Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
Oncol Rep. 2017 Aug;38(2):899-907. doi: 10.3892/or.2017.5722. Epub 2017 Jun 14.
Molecule-targeted therapy, such as sorafenib, is one of the effectively therapeutic options for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib has been found in some HCC patients, resulting in poor prognosis. It is reported that PD-L1 and DNA methyltransferases (DNMTs) contribute to drug resistance. In this study, by inducing sorafenib-resistant HCC cell lines, we investigated their molecular and functional characteristics. Our data indicated that highly upregulated DNMT1 was positively correlated with PD-L1 overexpression in sorafenib-resistant HCC cells. We demonstrate that PD-L1 regulate DNMT1 through STAT3 signaling pathway. Knockdown of PD-L1 induced DNMT1-dependent DNA hypomethylation and restored the expression of methylation-silenced CDH1. Moreover, inactivation of NFκB blocked PD-L1/STAT3/DNMT1 pathway in sorafenib-resistant HCC cells. Functionally, genetic or pharmacological disruption of PD-L1 or/and DNMT1 sensitize HCC resistance to sorafenib. Importantly, dual inactivation of PD-L1 and DNMT1 by their inhibitor synergistically disrupts the colony formation of sorafenib-resistant HCC cells. These results demonstrate that targeting NFκB/PDL1/STAT3/DNMT1 axis is a new therapeutic strategy for preventing or overcoming the acquired resistance to sorafenib in HCC patients.
分子靶向治疗，如索拉非尼，是晚期肝细胞癌（HCC）的有效治疗选择之一。然而，一些 HCC 患者对索拉非尼产生了获得性耐药，导致预后不良。据报道，PD-L1 和 DNA 甲基转移酶（DNMTs）有助于耐药性的产生。在这项研究中，我们通过诱导索拉非尼耐药 HCC 细胞系，研究了它们的分子和功能特征。我们的数据表明，DNMT1 的高度上调与索拉非尼耐药 HCC 细胞中 PD-L1 的过表达呈正相关。我们证明 PD-L1 通过 STAT3 信号通路调节 DNMT1。PD-L1 的敲低诱导了 DNMT1 依赖性的 DNA 低甲基化，并恢复了甲基化沉默的 CDH1 的表达。此外，NFκB 的失活阻断了索拉非尼耐药 HCC 细胞中 PD-L1/STAT3/DNMT1 通路。功能上，PD-L1 或/和 DNMT1 的遗传或药理学破坏使 HCC 对索拉非尼的耐药性敏感。重要的是，其抑制剂对 PD-L1 和 DNMT1 的双重失活协同破坏了索拉非尼耐药 HCC 细胞的集落形成。这些结果表明，靶向 NFκB/PDL1/STAT3/DNMT1 轴是预防或克服 HCC 患者获得性索拉非尼耐药的新治疗策略。
