文章：

索拉非尼耐药性在肝细胞癌中由IL7和MAL2介导，可通过自噬诱导型订书肽克服

Sorafenib Resistance Contributed by IL7 and MAL2 in Hepatocellular Carcinoma Can Be Overcome by Autophagy-Inducing Stapled Peptides

原文发布日期：3 November 2023

DOI: 10.3390/cancers15215280

类型: Article

开放获取: 是

英文摘要：

Drug resistance poses a great challenge in systemic therapy for hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms associated with resistance to anti-cancer drugs, such as Sorafenib, remain unclear. In this study, we use transposon insertional mutagenesis to generate Sorafenib-resistant HCC cell lines in order to identify potential drug resistant causative genes. Interleukin 7 (IL7) and mal, T cell differentiation protein 2 (MAL2) were identified as candidate genes that promote survival by activating JAK/STAT and PI3K/AKT signaling pathways. Sorafenib-resistant cells exhibited higher clonogenic survival and lower drug sensitivity due toIL7andMAL2upregulation. Higher anti-apoptotic effect, clonogenic survival and increased PI3K/AKT/STAT3 activities were observed inIL7andMAL2co-overexpressing cells compared with controls or cells overexpressingIL7orMAL2individually. Given the critical role of MAL2 in endocytosis, we propose that MAL2 might facilitate the endocytic trafficking of IL7 and its cognate receptors to the plasma membrane, which leads to upregulated JAK/STAT and PI3K/AKT signaling pathways and Sorafenib resistance. Additionally, our previous studies showed that an autophagy-inducing stapled peptide promoted the endolysosomal degradation of c-MET oncogene and overcame adaptive Sorafenib resistance in c-MET+HCC cells. In this study, we demonstrate that these stapled peptides readily induced autophagy and inhibited the proliferation of both wild-type and Sorafenib-resistant HCC cells co-overexpressing bothIL7andMAL2. Furthermore, these peptides showed synergistic cytotoxicity with Sorafenib in drug-resistant HCC cells co-overexpressing bothIL7andMAL2. Our studies suggest that targeting autophagy may be a novel strategy to overcome IL7/MAL2-mediated Sorafenib resistance in HCC.

摘要翻译： 

耐药性是肝细胞癌（HCC）系统治疗面临的重大挑战。然而，与索拉非尼等抗癌药物耐药相关的潜在分子机制尚不明确。本研究利用转座子插入诱变技术构建索拉非尼耐药性HCC细胞系，以鉴定潜在的耐药致病基因。研究发现白细胞介素7（IL7）和T细胞分化蛋白2（MAL2）通过激活JAK/STAT和PI3K/AKT信号通路促进细胞存活。IL7和MAL2的上调使耐药细胞表现出更强的克隆形成能力和更低的药物敏感性。与对照组或单独过表达IL7/MAL2的细胞相比，IL7与MAL2共过表达的细胞具有更强的抗凋亡效应、克隆形成能力及更高的PI3K/AKT/STAT3通路活性。鉴于MAL2在内吞作用中的关键功能，我们提出MAL2可能通过促进IL7及其同源受体的内吞转运至质膜，从而上调JAK/STAT和PI3K/AKT信号通路并导致索拉非尼耐药。此外，我们前期研究表明自噬诱导型订书肽能促进c-MET癌基因的内溶酶体降解，并克服c-MET阳性HCC细胞的适应性索拉非尼耐药。本研究发现这些订书肽能有效诱导自噬，抑制野生型及IL7/MAL2共过表达的索拉非尼耐药HCC细胞增殖，且在耐药细胞中与索拉非尼产生协同细胞毒性。我们的研究表明，靶向自噬可能是克服HCC中IL7/MAL2介导的索拉非尼耐药的新策略。

原文链接：

Sorafenib Resistance Contributed by IL7 and MAL2 in Hepatocellular Carcinoma Can Be Overcome by Autophagy-Inducing Stapled Peptides