WWOX通过抑制mTOR通路调控巨噬细胞极化影响肝癌侵袭转移机制研究

原发性肝癌是我国较为常见且预后差的恶性肿瘤之一。循环肿瘤DNA(ctDNA)检测作为液体活检的一种在肿瘤临床研究与实践中发挥着重要作用。课题组前期利用全外显子组测序对高、低转移组肝癌病人的血浆、癌旁、癌和癌栓组织进行研究，发现血浆ctDNA可以准确反映高转移肝癌患者组织基因突变全貌。经过筛选分析发现WWOX基因多态性与肝癌细胞侵袭转移有关。综合临床肝癌样本、体内外实验及生物信息学分析初步证实：WWOX基因低表达与肝癌患者不良预后密切相关并可能通过调控肝癌肿瘤免疫微环境中M1/M2型巨噬细胞的极化影响肝癌的侵袭转移。进一步利用iTRAQ蛋白检测及绝对定量技术发现WWOX可能通过下调S6K蛋白表达水平调控mTOR通路以发挥其上述作用。在此基础上，本项目拟重点研究WWOX通过介导mTOR通路调控巨噬细胞极化以影响肝癌侵袭转移的具体分子机制，为肝癌免疫治疗提供有效的干预靶点。

Primary liver cancer is one of the most common malignant tumors in China with poor prognosis. Circulating tumor DNA (ctDNA) detection as a type of liquid biopsy has been playing an important role in cancer related research and clinical practice. Our group previously carried a whole exome sequencing investigation for both high and low metastasis groups of hepatocellular carcinoma (HCC) patients that included tumor tissues, peritumor tissues, plasma, and tumor thrombus samples. It was found that ctDNA in the plasma can accurately reflect the complete profile of genetic mutations in the high metastasis group of HCC patients. The further screening and analysis revealed that WWOX gene polymorphism is strongly related to the invasion and metastasis abilities of HCC cells. The comprehensive analysis of clinical HCC samples, in-vivo and in-vitro experiments, and the bioinformatic analysis have initially confirmed that the low expression of WWOX is closely related to the poor prognosis of HCC patients and can influence the ability of HCC cells to invade and metastasize by regulating the polarization of M1/M2 macrophages in the immune microenvironment of HCC. Furthermore, by using iTRAQ protein detection and absolute quantitative technologies we found that WWOX could down-regulate the expression level of S6K protein and, therefore, regulate mTOR pathway to achieve the previously mentioned effects. On this basis, this project intends to focus on the specific molecular mechanism by which WWOX mediates mTOR pathway regulation of macrophage polarization to affect the invasion and metastasis of HCC, and to provide effective intervention targets for immunotherapy of HCC.