刘晨冉, 程亚楠, 王妍, 尉迟之光, 于津浦. RYR1基因突变和表达异常在胃癌发生发展中作用机制研究[J]. 中国肿瘤临床. DOI: 10.12354/j.issn.1000-8179.2024.20240105
引用本文: 刘晨冉, 程亚楠, 王妍, 尉迟之光, 于津浦. RYR1基因突变和表达异常在胃癌发生发展中作用机制研究[J]. 中国肿瘤临床. DOI: 10.12354/j.issn.1000-8179.2024.20240105
Chenran Liu, Yanan Cheng, Yan Wang, Zhiguang Yuchi, Jinpu Yu. Role of RYR1 mutation and dysregulation in gastric cancer progression[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY. DOI: 10.12354/j.issn.1000-8179.2024.20240105
Citation: Chenran Liu, Yanan Cheng, Yan Wang, Zhiguang Yuchi, Jinpu Yu. Role of RYR1 mutation and dysregulation in gastric cancer progression[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY. DOI: 10.12354/j.issn.1000-8179.2024.20240105

RYR1基因突变和表达异常在胃癌发生发展中作用机制研究

Role of RYR1 mutation and dysregulation in gastric cancer progression

  • 摘要:
    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,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%),在本院胃癌患者中,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。

     

    Abstract:
    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 and Hospital (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 overexpressing RYR1.
    Results In TCGA gastric cancer patients, the mutation rate of RYR1 in Asian population was higher than that in others population (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 proliferation, 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 behaviors 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 overexpression promoted malignant progression of gastric cancer and chemoresistance by increasing the release of calcium ions from the endoplasmic reticulum. Thus, RYR1 inhibition can reduce the proliferation, migration, and invasion of gastric cancer cells and reverse chemoresistance, which highlights potential combination therapies for gastric cancer.

     

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