Six2调控DNMT1表观遗传修饰E-cadherin在肝癌上皮间质转化及化疗耐药 中的作用及机制研究

肿瘤的复发、转移和获得性耐药的高度关联是导致肝癌治疗失败的主因之一。上皮间质转化（EMT）可使肿瘤细胞具有干细胞的特征，促进侵袭转移及耐药。我们发现转录因子Six2通过下调E-cadherin的表达增强肝癌细胞干性及降低对5-FU敏感性。随后，表观基因组实验发现Six2通过刺激E-cadherin启动子甲基化抑制E-cadherin的表达。并证实沉默Six2使肝癌细胞中DNMT1表达减少。本课题拟进一步阐明Six2是否通过DNMT1介导甲基化修饰调控E-cadherin的表达，促进肝癌细胞EMT及干性能力，并下调5-FU敏感性；揭示Six2调控DNMT1的具体分子机制；探讨E-cadherin激发耐药的下游信号通道，明确Six2-DNMT1-E-cadherin轴的作用、表观遗传机制及临床意义；探讨Six2控制肝癌预后及化疗疗效的转化医学价值。本课题将有望揭示肝癌耐药新机制。

The high correlation between recurrence, metastasis and acquired drug resistance is one of the main cause of the failure of liver cancer treatment. Epithelial mesenchymal transformation (EMT) can make tumor cells have the characteristics of stem cells, promote invasion, metastasis and drug resistance. We found that transcription factor Six2 enhanced the liver cancer cells stemness and decreased the sensitivity to 5-FU via down-regulating the expression of E-cadherin. Subsequently, epigenome experiments showed that Six2 inhibited the expression of E-cadherin by stimulating methylation of E-cadherin promoters. It was also confirmed that silencing Six2 significantly decreased the expression of DNMT1 in liver cancer cells. The purpose of this study is to further elucidate whether Six2 regulates the expression of E-cadherin through DNMT1-mediated methylation modification, promotes the EMT, cells stemness ability, and down-regulates the sensitivity of 5-FU in liver cancer cells. and reveals the specific molecular mechanism of Six2 regulation of DNMT1. To explore the downstream signal channels of drug resistance stimulated by E-cadherin, to clarify the role,epigenetic mechanism and clinical significance of Six2-DNMT1-E-cadherin axis, and to explore the value of Six2 in the control of prognosis and therapeutic effect of chemotherapy in liver cancer This study is expected to reveal a new mechanism of drug resistance in liver cancer .