HBV相关性肝癌多药耐药调控的分子机制研究：SATB1的作用及意义

Primary liver cancer is one of the most common malignant tumors worldwide, and surgery was not available for many patients when definited as liver cancer, transcatheter arterial chemoembolization(TACE) can provide survive benefit for individuals who are not good candidates for curative treatments. HBV infection, the major cause of HCC, always leads to the insufficient local chemotherapeutic curative effect through regulation of multidrug resistance (MDR). Our previous studies indicated that HBx, one of seven proteins coded by HBV, could induce the expression of MDR proteins which was able to enhance drug resistance of liver cancer cell, but the mechanism remained unknown. Due to the insufficient curative effect of anti-HBV therapy, to explore specific and HBV related upstream genes of MDR proteins is essential for the improvement of chemotherapies in liver cancer associated with HBV. In addition, we also found that HBx could induce increased expression of SATB1 which was involved in the regulation HBx to MDR genes.Therefore, the mechanism that HBx regulate MDR proteins and induce multidrug resistance through SATB1 remained to be clarified. According to the previous research, we will further invest the role and the molecular mechanism of SATB1 in HBx upregulating MDR proteins and enhance drug resistance of HBV-related hepatocellular carcinoma, and to explore poteintial targets that could ameliorate local chemotherapeutic curative effect of HBV-related hepatocellular carcinoma.

原发性肝癌是常见恶性肿瘤，临床确诊时多已失去手术时机，此时，经导管肝动脉局部化疗栓塞成为中晚期肝癌患者延长生命的重要治疗手段。HBV感染为公认的肝癌主要病因，HBV相关性肝癌的多药耐药（MDR）使其局部化疗效果也差。我们预实验提示：在HBV编码的七个蛋白中，HBx能诱导MDR基因表达并增强肝癌细胞耐药性，但其调控机制不明。目前抗HBV治疗的疗效并不理想，研究HBx通过何种机制调控MDR基因，由此寻找潜在干预靶点尤为重要。我们进一步研究表明，HBx可诱导SATB1过表达；且SATB1参与了HBx对MDR基因及耐药性的调控。但HBV编码蛋白HBx通过SATB1调控MDR基因并诱导肝癌细胞多药耐药的分子机制不明。因此，本课题组拟在前期实验基础上，深入探讨SATB1在HBx上调MDR基因及增强HBV相关性肝癌多药耐药中的作用及其分子机制，以期寻找改善HBV相关性肝癌局部化疗效果的潜在干预靶点。

研究背景：原发性肝癌（HCC）是常见恶性肿瘤，临床确诊时多已失去手术时机。HBV感染为公认的HCC主要病因，目前抗HBV的疗效并不理想，要想持续清除体内病毒也很困难。HCC易出现早期转移，大部分患者临床确诊时已经失去了手术时机，此时，经导管肝动脉局部化疗栓塞（TACE）成为中晚期肝癌患者延长生命最重要的治疗手段，但HBV相关性HCC的多药耐药（MDR）使其局部化疗效果也差。那么，从抗HBV治疗入手达到抑制肝癌细胞多药耐药的目的，效果必然不能令人满意。研究HBx通过何种机制调控MDR基因，由此寻找潜在干预靶点尤为重要。.重要结果：我们首先检测了60例肝癌及癌旁组织中SATB1的表达，发现SATB1在肝癌组织中的表达明显高于相应癌旁组织，且SATB1的高表达与肝癌肿瘤大小、分化、门脉侵袭、淋巴转移、HBV感染等临床病理特征密切相关。进一步细胞水平检测发现HBV阳性及高侵袭性的肝癌细胞株中SATB1高表达；将HBV编码的七个蛋白分别转染肝癌细胞，HBx可诱导SATB1高表达；检测肝癌细胞中的相应信号通路分子，SATB1通过激活JNK+P38MAPK/c-jun/AP-1信号转导通路参与了对多药耐药基因MDR1及耐药性的调控。动物实验水平也证实了SATB1能促进肿瘤生长及转移。.科学意义：本课题组在前期实验基础上，深入探讨了SATB1在调控多药耐药基因及增强HBV相关性HCC多药耐药中的作用机制，对改善HBV相关性HCC局部化疗效果提供了重要理论依据。