FAM117B通过调控Nrf2信号影响胃癌细胞生长和化疗敏感性的机制研究

胃癌是常见的消化系统恶性肿瘤之一。其在发展的过程中由于受到复杂分子机制的调控会表现出恶性生长和对化疗药物不敏感，导致患者的预后较差。因此，研究影响胃癌细胞生长和化疗敏感性的分子机制并寻找有效的治疗靶点具有十分重要的意义。我们在前期的研究中发现FAM117B在胃癌肿瘤组织中高表达并且与病人的不良预后相关；FAM117B的表达能够影响胃癌细胞的生长和化疗敏感性。进一步的研究发现FAM117B不仅能够调控胃癌细胞中的Nrf2信号，而且还能够与Keap1的DGR结构域结合。基于这些前期发现，申请人提出假说：FAM117B通过与Nrf2竞争性结合Keap1，抑制胃癌细胞中Nrf2的泛素化降解，上调Nrf2的蛋白水平，并激活Nrf2信号通路，从而影响细胞的生长和化疗敏感性。本课题旨在证实这一科学假说，明确FAM117B调控胃癌细胞生长和化疗敏感性的分子机制，为胃癌的治疗提供新的靶点。

Gastric cancer is one of the most common malignancies of the digestive system. Due to the regulation of complex molecular mechanisms, it often shows malignant growth and insensitivity to chemotherapy drugs in the process of development, leading to poor prognosis of patients. Therefore, it is of great significance to study the molecular mechanism that affect the growth and chemosensitivity of gastric cancer cells and to search for effective therapeutic targets. In our previous study, we found that FAM117B was highly expressed in gastric cancer tissues and was associated with poor prognosis of patients. Moreover, FAM117B could affect the growth and chemosensitivity of gastric cancer cells. Further studies showed that FAM117B could not only regulate Nrf2 signaling in gastric cancer cells, but also bind to the DGR domain of Keap1. Based on these previous findings, the applicant proposed a hypothesis: FAM117B competed with Nrf2 for Keap1 binding, prevented the intracellular Nrf2 ubiquitination degradation, upregulated the protein level of Nrf2 and activated the Nrf2 signaling pathway, thus affecting the growth and chemosensitivity of gastric cancer cells. The aim of the study is to confirm this scientific hypothesis, clarify the molecular mechanism of FAM117B regulating the growth and chemosensitivity of gastric cancer cells, and provide a new target for the treatment of gastric cancer.