LINC01446通过调控GADD45A介导肝细胞肝癌对索拉非尼和瑞戈非尼交叉耐药的形成

Sorafenib is a first-line molecular targeting drug for patients with advanced Hepatocellular Carcinoma (HCC). Regorafenib is a second-line treatment for patients with advanced HCC that can prolong the survival of patients with sorafenib resistance. Our group established sorafenib-resistant HCC cell lines and animal models. Cross-drug resistance to regorafenib was identified in these sorafenib resistant cell lines and animal models. We found that the expression of LINC01446 in sorafenib-resistant cells was higher than that in wild-type cells, when the cells were treated with sorafenib or regorafenib. Knocking down LINC01446 restored the sensitivity to regorafenib in the sorafenib-resistant cells. Based on the preliminary work, we hypothesize that LINC01446 binds to the 3'UTR region of GADD45A mRNA to enforce the exposure of its AU-RICH region, resulting in the degradation of GADD45 mRNA and the reduction of its protein level, which consequentially leads to the cross-drug resistance to sorafenib and regorafenib in HCC. This project aims to explore the molecular mechanism that are involved in cross-drug resistance of targeted chemotherapy, and to clarify the role of LINC01446 in the cross-drug resistance to sorafenib and regorafenib in hepatocellular carcinoma. The findings from this project will provide new insights into drug selection, efficacy monitoring and prognosis assessment for advanced HCC treatment, and establish a theoretical basis for the optimization of sequential targeted therapies for advanced HCC.

索拉非尼为晚期肝癌病人的一线靶向药物，因耐药导致疗效不佳。瑞戈非尼是索拉非尼耐药后的二线续贯治疗药物。本课题组构建了索拉非尼耐药的肝癌细胞株及其耐药动物模型，发现耐药细胞株以及耐药动物模型存在对瑞戈非尼的交叉耐药。我们发现，LINC01446在索拉非尼和瑞戈非尼处理的索拉非尼耐药株中均相较野生株表达升高，将其敲减后可使索拉非尼耐药细胞株恢复对瑞戈非尼的敏感性。在大量前期工作的基础上，本课题组提出假说：LINC01446通过结合GADD45A的mRNA 3’UTR区，使其AU-RICH区被暴露，致其mRNA降解和蛋白水平的降低，继而使肝细胞肝癌产生对索拉非尼和瑞戈非尼的交叉耐药。本项目拟创新性地探索靶向药物交叉耐药机制，阐明LINC01446在肝细胞肝癌索拉非尼和瑞戈非尼交叉耐药中扮演的角色，为晚期肝癌治疗的药物选择、疗效监测及预后评估提供新思路，为肝癌序贯性靶向治疗的优化提供理论依据。

肝细胞肝癌是最常见的肝脏恶性肿瘤。索拉非尼为晚期肝癌病人的一线靶向药物，因耐药导致疗效不佳。瑞戈非尼是索拉非尼耐药后的续贯治疗药物。本课题组构建了耐索拉非尼的耐药细胞株及其裸鼠成瘤模型，发现耐药肝癌细胞株及其裸鼠模型对瑞戈非尼不敏感，存在交叉耐药。我们筛选出了耐药株中高表达的 lncRNA：LINC01446，并发现细胞在用小干扰 RNA 敲减 LINC01446 后，对瑞戈非尼的敏感性增强，与下游 NFKBIA 共同介导交叉耐药的形成。在大量前期工作的基础上，我们预期LINC01446 通过结合 NFKBIA 的 启动子区域，在转录水平上抑制 NFKBIA 的 RNA 生成，从而产生对索拉非尼和瑞戈非尼的交叉耐药。本项目拟研究 LINC01446 在肝癌中对索拉非尼和瑞戈非尼交叉耐药过程中扮演的角色，创新性探索靶向药物交叉耐药机制，为晚期肝癌治疗的药物选择、疗效预测及预后评估提供新思路。