miR-200b-3p靶向调控Liprin-alpha1诱导侵袭性伪足形成促进食管癌局部浸润的分子机制研究

Esophageal cancer was characterized by geographical and ethnic differences, the incidence of esophageal cancer in Xinjiang is much higher than the national average. Local infiltration is a crucial initial step in the metastasis of esophageal cancer, resulting in a five-year survival of as low as 20%. The invadopodia, a characteristic of tumor cells, is a key starting point for malignant phenotypes such as invasion and metastasis. In the previous study, we found that Liprin-a1 gene, was significantly up-regulated in esophageal cancer and miR-200b-3p was remarkably down-regulated, related with high malignancy behaviors and poor prognosis of esophageal cancer. But its mechanism of action is not yet clear. In this study, we hypothesized that miR-200b-3p targeted Liprin-a1, activated Cortactin, thereby promoting the development of invadopodia, causing extracellular matrix degradation. We are going to explore the esophageal cancer Liprin-a1 by invasive pseudopodia formation of esophageal cancer invasion and metastasis of the regulatory mechanism for Esophageal cancer clinical treatment of potential new targets and prognosis provide the basisregulation between miR-200b-3p and Liprin-a1 from the cell level, animal models, and clinical specimens three levels, using the fluorescence confocal, co-immunoprecipitation and other techniques involved. The study will provide the theoretical evidence for the treatment of esophageal cancer of Kazakh in Xinjiang.

食管癌发病具有明显地域和种族差异性，新疆食管癌发病率远高于全国平均水平。局部浸润是食管癌转移的关键起始步骤，导致五年生存率低至20%。肿瘤细胞特有结构侵袭性伪足的形成，是引起食管癌浸润转移等恶性表型的关键起始节点。本课题组前期发现与黏着斑和侵袭性伪足形成密切相关基因Liprin-a1在食管癌中表达上调，同时抑癌基因miR-200b-3p表达下调，造成食管癌恶性程度高，预后差，但其作用机制尚不明确。本研究围绕miR-200b-3p靶向调控Liprin-a1，激活侵袭性伪足中心分子Cortactin，从而促进侵袭性伪足的成熟，引起细胞外基质降解，介导食管癌发生局部浸润的分子机制，拟从细胞水平、动物模型、临床标本三个层面，应用荧光共聚焦、免疫共沉淀等技术，探讨食管癌中Liprin-a1通过侵袭性伪足形成促进食管癌浸润转移的调控机理，为食管癌的临床治疗潜在新靶点和预后预测提供依据。

食管癌发病具有明显地域和种族差异性，浸润转移是导致食管癌五年生存率低的主要原因。本课题围绕“miR-200b-3p低表达，转录后调控Liprin-α1过表达促进ESCC细胞形成侵袭性伪足和强化肿瘤细胞的局部浸润”，这一科学假说，采用体外细胞模型、体内荷瘤模型及临床组织标本的三个层面，运用基因过表达，RNA干扰，荧光素酶活性实验，激光共聚焦，分子影像等分子生物学和生物化学技术方法，深入解析miR-200b-3p转录后调控Liprin-α1基因在 ESCC细胞侵袭性伪足的形成和在肿瘤转移中的作用。结果发现：Liprin-α1在癌组织机构癌旁组织中表达具有明显差异，且与临床分期和淋巴结转移及预后呈负相关。同时体外细胞模型和体内荷瘤模型证实Liprin-α1可促进食管癌细胞的转移，并受上游miR-200-3p的负性调控，从而影响侵袭性伪足的形成，为ESCC的临床治疗和预后预测提供新的思路和实验依据。