全反式维甲酸ATRA抑制DKK1介导的PI3K-AKT信号通路降低肝癌干细胞干性增强化疗敏感性

耐药是影响肝癌合并门脉癌栓（PVTT）化疗疗效的主要原因之一。前期研究发现，耐药的肝癌细胞具有很强的肿瘤干细胞干性，全反式维甲酸（ATRA）可显著降低肝癌干细胞的干性，提高铂类药物化疗疗效，临床应用后证实获益。通过对ATRA联合铂类化疗敏感病人和ATRA处理过的细胞系进行高通量基因转录组测序，发现基因DKK1存在显著差异表达。进一步研究发现，DKK1可以降低肝癌干细胞的干性和细胞的增殖侵袭等功能；DKK1缺失可引起促肿瘤的PI3K-AKT信号通路的抑制；同时ATRA可以促进对Wnt信号通路具有抑制作用的HOXA5基因的表达，这暗示ATRA可能是通过促进HOXA5进而抑制DKK1介导的PI3K-AKT信号通路而降低肝癌肿干细胞干性和耐药性的。我们将通过一系列基础和临床实验研究ATRA调控DKK1降低肝癌干细胞干性和耐药性的机制及DKK1作为ATRA联合铂类药物化疗敏感标记物的可行性。

Drug resistance is one of the main reasons affecting the efficacy of liver cancer combined with portal vein thrombosis (PVTT) chemotherapy. Previous studies have found that drug-resistant liver cancer cells have strong tumor stem cell stemness. All-trans retinoic acid (ATRA) can significantly reduce the stemness of liver cancer stem cells, improve the efficacy of platinum-based chemotherapy, and have proven to be beneficial after clinical application. At the same time, high-throughput sequencing was performed on patients who were sensitive to the chemotherapy of ATRA combined with platinum drugs and ATRA-treated cell lines. The results indicated that the Wnt signaling pathway protein DKK1 over expressed in ATRA-sensitive patients, while down-regulated in ATRA-treated cells. According to TCGA database, DKK1 is closely related to the prognosis of liver cancer. Further studies indicated that DKK1 could also inhibit the stemness, proliferation, invasion and migration. Reduction of DKK1 could cause down-regulation of PI3K-AKT signaling pathway, which is helpful for tumorigenesis and metastasis. Meanwhile, ATRA could promote the expression of HOXA5, which can inhibit the Wnt signaling pathway. Above all, It is suggested that ATRA may reduce the stemness and drug resistance of hepatocellular carcinoma stem cells by promoting HOXA5 and then inhibiting DKK1-mediated PI3K-AKT signaling pathway. We will explore a series of basic and clinical experiments to study the mechanism of ATRA regulating DKK1 to reduce the stemness and drug resistance of cancer stem cells, and the feasibility of DKK1 as a sensitive marker for chemotherapy of ATRA combined with platinum drugs in order to develop an individualized and precise treatment strategy for liver cancer patients.