancer(THCA)is the most common malignant tumor in endocrine system and the incidence has been increasing worldwide.And the number of patients dying from THCA has also gradually risen because the incidence continues to increase,so the mechanisms related to effective targets is necessary to improve the survival.This study was to preliminarily investigate the effects of the COL4A2 gene on the regulation of thyroid cancer(THCA)cell proliferation and the associated pathways.Methods:Bioinformatics analysis revealed that COL4A2 was closely associated with cancer development.COL4A2 expression in THCA tissues was analyzed using immunohistochemistry,and survival information was determined via Kaplan-Meier curves.The expression of COL4A2 and AKT pathway-related genes were analyzed using qPCR and western blot analyses.Colony formation as well as CCK-8 assays exhibited the cell proliferation level and cell activity,respectively.Downstream of COL4A2 was identified by Gene set enrichment analysis(GSEA).The effects of the COL4A2 and AKT pathways on THCA tumor growth in vivo were determined using a mouse model.Results:Bioinformatics analysis exhibited that COL4A2 plays a significant role in cancer and that the AKT pathway is downstream of COL4A2.THCA patients with high COL4A2 expression had shorter recurrence-free survival.Upregulation of COL4A2 gene expression in 2 THCA cell lines promoted tumor cell growth and activity.The use of AKT pathway blockers also restrained the growth and activity of the 2 THCA cell lines.The use of AKT pathway blockers reduced tumor volume and mass and prolonged mouse survival.Conclusions:COL4A2 can promote the growth as well as development of THCA through the AKT pathway and COL4A2 could be used as a target for THCA.
基金The project supported by National Natural Science Foundation of China(81573503,81373443)by the Major Project of Jiangsu Provincial Department of Education(13KJA310003)
文摘OBJECTIVE To determine the role of the basic helix-loop-helix(b HLH)transcription factor,differentiated embryonic chondrocyte gene 1(DEC1),in the apoptosis induced by 1-methyl-4-phenylpyridiniumion(MPP+)in SH-SY5Y cells.METHODS SH-SY5Y cells were treated with different concentrations of MPP+for 24or 48 h.The cell inhibition and apoptosis were measured by MTT and DAPI staining.DEC1,the apoptosis-related proteins and PI3K/Akt/GSK3β/β-catenin signaling were determined by Western blotting.The expression of DEC1was regulated by overexpression and sh RNA.RESULTS MPP+induces apoptosis along with decreasing of DEC1expression in SH-SY5Y cells.Overexpression or knockdown of DEC1 can alleviate or enhance the cell inhibition induced by MPP+.And overexpression of DEC1 can alleviate the increased cleaved caspase 3/caspase 3 but not alleviate Bax/Bcl-2 induced by MPP+.Meanwhile,MPP+represses PI3Kp110α,p-Akt/Akt,p-GSK-3β/GSK-3βandβ-catenin expression,which is accompanied by decreasing DEC1 expressions.It is confirmed that the activator or inhibitor of PI3K/Akt/GSK-3βpathway can alleviate or enhance the repression of PI3K/Akt/GSK3β/β-catenin signaling cascade induced by MPP+.Further study,we find that overexpression of DEC1 alone can increase PI3Kp110α,p-Akt/Akt,p-GSK-3β/GSK-3β,andβ-catenin expression.More importantly,overexpression of DEC1 significantly alleviates the decreased levels of PI3Kp110α,p-Akt/Akt,p-GSK-3β/GSK-3β,andβ-catenin induced by MPP+.CONCLUSION DEC1 provides neuroprotection from apoptosis induced by MPP+through PI3K/Akt pathway in SH-SY5Y cells.Promisingly,DEC1 is a candidate gene that may provide a novel therapeutic approach for the treatment of Parkinson disease.
文摘There is evidence to suggest that follicle-stimulating hormone （FSH） can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor （VEGF） expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose- and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxlainducible factor-1 （HIF-1α）. Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase （PI3K）/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT （pAKT） protein staining than did benign ovarian cystadenoma samples （p 〈 0.01）. The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursulug effective treatment against this disease.
基金Anhui Provincial Department of Education Natural Science Key Project (No.2022AH051428)Graduate Innovation Program of Bengbu Medical College (No.Byycx22099)。
文摘Objective:The expression of pyroptosis related factors GSDMD,Caspase-1,NLRP3,IL-1β,IL-18 and PI3K/AKT signaling pathways in ovarian endometriosis was investigated and their correlations analyzed.Methods:A total of 50 patients with endometriosis who underwent ovarian cystectomy in the Department of Gynecology,the First Affiliated Hospital of Bengbu Medical College from January 2022 to January 2023 were enrolled as endometriosis group.In addition,55 patients with normal endometrial tissue who underwent hysteroscopic surgery in the hospital during the same period were selected as the control group,and patients with endometriosis were excluded during the operation.RT-qPCR,Western Blot was used to detect the expression of pyroptosis-related factor and PI3K/AKT signaling pathway mRAN,protein in the above tissues,and the correlation between the expression of the two was analyzed by Pearson correlation test.Results:The expression of pyroptosis-related factors and mRAN of PI3K/AKT signaling pathway in ectopic ovarian cyst tissues was significantly higher than that in the control group,and the difference was statistically significant(P<0.05).Pearson correlation analysis showed that pyroptosis-related factors in ectopic ovarian cysts were positively correlated with the mRNA expression levels of PI3K/AKT signaling pathway(P<0.05).Conclusion:The pyroptosis correlation factors GSDMD,Caspase-1,NLRP3,IL-1β,IL-18 and PI3K/AKT signaling pathways are highly expressed in ovarian endometriosis,and the pyroptosis-related factors are positively correlated with the expression of PI3K/AKT signaling pathway,suggesting that the regulation of endometriosis by activating the PI3K/AKT signaling pathway is likely to be achieved by activating the PI3K/AKT signaling pathway.
基金江苏省卫生健康委员会医学科研重点项目(K2023024)789 Outstanding Talent Program of SAHNMU(789ZYRC202090147)。
文摘Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.
基金supported by grants from the Agricultural and Social Development Project of Hangzhou(grant nos.20211231Y025 and 202204B11)the General Research Project of the Zhejiang Provincial Department of Education(grant nos.851100G02309 and 851100G02312).
文摘Background Gliomas represent the most prevalent primary neoplasm in the adult central nervous system.Despite advancements in therapeutic modalities,such as surgical intervention,radiotherapy,chemotherapy,and tumor treatment,the 5-year survival rate of glioma patients remains low.Therefore,there is an urgent need to develop additional treatment methods.Recent studies have suggested that FAM111B is involved in DNA repair,cell cycle regulation,and apoptosis.FAM111B mutations and overexpression are related to cancer.Methods We found that FAM111B was significantly overexpressed in glioma tissues compared to the adjacent tissues by analyzing data from the TCGA_GBM&LGG and CGGA databases.Moreover,overexpression of FAM111B was associated with shorter overall survival,and disease-specific survival and tended to increase with disease stage progression.Cellular experiments confirmed these results.These results suggest that overexpression of FAM111B promotes the proliferation,migration,and invasion of glioma cells,whereas the knockdown of FAM111B inhibits these activities.We also found that FAM111B regulated glioma cell proliferation,migration,and invasion via the PI3K/AKT pathway.Results FAM111B is capable of enhancing the proliferation,invasion,and migration capabilities of glioma cells and promotes the malignant progression of glioma via the PI3K/Akt signaling pathway.Conclusions This is the first study to demonstrate that FAM111B plays a crucial role in the proliferation,migration,and invasion of glioma cells.The malignant phenotype of FAM111B has also been shown to be closely associated with the PI3K/AKT pathway.FAM111B may be a predictive biomarker and a potential therapeutic target for gliomas.
基金Supported by Zhejiang Provincial Natural Science Foundation for Youths,No.QN25H160012Zhejiang Medical and Health Science and Technology Plan,No.2023RC006.
文摘SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer(CRC)progression,and it is consistently overexpressed in CRC.It facilitates CRC oncogenesis by mediating downstream signaling cascades of receptor tyrosine kinases,including the RAS/ERK,JAK/STAT,and PI3K/AKT pathways,which are clinically associated with poor prognosis.Furthermore,SHP2 orchestrates immunosuppressive signaling networks by impairing cytotoxic T cell infiltration and changing the phenotype of tumor-associated macrophages within the tumor microenvironment(TME).Targeting SHP2 represents a dual therapeutic strategy in CRC:It concurrently regulates RTK signaling and reprograms the immunosuppressive TME.SHP2 inhibitors,administered both as monotherapy and in combination regimens,have advanced into clinical trial phases.Consequently,SHP2 serves as both a molecular target for precision oncology and an immunomodulatory node,positioning it as a high-priority candidate for CRC treatment.
文摘BACKGROUND Type 2 diabetes mellitus(T2DM)is associated with significant metabolic and renal complications,including diabetic nephropathy(DN).AIM To investigate the role of ribonucleotide reductase regulatory subunit M2(RRM2)in T2DM and its potential involvement in renal injury through oxidative stress,apoptosis,and ferroptosis.METHODS A cross-sectional study was conducted,comprising 194 patients with T2DM and 120 healthy controls at our hospital between January 2022 and December 2023.The data were analyzed to ascertain the correlation between RRM2 levels and DN onset in patients with T2DM.The apoptosis rate,reactive oxygen species(ROS)levels,oxidative stress,cystine uptake,and ferrous ion(Fe2+)levels were quantified using the HK-2 cell lysates.Reverse transcription quantitative PCR and western blotting were used to assess mRNA and protein expression,respectively.RESULTS Serum RRM2 levels were significantly higher in T2DM patients than in controls(P<0.05)but declined in the macroalbuminuria subgroup.Receiver operating characteristic analysis identified 30 pg/mL as the optimal cut-off(area under the curve=0.958;sensitivity=86%;specificity=95%).RRM2 was negatively correlated with age,diabetes duration,systolic blood pressure,fasting blood glucose,glycosylated hemoglobin,serum creatinine,neutrophil gelatinase-associated lipocalin,kidney injury molecule-1,and malondialdehyde,and positively correlated with estimated glomerular filtration rate,glutathione(GSH),solute carrier family 7 member 11(SLC7A11),and GSH peroxidase 4(GPX4).Logistic regression confirmed RRM2 as an independent protective factor against DN[odds ratio(OR)=0.820,95%confidence interval(95%CI)=0.712-0.945,P=0.006].In vitro,RRM2 overexpression enhanced HK-2 cell proliferation,activated PI3K/Akt signaling,and reduced apoptosis,ROS,oxidative stress,and ferroptosis,accompanied by the restoration of GSH,Nrf2,SLC7A11,and GPX4.These protective effects were abolished by PI3K/Akt inhibition,highlighting RRM2’s renoprotective,pathway-dependent role.CONCLUSION These findings suggest that RRM2 plays a crucial protective role against diabetic renal injury by mitigating oxidative stress,apoptosis,and ferroptosis via PI3K/Akt activation.Serum RRM2 may serve as a novel biomarker for early DN detection,and therapeutic strategies targeting RRM2 may offer potential benefits in preventing diabetic kidney disease progression.
文摘AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway in retinal pigment epithelial(RPE)cells in humans subjected to photodamage.METHODS:Human adult RPE cell line-19(ARPE-19)was cultured in vitro and randomly divided into control,damage,overexpression,negative,and PI3K/Akt blocker groups to establish a photodamage model of ARPE-19 cells.The models were subjected to 24h of light exposure,after which the corresponding indices were detected.The cell counting kit-8 assay quantified cell viability,while flow cytometry determined apoptosis rates.The miRNA-21 mimics and miRNA mimic NC were transfected into ARPE-19 cells using a transient transfection technique.Quantitative reverse transcription polymerase chain reaction(SYBR Green)and Western blotting analyzed expression levels of miRNA-21-5p,PTEN,p-PI3K/PI3K,p-mTOR/mTOR,and p-Akt/Akt.Statistical analyses comprised one-way analysis of variance and the Student-Newman-Keuls test for multiple group comparisons.RESULTS:The photodamage group demonstrated reduced cell survival rates than the control group(P<0.01).The overexpression group exhibited higher cell survival rates than the injury group(P<0.01).The negative group showed no difference in viability(P>0.05).The PI3K/Akt blocker group demonstrated lower cell viability,compared with the overexpression group(P<0.01).CONCLUSION:miRNA-21-5p significantly increases ARPE-19 cell survival after photodamage and inhibits lightinduced ARPE-19 cell apoptosis,suggesting that it may play a protective role in RPE by activating the PI3K/Akt/mTOR pathway while downregulating PTEN expression.
