BACKGROUND MUC16,encoding cancer antigen 125,is a frequently mutated gene in gastric cancer.In addition,MUC16 mutations seem to result in a better prognosis in gastric cancer.However,the mechanisms that lead to a bett...BACKGROUND MUC16,encoding cancer antigen 125,is a frequently mutated gene in gastric cancer.In addition,MUC16 mutations seem to result in a better prognosis in gastric cancer.However,the mechanisms that lead to a better prognosis by MUC16 mutations have not yet been clarified.AIM To delve deeper into the underlying mechanisms that explain why MUC16 mutations signal a better prognosis in gastric cancer.METHODS We used multi-omics data,including mRNA,simple nucleotide variation,copy number variation and methylation data from The Cancer Genome Atlas,to explore the relationship between MUC16 mutations and prognosis.Cox regression and random survival forest algorithms were applied to search for hub genes.Gene set enrichment analysis was used to elucidate the molecular mechanisms.Single-sample gene set enrichment analysis and“EpiDISH”were used to assess immune cells infiltration,and“ESTIMATE”for analysis of the tumor microenvironment.RESULTS Our study found that compared to the wild-type group,the mutation group had a better prognosis.Additional analysis indicated that the MUC16 mutations appear to activate the DNA repair and p53 pathways to act as an anti-tumor agent.We also identified a key gene,NPY1R(neuropeptide Y receptor Y1),which was significantly more highly expressed in the MUC16 mutations group than in the MUC16 wild-type group.The high expression of NPY1R predicted a poorer prognosis,which was also confirmed in a separate Gene Expression Omnibus cohort.Further susceptibility analysis revealed that NPY1R might be a potential drug target for gastric cancer.Furthermore,in the analysis of the tumor microenvironment,we found that immune cells in the mutation group exhibited higher anti-tumor effects.In addition,the tumor mutation burden and cancer stem cells index were also higher in the mutation group than in the wild-type group.CONCLUSION We speculated that the MUC16 mutations might activate the p53 pathway and DNA repair pathway:alternatively,the tumor microenvironment may be involved.展开更多
MUC16(CA125) has remained the mainstay for ovarian cancer assessment and management since the early 1980's. With the exception of HE4, it is the only reliable serum biomarker for ovarian cancer. MUC16 belongs to a...MUC16(CA125) has remained the mainstay for ovarian cancer assessment and management since the early 1980's. With the exception of HE4, it is the only reliable serum biomarker for ovarian cancer. MUC16 belongs to a family of high-molecular weight glycoproteins known as mucins. The mucin family is comprised of large secreted transmembrane proteins that includes MUC1, MUC4 and MUC16. These mucins are often overexpressed in a variety of malignancies. MUC1 and MUC4 have been shown to contribute to breast and pancreatic tumorigenesis. Recent studies have uncovered unique biological functions for MUC16 that go beyond its role as a biomarker for ovarian cancer. Here, we provide an overview of the literature to highlight the importance of MUC16 in ovarian cancer tumorigenesis. We focus on the growing literature describing the role of MUC16 in proliferation, migration, metastasis, tumorigenesis and drug resistance. Accumulating experimental evidence suggest that the C-terminal domain of MUC16 is critical to mediate theses effects. The importance of MUC16 in the pathogenesis of ovarian cancer emphasizes the need to fully understand the signaling capabilities of MUC16 C-terminal domain to develop more efficient strategies for the successful treatment of ovarian cancer.展开更多
目的探究黏蛋白16(MUC16)基因在33种人肿瘤组织内的基因及蛋白表达水平,并探讨其临床意义及在肿瘤发生发展中潜在的机制。方法利用癌症基因组图谱(the cancer genome atlas,TCGA)、基因表达综合数据库(gene expression omnibus,GEO)数...目的探究黏蛋白16(MUC16)基因在33种人肿瘤组织内的基因及蛋白表达水平,并探讨其临床意义及在肿瘤发生发展中潜在的机制。方法利用癌症基因组图谱(the cancer genome atlas,TCGA)、基因表达综合数据库(gene expression omnibus,GEO)数据集、人类蛋白图谱(human protein atlas,HPA)和一些生物信息学工具来探索MUC16在33种肿瘤类型中的表达情况,分析其与肿瘤预后的关系和相关通路。结果基因表达以及免疫组织化学染色结果显示,MUC16基因在不同肿瘤中表达不同,且在多种常见肿瘤组织中的表达均升高(P均<0.05)。泛癌Cox回归分析表明,MUC16的高表达通常预示着间皮瘤、肺腺癌等6种肿瘤患者的总生存期(OS)更差。对MUC16以及邻近基因进行富集分析显示,MUC16与肿瘤转录失调密切相关。结论MUC16在多种肿瘤中的表达水平与癌旁组织不同,其功能机制与肿瘤转录失调密切相关。展开更多
基金National Natural Science Foundation of China,No.81902385The Project of Suzhou People's Livelihood Science and Technology,No.SYS2018037 and No.SYS201739+3 种基金The Six Talent Peaks Project in Jiangsu Province,No.WSW-059Postgraduate Research&Practice Innovation Program of Jiangsu Province,No.SJCX20_1073Medical Research Programs of Health Commission Foundation of Jiangsu Province,No.H2019071The Project of Medical Research of Jiangsu Province,No.Y2018094 and No.H2018056.
文摘BACKGROUND MUC16,encoding cancer antigen 125,is a frequently mutated gene in gastric cancer.In addition,MUC16 mutations seem to result in a better prognosis in gastric cancer.However,the mechanisms that lead to a better prognosis by MUC16 mutations have not yet been clarified.AIM To delve deeper into the underlying mechanisms that explain why MUC16 mutations signal a better prognosis in gastric cancer.METHODS We used multi-omics data,including mRNA,simple nucleotide variation,copy number variation and methylation data from The Cancer Genome Atlas,to explore the relationship between MUC16 mutations and prognosis.Cox regression and random survival forest algorithms were applied to search for hub genes.Gene set enrichment analysis was used to elucidate the molecular mechanisms.Single-sample gene set enrichment analysis and“EpiDISH”were used to assess immune cells infiltration,and“ESTIMATE”for analysis of the tumor microenvironment.RESULTS Our study found that compared to the wild-type group,the mutation group had a better prognosis.Additional analysis indicated that the MUC16 mutations appear to activate the DNA repair and p53 pathways to act as an anti-tumor agent.We also identified a key gene,NPY1R(neuropeptide Y receptor Y1),which was significantly more highly expressed in the MUC16 mutations group than in the MUC16 wild-type group.The high expression of NPY1R predicted a poorer prognosis,which was also confirmed in a separate Gene Expression Omnibus cohort.Further susceptibility analysis revealed that NPY1R might be a potential drug target for gastric cancer.Furthermore,in the analysis of the tumor microenvironment,we found that immune cells in the mutation group exhibited higher anti-tumor effects.In addition,the tumor mutation burden and cancer stem cells index were also higher in the mutation group than in the wild-type group.CONCLUSION We speculated that the MUC16 mutations might activate the p53 pathway and DNA repair pathway:alternatively,the tumor microenvironment may be involved.
基金Supported by Internal Funding from Universitéde Sherbrooke
文摘MUC16(CA125) has remained the mainstay for ovarian cancer assessment and management since the early 1980's. With the exception of HE4, it is the only reliable serum biomarker for ovarian cancer. MUC16 belongs to a family of high-molecular weight glycoproteins known as mucins. The mucin family is comprised of large secreted transmembrane proteins that includes MUC1, MUC4 and MUC16. These mucins are often overexpressed in a variety of malignancies. MUC1 and MUC4 have been shown to contribute to breast and pancreatic tumorigenesis. Recent studies have uncovered unique biological functions for MUC16 that go beyond its role as a biomarker for ovarian cancer. Here, we provide an overview of the literature to highlight the importance of MUC16 in ovarian cancer tumorigenesis. We focus on the growing literature describing the role of MUC16 in proliferation, migration, metastasis, tumorigenesis and drug resistance. Accumulating experimental evidence suggest that the C-terminal domain of MUC16 is critical to mediate theses effects. The importance of MUC16 in the pathogenesis of ovarian cancer emphasizes the need to fully understand the signaling capabilities of MUC16 C-terminal domain to develop more efficient strategies for the successful treatment of ovarian cancer.
文摘目的探究黏蛋白16(MUC16)基因在33种人肿瘤组织内的基因及蛋白表达水平,并探讨其临床意义及在肿瘤发生发展中潜在的机制。方法利用癌症基因组图谱(the cancer genome atlas,TCGA)、基因表达综合数据库(gene expression omnibus,GEO)数据集、人类蛋白图谱(human protein atlas,HPA)和一些生物信息学工具来探索MUC16在33种肿瘤类型中的表达情况,分析其与肿瘤预后的关系和相关通路。结果基因表达以及免疫组织化学染色结果显示,MUC16基因在不同肿瘤中表达不同,且在多种常见肿瘤组织中的表达均升高(P均<0.05)。泛癌Cox回归分析表明,MUC16的高表达通常预示着间皮瘤、肺腺癌等6种肿瘤患者的总生存期(OS)更差。对MUC16以及邻近基因进行富集分析显示,MUC16与肿瘤转录失调密切相关。结论MUC16在多种肿瘤中的表达水平与癌旁组织不同,其功能机制与肿瘤转录失调密切相关。
