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

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.

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。

作为一种结构转录因子，高迁移率蛋白A2（HMGA2）能够通过激活其靶基因的转录，来调控某些类型肿瘤的恶性进展。在乳腺癌、结直肠癌及肺癌中，HMGA2常常高表达，并且其高表达与这几种肿瘤病人的低生存率密切相关。然而，在癌症尤其是食管鳞状细胞癌（ESCC）中，高表达的HMGA2功能及其高表达的调控机制尚不清楚。在本研究中，我们发现HMGA2在翻译后水平上受到具有致癌作用的转录辅激活因子HBXIP调控，从而发挥促进食管鳞状细胞癌生长的作用。对包含多个正常食管组织和ESCC组织的组织芯片进行免疫组织化学分析发现，临床ESCC组织中HMGA2和HBXIP的表达之间存在正相关关系。同时发现，ESCC患者中HMGA2和HBXIP的表达增加与肿瘤分期恶性进展和生存率降低有关。在ESCC细胞系中的研究发现，HBXIP能够在翻译后水平调控HMGA2表达。在后续的调控机制研究中发现，癌蛋白HBXIP能够通过乙酰转移酶，p300/CBP相关因子（PCAF），诱发ESCC细胞中HMGA2的26位赖氨酸（K26）发生乙酰化，最终促使细胞中HMGA2蛋白不断积累。进一步研究表明，HBXIP能够通过Akt途径诱导PCAF的磷酸化和激活，从而导致HMGA2的乙酰化增强。HMGA2乙酰化可以阻止其泛素化和蛋白酶体依赖性降解，最终导致其稳定性大大提高。在功能方面，HBXIP介导的HMGA2稳定性增强明显提高了其激活靶基因的转录因子活性，从而加速了体外和体内ESCC细胞生长。作为一种经典的抗炎药，阿司匹林（ASA）能够通过靶向HBXIP和HMGA2抑制ESCC细胞的生长。最终本项目发现，HMGA2蛋白的稳定性受同一赖氨酸位点的竞争性乙酰化和泛素化修饰控制。该成果揭示了ESCC中HBXIP/Akt/PCAF轴介导的HMGA2翻译后调控的新机制。该研究为食管鳞状细胞癌分子靶向治疗提供了新的理论依据，具有重要的学术价值和良好的临床应用前景。在临床上，ASA可以通过阻断HBXIP/HMGA2作为ESCC的一种潜在治疗手段。