Colorectal cancer(CRC)is one of the most deadly cancers in the world with few reliable biomarkers that have been selected into clinical guidelines for prognosis of CRC patients.In this study,mRNA microarray datasets G...Colorectal cancer(CRC)is one of the most deadly cancers in the world with few reliable biomarkers that have been selected into clinical guidelines for prognosis of CRC patients.In this study,mRNA microarray datasets GSE113513,GSE21510,GSE44076,and GSE32323 were obtained from the Gene Expression Omnibus(GEO)and analyzed with bioinformatics to identify hub genes in CRC development.Differentially expressed genes(DEGs)were analyzed using the GEO2 R tool.Gene ontology(GO)and KEGG analyses were performed through the DAVID database.STRING database and Cytoscape software were used to construct a protein-protein interaction(PPI)network and identify key modules and hub genes.Survival analyses of the DEGs were performed on GEPIA database.The Connectivity Map database was used to screen potential drugs.A total of 865 DEGs were identified,including 374 upregulated and 491 downregulated genes.These DEGs were mainly associated with metabolic pathways,pathways in cancer,cell cycle and so on.The PPI network was identified with 863 nodes and 5817 edges.Survival analysis revealed that HMMR,PAICS,ETFDH,and SCG2 were significantly associated with overall survival of CRC patients.And blebbistatin and sulconazole were identified as candidate drugs.In conclusion,our study found four hub genes involved in CRC,which may provide novel potential biomarkers for CRC prognosis,and two potential candidate drugs for CRC.展开更多
Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this h...Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this hypothesis, we selected 38 potentially functional single nucleotide polymorphisms (SNPs) from 12 genes (BAX, BCL2, BID, CASP3, CASP6, CASP7, CASP8, CASP9, CASP10, FAS, FASLG and MCL1) involved in apoptosis to assess their prognostic significance in lung cancer in a Chinese case cohort with 568 non-small cell lung cancer (NSCLC) patients. Thirty-five SNPs passing quality control underwent association analyses, 11 of which were shown to be significantly associated with NSCLC survival (P<0.05). After Cox stepwise regression analyses, 3 SNPs were independently associated with the outcome of NSCLC (BID rs8190315: P=0.003; CASP9 rs4645981: P=0.007 and FAS rs1800682: P=0.016). A favorable survival of NSCLC was significantly associated with the genotypes of BID rs8190315 AG/GG (adjusted HR=0.65, 95% CI: 0.49-0.88), CASP9 rs4645981 AA (HR=0.22, 95% CI: 0.07-0.69) and FAS rs1800682 GG (adjusted HR=0.67, 95% CI: 0.46-0.97). Time-dependent receptor operation curve (ROC) analysis revealed that the area under curve (AUC) at year 5 was significantly increased from 0.762 to 0.819 after adding the risk score of these 3 SNPs to the clinical risk score. The remaining 32 SNPs were not significantly associated with NSCLC prognosis after adjustment for these 3 SNPs. These findings indicate that BID rs8190315, CASP9 rs4645981 and FAS rs1800682 polymorphisms in the apoptotic pathway may be involved in the prognosis of NSCLC in the Chinese population.展开更多
Triple negative breast cancer(TNBC) is an aggressive subtype of breast cancer that currently lacks effective biomarkers and therapeutic targets required to investigate the diagnosis and treatment of TNBC. Here we perf...Triple negative breast cancer(TNBC) is an aggressive subtype of breast cancer that currently lacks effective biomarkers and therapeutic targets required to investigate the diagnosis and treatment of TNBC. Here we performed a comprehensive differential analysis of 165 TNBC samples by integrating RNA-seq data of breast tumor tissues and adjacent normal tissues from both our cohort and The Cancer Genome Atlas(TCGA). Pathway enrichment analysis was conducted to evaluate the biological function of TNBC-specific expressed genes. Further multivariate Cox proportional hazard regression was performed to evaluate the effect of these genes on TNBC prognosis. In this report, we identified a total of 148 TNBC-specific expressed genes that were primarily enriched in mammary gland morphogenesis and hormone levels related pathways, suggesting that mammary gland morphogenesis might play a unique role in TNBC patients differing from other breast cancer types. Further survival analysis revealed that nine genes(FSIP1, ADCY5, FSD1, HMSD, CMTM5, AFF3, CYP2 A7, ATP1 A2,and C11 orf86) were significantly associated with the prognosis of TNBC patients, while three of them(ADCY5,CYP2 A7, and ATP1 A2) were involved in the hormone-related pathways. These findings indicated the vital role of the hormone-related genes in TNBC tumorigenesis and may provide some independent prognostic markers as well as novel therapeutic targets for TNBC.展开更多
Objective: The aim of this study is to identify the prognostic significance of X-ray cross-complementing gene 1(XRCC1) in patients with gastric cancer undergoing surgery and platinum-based adjuvant chemotherapy.Method...Objective: The aim of this study is to identify the prognostic significance of X-ray cross-complementing gene 1(XRCC1) in patients with gastric cancer undergoing surgery and platinum-based adjuvant chemotherapy.Methods: Immunohistochemistry(IHC) was used to evaluate XRCC1 protein expression profiles on surgical specimens of 612 gastric cancer patients. The relationship between XRCC1 expression and existing prognostic factors, platinum-based adjuvant chemotherapy, disease-free survival(DFS) and overall survival(OS) were analyzed.Results: Among 612 patients staged II/III in our study, 182(29.74%) were evaluated as XRCC1 IHC positive. XRCC1 expression was not significantly related to OS(P=0.347) or DFS(P=0.297). Compared with surgery only, platinum-based adjuvant chemotherapy significantly improved the OS(P=0.031). And the patients with negative XRCC1 expression benefited more from platinum-based adjuvant chemotherapy(P=0.049). Multivariate analysis demonstrated that tumor size, T category, N category, vascular or nerve invasion and platinum-based chemotherapy were good prognostic factors for OS(P<0.05). Though XRCC1 plays an important role in DNA repair pathways, no significant relationship is found in XRCC1 expression and OS among gastric cancer in our study.Conclusions: XRCC1 might be an alternative prognostic marker for the patients of gastric cancer after radical resection. The patients with negative XRCC1 expression can benefit more from platinum-based adjuvant chemotherapy.展开更多
Long noncoding RNA(lncRNA) HOTAIR and MALAT1 are implicated in the development of multiple cancers. Genetic variants within HOTAIR and MALAT1 may affect the gene expression, thereby modifying genetic susceptibility to...Long noncoding RNA(lncRNA) HOTAIR and MALAT1 are implicated in the development of multiple cancers. Genetic variants within HOTAIR and MALAT1 may affect the gene expression, thereby modifying genetic susceptibility to cervical cancer. A case-control study was designed, including 1 486 cervical cancer patients and 1 536 healthy controls. Based on RegulomeDB database, 11 SNPs were selected and genotyped by using Sequenom’s Mass ARRAY. Univariate and multivariate logistic regression models were used to calculate the odds ratio(OR) and 95% confidence interval(CI). We found that the A allele of rs35643724 in HOTAIR was associated with increased risk of cervical cancer, while the C allele of rs1787666 in MALAT1 was associated with decreased risk. Compared to individuals with 0–1 unfavorable allele, those with 3–4 unfavorable alleles showed18% increased odds of having cervical cancer. Our findings suggest that HOTAIR rs35643724 and MALAT1 rs1787666 might represent potential biomarkers for cervical cancer susceptibility.展开更多
Gastric cancer is one of the most common malignant gastrointestinal tumors whose morbidity and mortality account for the second and third place respectively in malignant tumors in China.As an important participant in ...Gastric cancer is one of the most common malignant gastrointestinal tumors whose morbidity and mortality account for the second and third place respectively in malignant tumors in China.As an important participant in tumor biology,the abnormal expression of long non-coding RNA(lncRNAs)in cancer cells is closely related to the occurrence and development of tumors and plays the role of oncogenes or tumor suppressor genes.In this study,we identified a novel lncRNA NFIA antisense RNA 1(NFIA-AS1)and explored its role and clinical significance in gastric cancer.Real-time quantitative PCR was performed to detect the expression of NFIA-AS1 in tumor tissues and corresponding normal tissues from 42 pairs of gastric cancer samples.The lower expression of NFIA-AS1 was significantly associated with larger tumor size,lower histological grade,and advanced TNM stage.Kaplan-meier analysis showed that NFIA-AS1 expression could be used as an independent predictor of overall survival.We also demonstrated that overexpression of NFIA-AS1 significantly inhibited the proliferation of gastric cancer cells through affecting p16 levels.In conclusion,our results suggest that the lncRNA NFIA-AS1 may play the role of tumor suppressor gene,and serve as a biomarker for prognosis or progression of gastric cancer.展开更多
Epidemiological and laboratory-based studies have identified infection with one of 15 high-risk human papillo-mavirus (HPV) types as a necessary but not sufficient cause of cervical cancer. The prevalence of genital H...Epidemiological and laboratory-based studies have identified infection with one of 15 high-risk human papillo-mavirus (HPV) types as a necessary but not sufficient cause of cervical cancer. The prevalence of genital HPV in-fections is high in young women, but most of the infections regress without interventions. Host genetic variations in genes involved in immune response pathways may be related to HPV clearance, and HPV E6/E7 oncoproteins interacting or downstream genes, both coding and non-coding, may contribute to the outcome of high risk HPV infection and cervical cancer. Of specific interest for this review has been the selection of genetic variants in genes involved in the above-referred pathways with a summary of their applications in association studies. Because the supportive and opposing data have been reported in different populations, well-designed international collabora-tive studies need to be conducted to define the consistency of the associations, paving the way to better define the patients at high risk of developing cervical cancer.展开更多
Objective:Although our previous genome-wide association study(GWAS)has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer(NSCLC),the causal variants remain unclear.The aims of this s...Objective:Although our previous genome-wide association study(GWAS)has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer(NSCLC),the causal variants remain unclear.The aims of this study were to identify the causal variants in 2q33.1 and to explore their biological functions in NSCLC.Methods:CCK-8,colony formation,EdU incorporation,Transwell,and quantitative real-time polymerase chain reaction assays were applied to examine variant function.The tumor xenograft model was used to examine variant function in vivo.Caspase-8 activity assays,flow cytometry analysis,and co-immunoprecipitation assays were used to explore the molecular mechanism.Results:The missense variant rs3769823(A>G),which caused the substitution of lysine with arginine at amino acid 14 in caspase-8(caspase-8K14R),was identified as a potential causal candidate in 2q33.1.Compared with the wild type caspase-8(caspase8WT)group,the caspase-8K14R group had higher expression of caspase-8 and cleaved caspase-8.Caspase-8K14R inhibited the proliferation and metastasis of human lung cancer cell lines in vitro.Moreover,caspase-8K14R repressed lung cancer cell growth in vivo.Mechanistically,caspase-8K14R was more sensitive than caspase-8WT to tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-mediated apoptosis and showed higher binding of caspase-8 and FADD.Conclusions:These results suggested that rs3769823 is the causal variant in chromosome 2q33.1 and is involved in an apoptosis pathway,leading to a decreased risk of NSCLC.展开更多
As one of the most common tumors in women, breast cancer has drawn considerable interest from investigators and clinicians in recent years. Despite early diagnosis and best therapeutic regimens available, the prognosi...As one of the most common tumors in women, breast cancer has drawn considerable interest from investigators and clinicians in recent years. Despite early diagnosis and best therapeutic regimens available, the prognosis of malignant or metastatic breast cancer patients is still not optimistic. Hedgehog signaling, a classical pathway indispensable to embryonic development, participates in the growth of a variety of tumors. In the present study,the effect of Sonic Hedgehog(Shh) on breast cancer cells was investigated. We identified that Shh signal stimulated the migration of MCF-7 breast cancer cells. Smo and Gli1 were involved in Shh-stimulated migration of MCF-7 cells. Activating Smo and Gli1 induced cell migration, which was blocked by their specific antagonists.The effect of Shh signaling on MCF-7 cells was independent of Wnt5 a, Dvl2 and Rab35, but directly dependent on Rac1. In conclusion, our study suggested that Shh promotes breast cancer cell migration via Rac1 independently of the non-canonical Wnt signaling pathway, which may represent a rational molecular target for combination medication in breast cancer.展开更多
Diet/sugar-free soft drinks are considered to be healthier than regular soft drinks.However,few studies have examined the relationship between the types of soft drinks(regular and diet/sugar-free)and lung cancer(LC)/a...Diet/sugar-free soft drinks are considered to be healthier than regular soft drinks.However,few studies have examined the relationship between the types of soft drinks(regular and diet/sugar-free)and lung cancer(LC)/all-cancer(AC)risk.In this study,we comprehensively assessed the influence of the type of soft drink consumption on LC/AC risk based on the Prostate,Lung,Colorectal,and Ovarian(PLCO)Cancer Screening Trial.Multivariable Cox proportional hazards and competing risks Fine-Gray regression models adjusted for relevant confounders were used to estimate hazard ratios(HRs)and subdistribution HRs for different types of soft drink consumption.In the PLCO population,female subgroup,and the ever/current smoker subgroup,consumption of both regular and diet soft drinks was associated with a significantly reduced risk of LC compared with no soft drinks at all.For the non-lung cancer(NLC)risk,consumption of only diet soft drinks had a significant positive association for the total population and female subgroup.Based on our findings,it was suggested that partial replacement of regular soft drinks with diet soft drinks might be beneficial to LC prevention,especially for females and ever/current smokers.Additionally,completely replacing regular soft drinks with diet soft drinks might be detrimental to NLC prevention,especially for females.展开更多
Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresist...Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity.Here,we found that heat shock protein 90 beta family member 1(HSP90B1)was significantly upregulated in radioresistant GBM cell lines.More importantly,HSP90B1 promoted the localization of glucose transporter type 1,a key rate-limiting factor of glycolysis,on the plasma membrane,which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells.These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients,a potential new approach to the treatment of glioblastoma.展开更多
Objective:Recent evidence indicates that dysregulation of microRNA(miRNA)biogenesis is implicated in cancer development and progression.Based on the important role of miRNA biogenesis genes in carcinogenesis,we hypoth...Objective:Recent evidence indicates that dysregulation of microRNA(miRNA)biogenesis is implicated in cancer development and progression.Based on the important role of miRNA biogenesis genes in carcinogenesis,we hypothesized that genetic variations of the miRNA biogenesis genes may modulate susceptibility to cervical cancer.Methods:We identified three single nucleotide polymorphisms(SNPs)located in the 3'-untranslated regions(3'-UTR)of of miRNA biogenesis key genes(rs1057035 in DICER,rs3803012 in RAN and rs10773771 in HIWI)and genotyped these SNPs in a case-control study of 1,486 cervical cancer cases and1,549 cancer-free controls in Chinese women.Results:Logistic regression analyses showed that no significant associations were observed between the three SNPs and cervical cancer risk[rs3803012 in RAN AG/GG vs.AA adjusted OR=1.104,95%confidence interval(CI):0.859-1.419;rs1057035 in DICER CT/CC vs.TT adjusted OR=0.962,95%CI:0.805-1.149;rs10773771 in HIWI CT/CC vs.TT adjusted OR=0.963,95%CI:0.826-1.122].Conclusions:The findings did not suggest that genetic variants in the 3'-UTR of RAN,DICER and HIWI of miRNA biogenesis genes were associated with the risk of cervical cancer in this Chinese population.展开更多
Background:MicroRNA(miRNA) polymorphisms may alter miRNA-related processes,and they likely contribute to cancer susceptibility.Various studies have investigated the associations between genetic variants in several key...Background:MicroRNA(miRNA) polymorphisms may alter miRNA-related processes,and they likely contribute to cancer susceptibility.Various studies have investigated the associations between genetic variants in several key miRNAs and the risk of human cancers;however,few studies have focused on head and neck squamous cell carcinoma(HNSCC) risk.This study aimed to evaluate the associations between several key miRNA polymorphisms and HNSCC risk in a Chinese population.Methods:In this study,we genotyped five common single-nucleotide polymorphisms(SNPs) in several key miRNAs(miR-149 rs2292832,miR-146 a rs2910164,miR-605 rs2043556,miR-608 rs4919510,and miR-196a2 rs11614913) and evaluated the associations between these SNPs and HNSCC risk according to cancer site with a case-control study including 576 cases and 1552 controls,which were matched by age and sex in a Chinese population.Results:The results revealed that miR-605 rs2043556[dominant model:adjusted odds ratio(OR) 0.71,95%confidence interval(CI) 0.58-0.88;additive model:adjusted OR 0.74,95%CI 0.62-0.89]and miR-196a2 rs11614913(dominant model:adjusted OR 1.36,95%C11.08-1.72;additive model:adjusted OR 1.28,95%C11.10-1.48) were significantly associated with the risk of oral squamous cell carcinoma(OSCC).Furthermore,when these two loci were evaluated together based on the number of putative risk alleles(rs2043556 A and rs11614913 G),a significant locus-dosage effect was noted on the risk of OSCC(P_(trend) < 0.001).However,no significant association was detected between the other three SNPs(miR-149 rs2292832,miR- 146 a rs2910164,and miR-608 rs4919510) and HNSCC risk.Conclusion:Our study provided the evidence that miR-605 rs2043556 and miR-196a2 rs11614913 may have an impact on genetic susceptibility to OSCC in Chinese population.展开更多
Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the car...Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.展开更多
Previous studies have demonstrated that Chinese lung adenocarcinoma(LUAD)patients have unique genetic characteristics,however,the specific genomic features relating to the development and treatment of LUAD in the Chin...Previous studies have demonstrated that Chinese lung adenocarcinoma(LUAD)patients have unique genetic characteristics,however,the specific genomic features relating to the development and treatment of LUAD in the Chinese population are not fully understood.Here,we applied the ultra-deep targeted sequencing to 66 Chinese LUAD samples,accompanied by comparative analysis with 162 Caucasian LUAD in The Cancer Genome Atlas.We focused on the 68 recurrently mutated genes and results revealed that the panel-based tumor mutational burden(pTMB)is significantly higher in the Chinese LUAD(P=0.0017).Additionally,the percentage of smoking-associated C>A transversion is significantly lower in Chinese LUAD(15.5%vs.39.7%,P=5.69×10^(-27)),while C>T transition is more frequent in Chinese LUAD(35.8%vs.25.7%,P=2.67×10^(-5)),which indicated the ethnic difference in mutation types.Notably,novel driver genes(GNAS and JAK1)that are peculiar to Chinese LUAD were identified,and a more convergent distribution of mutations was observed in the Chinese cohort(P=0.012)compared with scattered mutations in Caucasian LUAD.Our results present a distinct genomic profile of Chinese LUAD compared to Caucasians LUAD and elucidate the ethnic difference in mutation distribution besides the type and rate.展开更多
Background:Previous studies have revealed the critical role of transglutaminase 2(TGM2)as a potential therapeutic target in cancers,but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer(GC)are no...Background:Previous studies have revealed the critical role of transglutaminase 2(TGM2)as a potential therapeutic target in cancers,but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer(GC)are not fully understood.In this study,we examined the role and potential mechanism of TGM2 in GC.Methods:Western blotting,immunohistochemistry,CCK8,colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC.Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC.Gene set enrichment analysis,quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC.Gain/loss-offunction and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2.Co-immunoprecipitation,mass spectrometry,quantitative PCR and western blotting were conducted to identify STAT1-interacting proteins and elucidate their regulatory mechanisms.Mutations in TGM2 and two molecules(ZM39923 and A23187)were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism.Results:In this study,we demonstrated elevated TGM2 expression in the GC tissues,which closely related to pathological grade,and predicted poor survival in patients with GC.TGM2 overexpression or knockdown promoted(and inhibited)cell proliferation,migration,and invasion,which were reversed by STAT1 knockdown or overexpression.Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation.Then,tripartite motif-containing protein 21(TRIM21)was identified as a ubiquitin E3 ligase of STAT1 in GC.TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP-binding enzymatic activity.A23187 abolished the role of TGM2 in STAT1 and reversed the pro-tumor role of TGM2 in vitro and in vivo.Conclusions:This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target,which elucidates the development of medicine or strategies by regulating the GTP-binding activity of TGM2 in GC.展开更多
Background:N6-methyladenosine(m^(6)A)modification is the most common modification that occurs in eukaryotes.Although substantial effort has been made in the prevention and treatment of gastric cancer(GC)in recent year...Background:N6-methyladenosine(m^(6)A)modification is the most common modification that occurs in eukaryotes.Although substantial effort has been made in the prevention and treatment of gastric cancer(GC)in recent years,the prognosis of GC patients remains unsatisfactory.The regulatory mechanism between m^(6)A modification and GC development needs to be elucidated.In this study,we examined m^(6)A modification and the downstream mechanism in GC.Methods:Dot blotting assays,The Cancer Genome Atlas analysis,and quantitative real‑time PCR(qRT-PCR)were used to measure the m^(6)A levels in GC tissues.Methylated RNA-immunoprecipitation sequencing and RNA sequencingwere performed to identify the targets ofm^(6)Amodification.Western blotting,Transwell,wound healing,and angiogenesis assays were conducted to examine the role of centromere protein F(CENPF)in GC in vitro.Xenograft,immunohistochemistry,and in vivo metastasis experiments were conducted to examine the role of CENPF in GC in vivo.Methylated RNA-immunoprecipitation-qPCR,RNA immunoprecipitation-qPCR and RNA pulldown assays were used to verify the m^(6)A modification sites of CENPF.Gain/loss-of-function and rescue experiments were conducted to determine the relationship between CENPF and the mitogen-activated protein kinase(MAPK)signaling pathway in GC cells.Coimmunoprecipitation,mass spectrometry,qRT-PCR,and immunofluorescence assays were performed to explore the proteins that interact with CENPF and elucidate the regulatory mechanisms between them.Results:CENPF was upregulated in GC and facilitated the metastasis of GC both in vitro and in vivo.Mechanistically,increasedm^(6)A modification of CENPF was mediated by methyltransferase 3,and this modified molecule could be recognized by heterogeneous nuclear ribonucleoprotein A2/B1(HNRNPA2B1),thereby promoting its mRNA stability.In addition,the metastatic phenotype of CENPF was dependent on the MAPK signaling pathway.Furthermore,CENPF could bind to FAK and promote its localization in the cytoplasm.Moreover,we discovered that high expression of CENPF was related to lymphatic invasion and overall survival in GC patients.Conclusions:Our findings revealed that increased m^(6)A modification of CENPF facilitates the metastasis and angiogenesis of GC through the CENPF/FAK/MAPK and epithelial-mesenchymal transition axis.CENPF expression was correlated with the clinical features of GC patients;therefore,CENPF may serve as a prognostic marker of GC.展开更多
Background:A polygenic risk score(PRS)derived from 112 single-nucleotide polymorphisms(SNPs)for gastric cancer has been reported in Chinese populations(PRS-112).However,its performance in other populations is unknown....Background:A polygenic risk score(PRS)derived from 112 single-nucleotide polymorphisms(SNPs)for gastric cancer has been reported in Chinese populations(PRS-112).However,its performance in other populations is unknown.A functional PRS(fPRS)using functional SNPs(fSNPs)may improve the generalizability of the PRS across populations with distinct ethnicities.Methods:We performed functional annotations on SNPs in strong linkage disequilibrium(LD)with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation.Subsequently,we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort.Finally,the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer.Results:During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases,we found no significant association between the PRS-112 and gastric cancer risk in the European population(hazard ratio[HR]=1.00[95%confidence interval(CI)0.93–1.09],P=0.846).We identified 125 fSNPs,including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs,and used them to construct the fPRS-125.Our result showed that the fPRS-125 was significantly associated with gastric cancer risk(HR=1.11[95%CI,1.03–1.20],P=0.009).Compared to participants with a low fPRS-125(bottom quintile),those with a high fPRS-125(top quintile)had a higher risk of incident gastric cancer(HR=1.43[95%CI,1.12–1.84],P=0.005).Moreover,we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer(HR=4.99[95%CI,1.55–16.10],P=0.007)compared to those with both a favorable lifestyle and a low genetic risk.Conclusion:These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.展开更多
Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy and lacks effective treatment.Bulk-sequencing of different gene transcripts by comparing HCC tissues and adjacent normal tissues provides some clues fo...Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy and lacks effective treatment.Bulk-sequencing of different gene transcripts by comparing HCC tissues and adjacent normal tissues provides some clues for investigating the mechanisms or identifying potential targets for tumor progression.However,genes that are exclusively expressed in a subpopulation of HCC may not be enriched or detected through such a screening.In the current study,we performed a single cell-clone-based screening and identified galectin-14 as an essential molecule in the regulation of tumor growth.The aberrant expression of galectin-14 was significantly associated with a poor overall survival of liver cancer patients with database analysis.Knocking down galectin-14 inhibited the proliferation of tumor growth,whereas overexpressing galectin-14 promoted tumor growth in vivo.Non-targeted metabolomics analysis indicated that knocking down galectin-14 decreased glycometabolism;specifically that glycoside synthesis was significantly changed.Further study found that galectin-14 promoted the expression of cell surface heparan sulfate proteoglycans(HSPGs)that functioned as co-receptors,thereby increasing the responsiveness of HCC cells to growth factors,such as epidermal growth factor and transforming growth factor-alpha.In conclusion,the current study identifies a novel HCC-specific molecule galectin-14,which increases the expression of cell surface HSPGs and the uptake of growth factors to promote HCC cell proliferation.展开更多
Although vaccines have been developed,mutations of SARS-CoV-2,especially the dominant B.1.617.2(delta)and B.1.529(omicron)strains with more than 30 mutations on their spike protein,have caused a significant decline in...Although vaccines have been developed,mutations of SARS-CoV-2,especially the dominant B.1.617.2(delta)and B.1.529(omicron)strains with more than 30 mutations on their spike protein,have caused a significant decline in prophylaxis,calling for the need for drug improvement.Antibodies are drugs preferentially used in infectious diseases and are easy to get from immunized organisms.The current study combined molecular modeling and single memory B cell sequencing to assess candidate sequences before experiments,providing a strategy for the fabrication of SARS-CoV-2 neutralizing antibodies.A total of 128 sequences were obtained after sequencing 196 memory B cells,and 42 sequences were left after merging extremely similar ones and discarding incomplete ones,followed by homology modeling of the antibody variable region.Thirteen candidate sequences were expressed,of which three were tested positive for receptor binding domain recognition but only one was confirmed as having broad neutralization against several SARS-CoV-2 variants.The current study successfully obtained a SARS-CoV-2 antibody with broad neutralizing abilities and provided a strategy for antibody development in emerging infectious diseases using single memory B cell BCR sequencing and computer assistance in antibody fabrication.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.81672748 and No.81871936)。
文摘Colorectal cancer(CRC)is one of the most deadly cancers in the world with few reliable biomarkers that have been selected into clinical guidelines for prognosis of CRC patients.In this study,mRNA microarray datasets GSE113513,GSE21510,GSE44076,and GSE32323 were obtained from the Gene Expression Omnibus(GEO)and analyzed with bioinformatics to identify hub genes in CRC development.Differentially expressed genes(DEGs)were analyzed using the GEO2 R tool.Gene ontology(GO)and KEGG analyses were performed through the DAVID database.STRING database and Cytoscape software were used to construct a protein-protein interaction(PPI)network and identify key modules and hub genes.Survival analyses of the DEGs were performed on GEPIA database.The Connectivity Map database was used to screen potential drugs.A total of 865 DEGs were identified,including 374 upregulated and 491 downregulated genes.These DEGs were mainly associated with metabolic pathways,pathways in cancer,cell cycle and so on.The PPI network was identified with 863 nodes and 5817 edges.Survival analysis revealed that HMMR,PAICS,ETFDH,and SCG2 were significantly associated with overall survival of CRC patients.And blebbistatin and sulconazole were identified as candidate drugs.In conclusion,our study found four hub genes involved in CRC,which may provide novel potential biomarkers for CRC prognosis,and two potential candidate drugs for CRC.
基金supported in part by the National Natural Science Foundation of China (81270044,30972541,30901233)the Doctoral Fund of Ministry of Education of China (20093234110001)A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institution
文摘Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this hypothesis, we selected 38 potentially functional single nucleotide polymorphisms (SNPs) from 12 genes (BAX, BCL2, BID, CASP3, CASP6, CASP7, CASP8, CASP9, CASP10, FAS, FASLG and MCL1) involved in apoptosis to assess their prognostic significance in lung cancer in a Chinese case cohort with 568 non-small cell lung cancer (NSCLC) patients. Thirty-five SNPs passing quality control underwent association analyses, 11 of which were shown to be significantly associated with NSCLC survival (P<0.05). After Cox stepwise regression analyses, 3 SNPs were independently associated with the outcome of NSCLC (BID rs8190315: P=0.003; CASP9 rs4645981: P=0.007 and FAS rs1800682: P=0.016). A favorable survival of NSCLC was significantly associated with the genotypes of BID rs8190315 AG/GG (adjusted HR=0.65, 95% CI: 0.49-0.88), CASP9 rs4645981 AA (HR=0.22, 95% CI: 0.07-0.69) and FAS rs1800682 GG (adjusted HR=0.67, 95% CI: 0.46-0.97). Time-dependent receptor operation curve (ROC) analysis revealed that the area under curve (AUC) at year 5 was significantly increased from 0.762 to 0.819 after adding the risk score of these 3 SNPs to the clinical risk score. The remaining 32 SNPs were not significantly associated with NSCLC prognosis after adjustment for these 3 SNPs. These findings indicate that BID rs8190315, CASP9 rs4645981 and FAS rs1800682 polymorphisms in the apoptotic pathway may be involved in the prognosis of NSCLC in the Chinese population.
基金supported by the Nanjing Medical Science and Technique Development Foundation(ZKX17041)the Natural Science Foundation of Jiangsu Province(BK20161120)+2 种基金the Maternal and child health research project of Jiangsu Province(F201628)the Priority Academic Program Development of Jiangsu Higher Education Institutions(Public Health and Preventive Medicine)Top-notch Academic Programs Project of Jiangsu Higher Education Institutions(PPZY2015A067)。
文摘Triple negative breast cancer(TNBC) is an aggressive subtype of breast cancer that currently lacks effective biomarkers and therapeutic targets required to investigate the diagnosis and treatment of TNBC. Here we performed a comprehensive differential analysis of 165 TNBC samples by integrating RNA-seq data of breast tumor tissues and adjacent normal tissues from both our cohort and The Cancer Genome Atlas(TCGA). Pathway enrichment analysis was conducted to evaluate the biological function of TNBC-specific expressed genes. Further multivariate Cox proportional hazard regression was performed to evaluate the effect of these genes on TNBC prognosis. In this report, we identified a total of 148 TNBC-specific expressed genes that were primarily enriched in mammary gland morphogenesis and hormone levels related pathways, suggesting that mammary gland morphogenesis might play a unique role in TNBC patients differing from other breast cancer types. Further survival analysis revealed that nine genes(FSIP1, ADCY5, FSD1, HMSD, CMTM5, AFF3, CYP2 A7, ATP1 A2,and C11 orf86) were significantly associated with the prognosis of TNBC patients, while three of them(ADCY5,CYP2 A7, and ATP1 A2) were involved in the hormone-related pathways. These findings indicated the vital role of the hormone-related genes in TNBC tumorigenesis and may provide some independent prognostic markers as well as novel therapeutic targets for TNBC.
基金supported by the National Natural Science Foundation of China(No.81100274,81001428)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)
文摘Objective: The aim of this study is to identify the prognostic significance of X-ray cross-complementing gene 1(XRCC1) in patients with gastric cancer undergoing surgery and platinum-based adjuvant chemotherapy.Methods: Immunohistochemistry(IHC) was used to evaluate XRCC1 protein expression profiles on surgical specimens of 612 gastric cancer patients. The relationship between XRCC1 expression and existing prognostic factors, platinum-based adjuvant chemotherapy, disease-free survival(DFS) and overall survival(OS) were analyzed.Results: Among 612 patients staged II/III in our study, 182(29.74%) were evaluated as XRCC1 IHC positive. XRCC1 expression was not significantly related to OS(P=0.347) or DFS(P=0.297). Compared with surgery only, platinum-based adjuvant chemotherapy significantly improved the OS(P=0.031). And the patients with negative XRCC1 expression benefited more from platinum-based adjuvant chemotherapy(P=0.049). Multivariate analysis demonstrated that tumor size, T category, N category, vascular or nerve invasion and platinum-based chemotherapy were good prognostic factors for OS(P<0.05). Though XRCC1 plays an important role in DNA repair pathways, no significant relationship is found in XRCC1 expression and OS among gastric cancer in our study.Conclusions: XRCC1 might be an alternative prognostic marker for the patients of gastric cancer after radical resection. The patients with negative XRCC1 expression can benefit more from platinum-based adjuvant chemotherapy.
基金supported by National Natural Science Foundation of China(81502873)the Natural Science Foundation of Jiangsu Province(BK20150997)+3 种基金Priority Academic Program for the Development of Jiangsu Higher Education Institutions(Public Health and Preventive Medicine)Innovation Fund of State key Laboratory of Reproductive Medicine(SKLRMGC201802)Clinical Medicine Research Fund of the Chinese Medical Association(17020420711)Top-notch Academic Programs Project of Jiangsu Higher Education Institutions(PPZY2015A067)
文摘Long noncoding RNA(lncRNA) HOTAIR and MALAT1 are implicated in the development of multiple cancers. Genetic variants within HOTAIR and MALAT1 may affect the gene expression, thereby modifying genetic susceptibility to cervical cancer. A case-control study was designed, including 1 486 cervical cancer patients and 1 536 healthy controls. Based on RegulomeDB database, 11 SNPs were selected and genotyped by using Sequenom’s Mass ARRAY. Univariate and multivariate logistic regression models were used to calculate the odds ratio(OR) and 95% confidence interval(CI). We found that the A allele of rs35643724 in HOTAIR was associated with increased risk of cervical cancer, while the C allele of rs1787666 in MALAT1 was associated with decreased risk. Compared to individuals with 0–1 unfavorable allele, those with 3–4 unfavorable alleles showed18% increased odds of having cervical cancer. Our findings suggest that HOTAIR rs35643724 and MALAT1 rs1787666 might represent potential biomarkers for cervical cancer susceptibility.
基金supported by grants from the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX17_1301 to E.Z.)the National Natural Science Foundation of China (81730066 to D.M.).
文摘Gastric cancer is one of the most common malignant gastrointestinal tumors whose morbidity and mortality account for the second and third place respectively in malignant tumors in China.As an important participant in tumor biology,the abnormal expression of long non-coding RNA(lncRNAs)in cancer cells is closely related to the occurrence and development of tumors and plays the role of oncogenes or tumor suppressor genes.In this study,we identified a novel lncRNA NFIA antisense RNA 1(NFIA-AS1)and explored its role and clinical significance in gastric cancer.Real-time quantitative PCR was performed to detect the expression of NFIA-AS1 in tumor tissues and corresponding normal tissues from 42 pairs of gastric cancer samples.The lower expression of NFIA-AS1 was significantly associated with larger tumor size,lower histological grade,and advanced TNM stage.Kaplan-meier analysis showed that NFIA-AS1 expression could be used as an independent predictor of overall survival.We also demonstrated that overexpression of NFIA-AS1 significantly inhibited the proliferation of gastric cancer cells through affecting p16 levels.In conclusion,our results suggest that the lncRNA NFIA-AS1 may play the role of tumor suppressor gene,and serve as a biomarker for prognosis or progression of gastric cancer.
文摘Epidemiological and laboratory-based studies have identified infection with one of 15 high-risk human papillo-mavirus (HPV) types as a necessary but not sufficient cause of cervical cancer. The prevalence of genital HPV in-fections is high in young women, but most of the infections regress without interventions. Host genetic variations in genes involved in immune response pathways may be related to HPV clearance, and HPV E6/E7 oncoproteins interacting or downstream genes, both coding and non-coding, may contribute to the outcome of high risk HPV infection and cervical cancer. Of specific interest for this review has been the selection of genetic variants in genes involved in the above-referred pathways with a summary of their applications in association studies. Because the supportive and opposing data have been reported in different populations, well-designed international collabora-tive studies need to be conducted to define the consistency of the associations, paving the way to better define the patients at high risk of developing cervical cancer.
基金supported by Grants from the National Natural Science Foundation of China(Grant Nos.82103926 and 81702266)Science Fund for Creative Research Groups of the National Natural Science Foundation of China(Grant No.81521004)+3 种基金Natural Science Foundation of Jiangsu Province(Grant No.BK20210534)Postdoctoral Science Foundation of China(Grant No.2021M691636)CAMS Innovation Fund for Medical Sciences(Grant No.2019RU038)Graduate Research and Innovation Program of Jiangsu Province(Grant Nos.KYCX20_1442 and KYCX20_1412).
文摘Objective:Although our previous genome-wide association study(GWAS)has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer(NSCLC),the causal variants remain unclear.The aims of this study were to identify the causal variants in 2q33.1 and to explore their biological functions in NSCLC.Methods:CCK-8,colony formation,EdU incorporation,Transwell,and quantitative real-time polymerase chain reaction assays were applied to examine variant function.The tumor xenograft model was used to examine variant function in vivo.Caspase-8 activity assays,flow cytometry analysis,and co-immunoprecipitation assays were used to explore the molecular mechanism.Results:The missense variant rs3769823(A>G),which caused the substitution of lysine with arginine at amino acid 14 in caspase-8(caspase-8K14R),was identified as a potential causal candidate in 2q33.1.Compared with the wild type caspase-8(caspase8WT)group,the caspase-8K14R group had higher expression of caspase-8 and cleaved caspase-8.Caspase-8K14R inhibited the proliferation and metastasis of human lung cancer cell lines in vitro.Moreover,caspase-8K14R repressed lung cancer cell growth in vivo.Mechanistically,caspase-8K14R was more sensitive than caspase-8WT to tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-mediated apoptosis and showed higher binding of caspase-8 and FADD.Conclusions:These results suggested that rs3769823 is the causal variant in chromosome 2q33.1 and is involved in an apoptosis pathway,leading to a decreased risk of NSCLC.
基金supported by grants from the National Natural Science Foundation of China(No.81672748 and 81871936 to S.Y.C. No.81572720 to S.Y.)
文摘As one of the most common tumors in women, breast cancer has drawn considerable interest from investigators and clinicians in recent years. Despite early diagnosis and best therapeutic regimens available, the prognosis of malignant or metastatic breast cancer patients is still not optimistic. Hedgehog signaling, a classical pathway indispensable to embryonic development, participates in the growth of a variety of tumors. In the present study,the effect of Sonic Hedgehog(Shh) on breast cancer cells was investigated. We identified that Shh signal stimulated the migration of MCF-7 breast cancer cells. Smo and Gli1 were involved in Shh-stimulated migration of MCF-7 cells. Activating Smo and Gli1 induced cell migration, which was blocked by their specific antagonists.The effect of Shh signaling on MCF-7 cells was independent of Wnt5 a, Dvl2 and Rab35, but directly dependent on Rac1. In conclusion, our study suggested that Shh promotes breast cancer cell migration via Rac1 independently of the non-canonical Wnt signaling pathway, which may represent a rational molecular target for combination medication in breast cancer.
基金supported by the National Natural Science Foundation of China (Projects No. 82173620to Y.Z. and 82204156 to D.Y.)Priority Academic Program Development of Jiangsu Higher Education Institution
文摘Diet/sugar-free soft drinks are considered to be healthier than regular soft drinks.However,few studies have examined the relationship between the types of soft drinks(regular and diet/sugar-free)and lung cancer(LC)/all-cancer(AC)risk.In this study,we comprehensively assessed the influence of the type of soft drink consumption on LC/AC risk based on the Prostate,Lung,Colorectal,and Ovarian(PLCO)Cancer Screening Trial.Multivariable Cox proportional hazards and competing risks Fine-Gray regression models adjusted for relevant confounders were used to estimate hazard ratios(HRs)and subdistribution HRs for different types of soft drink consumption.In the PLCO population,female subgroup,and the ever/current smoker subgroup,consumption of both regular and diet soft drinks was associated with a significantly reduced risk of LC compared with no soft drinks at all.For the non-lung cancer(NLC)risk,consumption of only diet soft drinks had a significant positive association for the total population and female subgroup.Based on our findings,it was suggested that partial replacement of regular soft drinks with diet soft drinks might be beneficial to LC prevention,especially for females and ever/current smokers.Additionally,completely replacing regular soft drinks with diet soft drinks might be detrimental to NLC prevention,especially for females.
基金supported by the National Natural Science Foundation of China(Grant Nos.82072765 to X.Q.and 82172667 to X.W.).
文摘Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity.Here,we found that heat shock protein 90 beta family member 1(HSP90B1)was significantly upregulated in radioresistant GBM cell lines.More importantly,HSP90B1 promoted the localization of glucose transporter type 1,a key rate-limiting factor of glycolysis,on the plasma membrane,which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells.These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients,a potential new approach to the treatment of glioblastoma.
文摘Objective:Recent evidence indicates that dysregulation of microRNA(miRNA)biogenesis is implicated in cancer development and progression.Based on the important role of miRNA biogenesis genes in carcinogenesis,we hypothesized that genetic variations of the miRNA biogenesis genes may modulate susceptibility to cervical cancer.Methods:We identified three single nucleotide polymorphisms(SNPs)located in the 3'-untranslated regions(3'-UTR)of of miRNA biogenesis key genes(rs1057035 in DICER,rs3803012 in RAN and rs10773771 in HIWI)and genotyped these SNPs in a case-control study of 1,486 cervical cancer cases and1,549 cancer-free controls in Chinese women.Results:Logistic regression analyses showed that no significant associations were observed between the three SNPs and cervical cancer risk[rs3803012 in RAN AG/GG vs.AA adjusted OR=1.104,95%confidence interval(CI):0.859-1.419;rs1057035 in DICER CT/CC vs.TT adjusted OR=0.962,95%CI:0.805-1.149;rs10773771 in HIWI CT/CC vs.TT adjusted OR=0.963,95%CI:0.826-1.122].Conclusions:The findings did not suggest that genetic variants in the 3'-UTR of RAN,DICER and HIWI of miRNA biogenesis genes were associated with the risk of cervical cancer in this Chinese population.
基金supported in part by Grants from the National Natural Science Foundation of China(Nos.81473048 and 81302361)Priority Academic Program Development of Jiangsu Higher Education Institutions(Public Health and Preventive Medicine)+2 种基金Specialized Research Fund for the Doctoral Program of Higher Education of China(No.20133234120013)China Postdoctoral Science Foundation(No.2013M540457)Jiangsu Planned Projects for Postdoctoral Research Funds(No.1301018A)
文摘Background:MicroRNA(miRNA) polymorphisms may alter miRNA-related processes,and they likely contribute to cancer susceptibility.Various studies have investigated the associations between genetic variants in several key miRNAs and the risk of human cancers;however,few studies have focused on head and neck squamous cell carcinoma(HNSCC) risk.This study aimed to evaluate the associations between several key miRNA polymorphisms and HNSCC risk in a Chinese population.Methods:In this study,we genotyped five common single-nucleotide polymorphisms(SNPs) in several key miRNAs(miR-149 rs2292832,miR-146 a rs2910164,miR-605 rs2043556,miR-608 rs4919510,and miR-196a2 rs11614913) and evaluated the associations between these SNPs and HNSCC risk according to cancer site with a case-control study including 576 cases and 1552 controls,which were matched by age and sex in a Chinese population.Results:The results revealed that miR-605 rs2043556[dominant model:adjusted odds ratio(OR) 0.71,95%confidence interval(CI) 0.58-0.88;additive model:adjusted OR 0.74,95%CI 0.62-0.89]and miR-196a2 rs11614913(dominant model:adjusted OR 1.36,95%C11.08-1.72;additive model:adjusted OR 1.28,95%C11.10-1.48) were significantly associated with the risk of oral squamous cell carcinoma(OSCC).Furthermore,when these two loci were evaluated together based on the number of putative risk alleles(rs2043556 A and rs11614913 G),a significant locus-dosage effect was noted on the risk of OSCC(P_(trend) < 0.001).However,no significant association was detected between the other three SNPs(miR-149 rs2292832,miR- 146 a rs2910164,and miR-608 rs4919510) and HNSCC risk.Conclusion:Our study provided the evidence that miR-605 rs2043556 and miR-196a2 rs11614913 may have an impact on genetic susceptibility to OSCC in Chinese population.
基金supported by the National Natural Science Foundation of China(Grant Nos.81902836 and 81572602)the China Postdoctoral Science Foundation(Grant Nos.2017M610339 and 2018M630584)。
文摘Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.
基金supported by grants from projects supported by the National Natural Science Foundation of China(91959113,81972358,and 81572893)the Natural Science Foundation of Jiangsu Province(BK20180036 and BE2017733)。
文摘Previous studies have demonstrated that Chinese lung adenocarcinoma(LUAD)patients have unique genetic characteristics,however,the specific genomic features relating to the development and treatment of LUAD in the Chinese population are not fully understood.Here,we applied the ultra-deep targeted sequencing to 66 Chinese LUAD samples,accompanied by comparative analysis with 162 Caucasian LUAD in The Cancer Genome Atlas.We focused on the 68 recurrently mutated genes and results revealed that the panel-based tumor mutational burden(pTMB)is significantly higher in the Chinese LUAD(P=0.0017).Additionally,the percentage of smoking-associated C>A transversion is significantly lower in Chinese LUAD(15.5%vs.39.7%,P=5.69×10^(-27)),while C>T transition is more frequent in Chinese LUAD(35.8%vs.25.7%,P=2.67×10^(-5)),which indicated the ethnic difference in mutation types.Notably,novel driver genes(GNAS and JAK1)that are peculiar to Chinese LUAD were identified,and a more convergent distribution of mutations was observed in the Chinese cohort(P=0.012)compared with scattered mutations in Caucasian LUAD.Our results present a distinct genomic profile of Chinese LUAD compared to Caucasians LUAD and elucidate the ethnic difference in mutation distribution besides the type and rate.
基金the National Natural Science Foundation of China(81802996,81871946,and 82072708)Special Foundation for National Science and Technology Basic Research Program of China(2019FY101104)+2 种基金the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMUthe Priority Academic ProgramDevelopment of JiangsuHigher Education Institutions(JX10231801)Jiangsu Key Medical Discipline(General Surgery)(ZDXKA2016005),Jiangsu Key Lab of Cancer Biomarkers,Prevention and Treatment,Collaborative Innovation Center for Cancer Personalized Medicine,Nanjing Medical University.
文摘Background:Previous studies have revealed the critical role of transglutaminase 2(TGM2)as a potential therapeutic target in cancers,but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer(GC)are not fully understood.In this study,we examined the role and potential mechanism of TGM2 in GC.Methods:Western blotting,immunohistochemistry,CCK8,colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC.Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC.Gene set enrichment analysis,quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC.Gain/loss-offunction and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2.Co-immunoprecipitation,mass spectrometry,quantitative PCR and western blotting were conducted to identify STAT1-interacting proteins and elucidate their regulatory mechanisms.Mutations in TGM2 and two molecules(ZM39923 and A23187)were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism.Results:In this study,we demonstrated elevated TGM2 expression in the GC tissues,which closely related to pathological grade,and predicted poor survival in patients with GC.TGM2 overexpression or knockdown promoted(and inhibited)cell proliferation,migration,and invasion,which were reversed by STAT1 knockdown or overexpression.Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation.Then,tripartite motif-containing protein 21(TRIM21)was identified as a ubiquitin E3 ligase of STAT1 in GC.TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP-binding enzymatic activity.A23187 abolished the role of TGM2 in STAT1 and reversed the pro-tumor role of TGM2 in vitro and in vivo.Conclusions:This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target,which elucidates the development of medicine or strategies by regulating the GTP-binding activity of TGM2 in GC.
基金Special Foundation for National Science and Technology Basic Research Program of China,Grant/Award Number:2019FY101104National Natural Science Foundation of China,Grant/Award Numbers:81871946,82072708+6 种基金Primary Research&Development Plan of Jiangsu Province,Grant/Award Number:BE2016786Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMUPriority Academic Program Development of Jiangsu Higher Education Institutions,Grant/Award Number:JX10231801Jiangsu Key Medical Discipline,Grant/Award Number:ZDXKA2016005Jiangsu Key Lab of Cancer Biomarkers,Prevention and TreatmentCollaborative Innovation Centre for Cancer Personalized MedicineNanjing Medical University。
文摘Background:N6-methyladenosine(m^(6)A)modification is the most common modification that occurs in eukaryotes.Although substantial effort has been made in the prevention and treatment of gastric cancer(GC)in recent years,the prognosis of GC patients remains unsatisfactory.The regulatory mechanism between m^(6)A modification and GC development needs to be elucidated.In this study,we examined m^(6)A modification and the downstream mechanism in GC.Methods:Dot blotting assays,The Cancer Genome Atlas analysis,and quantitative real‑time PCR(qRT-PCR)were used to measure the m^(6)A levels in GC tissues.Methylated RNA-immunoprecipitation sequencing and RNA sequencingwere performed to identify the targets ofm^(6)Amodification.Western blotting,Transwell,wound healing,and angiogenesis assays were conducted to examine the role of centromere protein F(CENPF)in GC in vitro.Xenograft,immunohistochemistry,and in vivo metastasis experiments were conducted to examine the role of CENPF in GC in vivo.Methylated RNA-immunoprecipitation-qPCR,RNA immunoprecipitation-qPCR and RNA pulldown assays were used to verify the m^(6)A modification sites of CENPF.Gain/loss-of-function and rescue experiments were conducted to determine the relationship between CENPF and the mitogen-activated protein kinase(MAPK)signaling pathway in GC cells.Coimmunoprecipitation,mass spectrometry,qRT-PCR,and immunofluorescence assays were performed to explore the proteins that interact with CENPF and elucidate the regulatory mechanisms between them.Results:CENPF was upregulated in GC and facilitated the metastasis of GC both in vitro and in vivo.Mechanistically,increasedm^(6)A modification of CENPF was mediated by methyltransferase 3,and this modified molecule could be recognized by heterogeneous nuclear ribonucleoprotein A2/B1(HNRNPA2B1),thereby promoting its mRNA stability.In addition,the metastatic phenotype of CENPF was dependent on the MAPK signaling pathway.Furthermore,CENPF could bind to FAK and promote its localization in the cytoplasm.Moreover,we discovered that high expression of CENPF was related to lymphatic invasion and overall survival in GC patients.Conclusions:Our findings revealed that increased m^(6)A modification of CENPF facilitates the metastasis and angiogenesis of GC through the CENPF/FAK/MAPK and epithelial-mesenchymal transition axis.CENPF expression was correlated with the clinical features of GC patients;therefore,CENPF may serve as a prognostic marker of GC.
基金supported by grants from the National Natural Science Foundation of China(Nos.82125033,82230110,81872702,82003534,and 82273714)the Natural Science Foundation of Jiangsu Province(No.BK20200674)CAMS Innovation Fund for Medical Sciences(No.2019RU038).
文摘Background:A polygenic risk score(PRS)derived from 112 single-nucleotide polymorphisms(SNPs)for gastric cancer has been reported in Chinese populations(PRS-112).However,its performance in other populations is unknown.A functional PRS(fPRS)using functional SNPs(fSNPs)may improve the generalizability of the PRS across populations with distinct ethnicities.Methods:We performed functional annotations on SNPs in strong linkage disequilibrium(LD)with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation.Subsequently,we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort.Finally,the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer.Results:During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases,we found no significant association between the PRS-112 and gastric cancer risk in the European population(hazard ratio[HR]=1.00[95%confidence interval(CI)0.93–1.09],P=0.846).We identified 125 fSNPs,including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs,and used them to construct the fPRS-125.Our result showed that the fPRS-125 was significantly associated with gastric cancer risk(HR=1.11[95%CI,1.03–1.20],P=0.009).Compared to participants with a low fPRS-125(bottom quintile),those with a high fPRS-125(top quintile)had a higher risk of incident gastric cancer(HR=1.43[95%CI,1.12–1.84],P=0.005).Moreover,we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer(HR=4.99[95%CI,1.55–16.10],P=0.007)compared to those with both a favorable lifestyle and a low genetic risk.Conclusion:These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.
基金The current study was supported by the National Natural Science Foundation of China(Grant Nos 81972284 and 82273239)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.22KJB310001)Nanjing Medical University Science and Technology Development Foundation(Grant Nos.NMUB-20220050 and NMUB20210006).
文摘Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy and lacks effective treatment.Bulk-sequencing of different gene transcripts by comparing HCC tissues and adjacent normal tissues provides some clues for investigating the mechanisms or identifying potential targets for tumor progression.However,genes that are exclusively expressed in a subpopulation of HCC may not be enriched or detected through such a screening.In the current study,we performed a single cell-clone-based screening and identified galectin-14 as an essential molecule in the regulation of tumor growth.The aberrant expression of galectin-14 was significantly associated with a poor overall survival of liver cancer patients with database analysis.Knocking down galectin-14 inhibited the proliferation of tumor growth,whereas overexpressing galectin-14 promoted tumor growth in vivo.Non-targeted metabolomics analysis indicated that knocking down galectin-14 decreased glycometabolism;specifically that glycoside synthesis was significantly changed.Further study found that galectin-14 promoted the expression of cell surface heparan sulfate proteoglycans(HSPGs)that functioned as co-receptors,thereby increasing the responsiveness of HCC cells to growth factors,such as epidermal growth factor and transforming growth factor-alpha.In conclusion,the current study identifies a novel HCC-specific molecule galectin-14,which increases the expression of cell surface HSPGs and the uptake of growth factors to promote HCC cell proliferation.
基金supported by the Jiangsu Provincial Key Research and Development Program (Grant No.BE2020616)the National Key R&D Program of China (Grant No.2018YFC1200603)+1 种基金the National Science and Technology Major Project (Grant No.2019SWAQ05-5-4)Jiangsu Key Lab of Cancer Biomarkers,Prevention and Treatment,Collaborative Innovation Center for Cancer Personalized Medicine,Nanjing Medical University.
文摘Although vaccines have been developed,mutations of SARS-CoV-2,especially the dominant B.1.617.2(delta)and B.1.529(omicron)strains with more than 30 mutations on their spike protein,have caused a significant decline in prophylaxis,calling for the need for drug improvement.Antibodies are drugs preferentially used in infectious diseases and are easy to get from immunized organisms.The current study combined molecular modeling and single memory B cell sequencing to assess candidate sequences before experiments,providing a strategy for the fabrication of SARS-CoV-2 neutralizing antibodies.A total of 128 sequences were obtained after sequencing 196 memory B cells,and 42 sequences were left after merging extremely similar ones and discarding incomplete ones,followed by homology modeling of the antibody variable region.Thirteen candidate sequences were expressed,of which three were tested positive for receptor binding domain recognition but only one was confirmed as having broad neutralization against several SARS-CoV-2 variants.The current study successfully obtained a SARS-CoV-2 antibody with broad neutralizing abilities and provided a strategy for antibody development in emerging infectious diseases using single memory B cell BCR sequencing and computer assistance in antibody fabrication.
