LncRNA H19/miRNA-22-3p/SIRT1轴调控EMT促进食管癌侵袭转移作用及其机制研究

转移是导致食管癌预后不良的主要原因，表观遗传学在其中发挥重要的调控作用。我们建立了高转移性食管癌细胞株TE-1/P6，发现该细胞中组蛋白去乙酰化酶SIRT1表达上调并通过抑制E-cadherin促进侵袭转移。通过测序，我们发现lncRNA H19在TE-1/P6中上调580倍并通过上调SIRT1促进侵袭转移。荧光素酶报告实验证实miRNA-22-3p可分别与lncRNA H19和SIRT1结合。据此，我们提出假设：lncRNA H19竞争吸附miRNA-22-3p，削弱其对SIRT1的转录抑制，下调E-cadherin、诱导EMT，促进食管癌侵袭转移。我们拟从组织、动物、细胞及分子四个层面深入研究lncRNA H19/miRNA-22-3p/SIRT1/E-cadherin促进食管癌侵袭转移的分子机制，同时利用PDX模型探索SIRT1抑制剂对侵袭转移的影响，为食管癌精准治疗提供新思路。

Metastasis is the main cause of poor prognosis of esophageal cancer, and epigenetics plays an important role in tumor metastasis. We established a highly metastatic esophageal cancer cell line TE-1/P6, and found that histone deacetylase SIRT1 was up-regulated to promote metastasis by down-regulating E-cadherin. By sequencing, we found that lncRNA H19 was up-regulated 580-fold in TE-1/P6 and promoted metastasis by up-regulating SIRT1. The result of luciferase reporter assay confirmed that miRNA-22-3p could bind to lncRNA H19 and SIRT1, respectively. Based on this, we hypothesized that lncRNA H19 competitively sponges miRNA-22-3p to impair its transcriptional inhibition of SIRT1, down-regulates E-cadherin, induces EMT and promotes metastasis of esophageal cancer. In this study, we intend to reveal the novel molecular mechanism of lncRNA H19/miRNA-22-3p/SIRT1/E-cadherin axis to promote metastasis of esophageal cancer from tissue, animal, cellular and molecular level, and use PDX model to explore the effect of the SIRT1 inhibitor on metastasis, so as to provide new ideas for precise therapy of esophageal cancer.