ESRP1通过调控HDAC6可变剪切抑制胃癌转移的作用机制研究

肿瘤转移是影响胃癌预后的关键因素。ESRP1是一种上皮细胞特异性剪切因子，在维持细胞上皮特性和调控肿瘤进展发挥重要作用，但在胃癌中作用尚不明确。课题组前期发现ESRP1在区域淋巴结或远处转移的胃癌患者中表达降低，且ESRP1低表达患者预后较高表达患者更差；ESRP1通过促进E-cadherin表达而抑制胃癌细胞转移；测序结果显示ESRP1调控HDAC6可变剪切，过表达HDAC6变异体抑制胃癌细胞转移。故我们推测ESRP1通过调控HDAC6可变剪切促进E-cadherin转录进而抑制胃癌转移。为验证以上假说，课题拟进一步通过细胞和动物模型验证ESRP1在胃癌侵袭转移中的作用；利用剪切报告基因系统、ChIP等实验阐明ESRP1通过可变剪切调控HDAC6去乙酰化酶活性进而影响E-cadherin转录及胃癌转移的分子机制。本课题顺利实施将有助于深入探究胃癌转移机制，为胃癌诊治提供新思路及潜在靶点。

Metastasis is a key factor that affect gastric cancer patients’ prognosis. Epithelial splicing regulatory protein 1 (ESRP1) is a specific epithelial splicing factor that plays important roles in maintaining the epithelial cells characteristics and controlling tumor progression. However, the roles of ESRP1 in gastric cancer are unclear. Our study found that ESRP1 was significantly low-expressed in gastric cancer with regional lymph nodes metastasis or distant metastasis. Comparing with the ESRP1 high-expressed patients, ESRP1 low-expressed patients presented worse prognosis. ESRP1 could suppress gastric cancer cells migration in vitro and in vivo, and enhance the expression of E-cadherin. Using the RNA-sequence and RIP-sequence, we demonstrated that ESRP1 could regulate HDAC6 alternative splicing, and HDAC6 variant (HDAC6-ΔE5) inhibited gastric cancer cells migration. Therefore, we speculated that ESRP1 suppressed gastric cancer metastasis and promoted E-cadherin expression via regulating HDAC6 alternative splicing. To clarify the hypothesis, we would further verify the function of ESRP1 in gastric cancer metastasis with cell and animal models. Splicing reporter gene system and ChIP would be used to confirm ESRP1 suppresses gastric cancer metastasis and regulates E-cadherin transcription mediating by the histone deacetylases activities of HDAC6. This subject will help to further understand the molecular mechanisms of gastric cancer metastasis, and provide a novel therapeutic strategy and potential target for gastric cancer treatment.