Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma

Liu,Jianhua; Liu,Yahui; Meng,Lingyu; Liu,Kai; Ji,Bai

doi:10.3892/or.2017.5722

Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma

Authors:
- Jianhua Liu
- Yahui Liu
- Lingyu Meng
- Kai Liu
- Bai Ji
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Affiliations: Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: June 14, 2017 https://doi.org/10.3892/or.2017.5722
Pages: 899-907
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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