癌蛋白HBXIP通过上调HMGA2蛋白表达促进食管鳞状细胞癌生长的分子机制研究

食管鳞状细胞癌是常见的消化系统恶性肿瘤，阐明其发生发展的分子机制已成为当今的研究热点。高迁移率蛋白A2（HMGA2）在食管鳞状细胞癌中显著高表达，且与患者不良预后呈正相关。然而，调控HMGA2高表达的分子机制尚不清楚。本课题组前期预实验发现癌蛋白HBXIP在食管鳞状细胞癌中的表达明显高于癌旁组织，且与HMGA2表达呈正相关，并发现HBXIP主要上调HMGA2蛋白表达水平。本申请拟在上述发现基础上，从分子、细胞、组织和动物模型等层次深入研究癌蛋白HBXIP上调HMGA2蛋白表达促进食管鳞状细胞癌生长的分子机制：明确HBXIP在食管鳞状细胞癌中上调HMGA2表达的作用；阐明HBXIP通过调控HMGA2的乙酰化影响其泛素化和蛋白稳定性的分子机制；揭示HBXIP通过调控HMGA2蛋白翻译后修饰及其下游靶基因促进食管鳞状细胞癌生长的作用。本创新发现将为食管鳞状细胞癌的防治和新药研发提供新的靶点。

Esophageal squamous cell carcinoma is a common digestive system malignant tumor. Clarifying the molecular mechanism of its occurrence and development is an international research hotspot. High mobility group protein A2 (HMGA2) is highly expressed in esophageal squamous cell carcinoma and its expression is positively correlated with poor prognosis of patients. However, the reason for the high expression of HMGA2 is not clear. We have found that the expression of oncoprotein HBXIP in esophageal squamous cell carcinoma was significantly higher than that in normal tissues and was positively correlated with HMGA2 expression. In addition, we also found that HBXIP efficiently up-regulated HMGA2 protein expression. Based on the above findings, we will further study the molecular mechanism that oncoprotein HBXIP promotes the growth of esophageal squamous cell carcinoma involving upregulating HMGA2 protein expression. This program will conduct series of studies at molecular, cell, tissue and animal levels as follows: 1. reveal the role of HBXIP in upregulating HMGA2 expression in esophageal squamous cell carcinoma; 2. clarify the molecular mechanism of HBXIP stabilizing HMGA2 by regulating acetylation and ubiquitination of HMGA2; 3. reveal the effect of HBXIP on the growth of esophageal squamous cell carcinoma by regulating the post-translational modification of HMGA2. Our innovation will provide new targets for the prevention, treatment and drug discovery of esophageal squamous cell carcinoma.