糖代谢异常在肝癌介入中的作用及治疗研究

Transarterial chemoembolization (TACE) has been recommended as the preferred method for patients with unresectable hepatic carcinoma. However, the high incidence of palindromia and metastasis of hepatocellular carcinoma after interventional therapy has been a disturbing problem constraining the curative effect and wide application of intervenional therapy. The anomalous glucose metabolism of hepatocellular carcinoma mainly manifest as glycolysis. Previous studies have dedicated that abnormal glycolysis plays an important role in tumorgenesis and development of hepatic carcinoma, and relative glucolysis proteins have been regarded as a novel therapeutical target. Thus, abnormal glucolysis might be an essential element in neoplasm recurrence and metastasis after interventional therapy. However, the role of glucolysis in the palindromia and metastasis of hepatocellular carcinoma after interventional therapy remains unclear. Through establishing wild rat with hepatic carcinoma, we aim to explore the alteration of glucolysis relative proteins after transcatheter arterial embolization (TAE), and the relationship with tumor proliferation, metastasis and angiogenesis. Then by constructing relative ShRNA, we would explore the effects of ShRNA on liver tumors in rat. By culturing human hepatic carcinoma cells HepG2 in hypoxia condition, further explore the mechanism and signal pathway of hypoxia regulating glucolysis relative proteins. This research could provide not only a deep insight for the mechanism of palindromia and metastasis of liver cancer, but also a novel theoretical foundation for clinical diagnosis and therapy.

经肝动脉化疗栓塞已成为肝癌患者非手术切除的首选治疗方法。但是，介入治疗后肿瘤的复发和转移仍是掣肘其疗效和广泛应用的重要因素。肝癌细胞的异常糖代谢主要表现为糖酵解。研究发现糖酵解异常在肝癌的发生发展中具有重要作用，相关的糖酵解蛋白已被推荐作为新的药物治疗靶点。据此推测糖酵解异常也可能在介入治疗术后肿瘤复发和转移中发挥重要作用。然而，糖酵解异常在介入治疗术后肿瘤的复发及转移中的作用迄今尚无相关研究。因此，本项目拟通过构建大鼠肝癌模型，探究肝动脉栓塞术前后糖酵解相关蛋白的变化，及其与肿瘤增殖、转移以及血管生成等的关系，并通过构建ShRNA进一步行体内干预，探究其疗效；进一步通过建立人肝癌细胞HepG2缺氧模型，探究缺氧调节糖酵解相关蛋白改变的机制和信号通路。希望通过此研究，加深和明确介入治疗后肝癌复发和转移的相关机制，也为肝癌的临床诊疗提供新的理论基础和治疗靶点。

中文摘要：肝动脉化疗栓塞（TACE）是治疗肝癌的重要手段之一。但是，TACE术后肿瘤的复发与转移仍是其目前面临的一大难题。本研究发现，在肝癌组织中，HIF-1α的表达显著增加，通过抑制HIF-1α可显著降低糖酵解相关蛋白的表达。其次，在糖酵解导致的酸性环境中，HIF-1α可通过上调NHE1的表达，降低细胞内pH值，从而促进肿瘤的增殖与转移。此外，本课题也进一步发现，EGF可通过ERK1/2通路调控HIF-1α的表达。综上，本课题初步阐明了肝癌组织缺氧后糖酵解发生的机制及其微环境调控作用，为肝癌的治疗提供了新的治疗靶点。在本课题的支持下，课题组目前已发表论文8篇。