钙离子通道TRPV6通过促进ANXA11/p21通路抑制食管鳞癌增殖的机制研究

食管鳞癌高死亡率与增殖密切相关。我们前期研究发现钙离子通道蛋白TRPV6在食管鳞癌低表达，且抑制肿瘤细胞增殖。然而，TRPV6低表达的调控及其抑制食管鳞癌增殖的作用机制尚未明确。生物信息分析我们发现TRPV6低表达与其DNA高度甲基化和转录因子MYC负调控密切相关。机制研究发现TRPV6可介导Ca2+激活ANXA11/CREB/p21通路阻滞细胞周期G1/S进程，而抑制肿瘤增殖。本项目拟利用甲基化敏感性高分辨率熔解、ChIP-Seq等技术研究TRPV6低表达的调控机制。通过Trpv6敲除小鼠诱发食管癌模型明确TRPV6对食管鳞癌增殖的抑制作用，进一步揭示其抑制增殖的分子机制。采用组织芯片明确TRPV6及其下游调控蛋白与患者预后相关性，最后探讨细胞周期阻滞剂作为TRPV6低表达食管鳞癌的治疗策略。因此本项目阐明TRPV6低表达以及抑制食管鳞癌增殖的新机制，以期为食管鳞癌的诊治提供新的靶点。

The high mortality of esophageal squamous cell carcinoma (ESCC) is predominantly related to its aggressive proliferation. Thus, it is of great scientific interest and clinical urgency to explore the underlying mechanism of ESCC proliferation and identify prognostic factor or clinical target for ESCC. To this end, we revealed that TRPV6 (transient receptor potential vanilloid 6), a highly selective calcium channel, was markedly downregulated in ESCC tissues. Furthermore, we found that TRPV6 played a tumor-suppressive role both in vitro and in vivo. However, the mechanisms underlying TRPV6 downregulation and its inhibitory effects on ESCC proliferation remain largely unknown. Our preliminary analysis showed that TRPV6 was tightly controlled by DNA hypermethylation and transcription repressor MYC. TRPV6 further performed tumor suppressive roles in ESCC by upregulating Ca2+-dependent proteins like ANXA11 to active CREB and thus inhibited cell cycle progression in G1 phase. In the proposed study, we plan to elucidate the biological effects of TRPV6 on ESCC proliferation via Trpv6 knockout mice with esophageal cancer model, and further explore the potential roles of TRPV6 as a tumor suppressor. Furthermore, we aim to elucidate the role of TRPV6 and its downstream proteins in predicting survival of patients with ESCC. Finally, we would like to evaluate the potential therapeutic efficacy of CDK4/6 inhibitor in ESCC with low expressed TRPV6. Therefore, these findings will provide the theoretical foundation for defining novel therapeutic targets or prognosis markers on TRPV6/ANXA11/CREB axis for ESCC.