首页|RYR1基因突变和表达异常在胃癌发生发展中作用机制研究

RYR1基因突变和表达异常在胃癌发生发展中作用机制研究

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目的:探讨RYR1基因与胃癌发生发展的相关性以及RYR1促进胃癌恶性进展的作用机制.方法:分析TCGA数据库胃癌患者数据,并回顾性选取 2010年 12月至 2012年 12月就诊于天津医科大学肿瘤医院的 81例胃癌患者的组织样本进行高通量靶向测序和转录组测序(TJMUCH队列),收集临床病理信息,比较RYR1基因突变与表达之间相关性,分析RYR1基因对胃癌患者预后的影响,构建RYR1过表达细胞系探索RYR1促进胃癌发生发展的作用机制.结果:在TCGA数据库胃癌患者中,亚洲人群RYR1突变率更高(12.68%vs.8.13%),在TJMUCH队列胃癌患者中,RYR1基因突变率位于第 9位,突变率为 33.33%.RYR1突变与表达水平显著负相关(P=0.006 9,P<0.000 1),但RYR1高表达患者的总生存期显著差于低表达RYR1患者(P=0.009 0,P=0.042 0).RYR1的过表达会促进细胞增殖、迁移、侵袭,减少凋亡,且可下调胃癌细胞对化疗药物的敏感性.抑制RYR1介导的钙离子过度释放可以抑制其恶性生物学行为,并逆转化疗耐药.结论:RYR1基因在亚洲胃癌患者中突变率较高,RYR1突变与表达水平显著负相关,RYR1高表达是胃癌新的预后预测标志物.RYR1过表达可增加内质网钙离子释放而促进胃癌恶性进展,并产生化疗抵抗.靶向阻断RYR1活性可抑制胃癌细胞的增殖、迁移和侵袭,并逆转化疗药抵抗,为胃癌的联合治疗提供新思路.
Role of RYR1 mutation and dysregulation in gastric cancer progression
Objective:To investigate the correlation between RYR1 gene and the development of gastric cancer,as well as the mechanism of RYR1 in promoting the progression of gastric cancer.Methods:We analyzed gastric cancer data from TCGA and conducted high-throughput targeted sequencing and transcriptome sequencing on 81 gastric cancer tissue samples at Tianjin Medical University Cancer Institute&Hos-pital(TJMUCH)from December 2010 to December 2012.We collected clinicopathological data,compared the correlation between RYR1 mutations and expression levels,and analyzed the impact of RYR1 on the prognosis of patients with gastric cancer.Additionally,we explored the underlying molecular mechanism to study its role in promoting the development of gastric cancer by generating stable cell lines overex-pressing RYR1.Results:In TCGA gastric cancer patients,the mutation rate of RYR1 in Asian population was higher than that in others popula-tion(12.68%vs.8.13%).In gastric cancer patients from TJMUCH,RYR1 mutations ranked ninth in frequency,with a mutation rate of 33.33%.Mutations in RYR1 were negatively correlated with RYR1 expression(P=0.006 9,P<0.000 1).Patients with high RYR1 expression had significantly worse overall survival than those with low RYR1 expression(P=0.009 0,P=0.042 0).Overexpression of RYR1 promoted prolifera-tion,migration,invasion and reduced apoptosis of gastric cancer cell lines.Moreover,RYR1 overexpression was associated with decreased sensitivity to chemotherapeutic drugs in gastric cancer cells.Inhibiting RYR1-mediated calcium over-release could suppress malignant beha-viors and reverse chemoresistance.Conclusions:RYR1 had a high mutation rate in Asian gastric cancer patients and a significantly negative correlation with RYR1 mRNA levels.High RYR1 expression serves as a novel prognostic predictive marker for gastric cancer.RYR1 overex-pression promoted malignant progression of gastric cancer and chemoresistance by increasing the release of calcium ions from the endo-plasmic reticulum.Thus,RYR1 inhibition can reduce the proliferation,migration,and invasion of gastric cancer cells and reverse chemores-istance,which highlights potential combination therapies for gastric cancer.

gastric cancerRYR1 genegene mutationgene expressioncalcium ion

刘晨冉、程亚楠、王妍、尉迟之光、于津浦

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天津医科大学肿瘤医院肿瘤分子诊断中心,国家恶性肿瘤临床医学研究中心,天津市恶性肿瘤临床医学研究中心,天津市"肿瘤防治"重点实验室,天津市肿瘤免疫与生物治疗重点实验室(天津市 300060)

天津大学药物科学与技术学院

胃癌 RYR1基因 基因突变 基因表达 钙离子

天津医科大学肿瘤医院肿瘤研究所"肿瘤防治研究专项"重点研究计划(十四五)天津市医学重点学科(专科)建设项目

YZ-01-2TJYXZDXK-009A

2024

中国肿瘤临床
中国抗癌协会

中国肿瘤临床

CSTPCD北大核心
影响因子:1.32
ISSN:1000-8179
年,卷(期):2024.51(6)
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