MIF/β-catenin通路抑制BMSCs衰老对肝癌细胞索拉非尼耐药的影响

Hepatocellular carcinoma (HCC) is a high morbidity and high mortality malignant disease. The treatment of advanced HCC is still a problem worldwide. Sorafenib, a multikinase inhibitor, is the preferred and only recommended systemic therapy for advanced HCC in the guideline for the diagnosis and treatment of liver cancer. However, its acquired resistance has become a bottleneck that compromise HCC patients’ prognosis. Our previous study found that mesenchymal stem cells (MSCs) participated in tumor microenvironment (TME) of HCC. Co-cultured HCC cells and bone marrow-derived MSCs (BMSCs), HCC cells inhibited BMSCs senescence and promoted sorafenib resistance. Through protein screening, we found that the secretion of various cytokines, including MIF, by HCCs could be a potential mechanism regulating the senescence of BMSCs. Therefore, in this study, we assume that to promote sorafenib resistance, HCC cells could regulate the senescence of MSCs by paracrine cytokines. To clarify the role of MIF / β-catenin signaling pathway in the regulation of MSCs in HCC sorafenib resistance, in vivo and in vitro co-culture systems will be performed. We would like to provide new ideas for the intervention strategies for sorafenib resistance from the viewpoint of HCC regulating the TME.

肝细胞癌是高发病率和高死亡率的恶性肿瘤，晚期肝癌的治疗仍是目前肝癌治疗领域的难题。多激酶抑制剂索拉非尼是肝癌诊疗指南中首先也是唯一推荐的晚期肝癌系统性治疗用药，但其获得性耐药已成为提高肝癌疗效的瓶颈。我们前期研究发现，间充质干细胞（MSCs）参与构成肝癌微环境，共培养肝癌细胞（HCCs）和骨髓来源MSCs（BMSCs）时，HCCs抑制BMSCs衰老，促进HCCs索拉非尼耐药。通过蛋白芯片筛选发现，HCCs分泌包括MIF在内的多种细胞因子可能是调控BMSCs衰老的潜在机制。因此，本研究拟从HCCs调节微环境BMSCs的角度切入，提出HCCs旁分泌MIF激活β-catenin，抑制BMSCs衰老，促进肝癌索拉非尼耐药的假说，拟通过体内、外共培养实验模型，探索MIF/β-catenin在调节BMSCs影响索拉非尼耐药中的机制，从肿瘤细胞调控微环境的角度，为改善索拉非尼耐药提供新的思路及干预策略。

肝细胞癌是高发病率和高死亡率的恶性肿瘤，多激酶抑制剂索拉非尼是晚期肝癌系统性治疗一线用药，但其获得性耐药已成为提高肝癌疗效的瓶颈。间充质干细胞(MSCs)是多种实体肿瘤微环境中的重要间质成分之一，现有研究表明，MSCs通过激活肿瘤细胞增殖相关通路或促进细胞干性，参与肿瘤耐药。然而，MSCs是否在索拉非尼治疗耐药中发挥作用尚未阐明。本项目通过体内、外共培养实验模型，发现肝癌细胞与骨髓来源MSCs(BMSCs)相互作用，改善BMSCs衰老，降低肝癌细胞对索拉非尼的药物敏感性，减少肿瘤细胞凋亡，促进皮下瘤生长。潜在机制探究发现，肝癌细胞与BMSCs相互作用，促进BMSCs中TGFβ上调并激活Sox9相关通路，部分改善了索拉非尼诱导的炎症相关衰老表型，上调了肝癌细胞增殖相关信号通路和组织发育相关通路，参与调节肝癌细胞索拉非尼耐药。进一步关键分子挖掘发现，肝癌细胞中高DLK1表达是共培养体系中介导索拉非尼耐药的关键靶点。本项目从肿瘤细胞调控肿瘤微环境的角度，为改善索拉非尼耐药提供了新的思路及干预策略。