A role for the NPM1/PTPN14/YAP axis in mediating hypoxia-induced chemoresistance to sorafenib in hepatocellular carcinoma

Dengke Zhang,Jingjing Song,Qiaoyou Weng,Jiansong Ji,Chenying Lu,Xiaoxi Fan,Bufu Tang,Jianfei Tu,Liyun Zheng,Miaomiao Meng,Fazong Wu,Yang Yang,Zhongwei Zhao,Min Xu,Shiji Fang

doi:10.1186/s12935-022-02479-0

Abstract

BackgroundTumor microenvironments are characterized by resistance to chemotherapeutic agents and radiotherapy. Hypoxia plays an important role in the development of tumor resistance, as well as the generation of metastatic potential. YAP also participates in the regulation of hypoxia-mediated chemoresistance, and is negatively regulated by protein tyrosine phosphatase non-receptor type 14 (PTPN14).MethodsThe PTPN14 expression in hepatocellular carcinoma (HCC) tissues were evaluated by qRT-PCR, western blot and tissue microarrays. The effect of PTPN14 on HCC progression was investigated in vitro and in vivo.ResultsHere, we report that PTPN14 expression was downregulated in HCC tissues and cell lines. Silencing PTPN14 significantly enhanced proliferation, migration, invasion of HepG2 cells in vitro and tumor growth and metastasis in vivo, whereas overexpression of PTPN14 significantly inhibited these abilities in SK-Hep1 cells. We also found that hypoxia-induced nuclear translocation and accumulation of PTPN14 led to resistance to sorafenib in HCC cells. Further mechanistic studies suggested that NPM1 regulates PTPN14 localization, and that NPM1 regulates YAP by retaining PTPN14 in the nucleus under hypoxic conditions.ConclusionsThese data suggest that a therapeutic strategy against chemoresistant HCC may involve disruption of NPM1-mediated regulation of YAP by retaining PTPN14 in the nucleus under hypoxic conditions.

Highlights

Tumor microenvironments are characterized by resistance to chemotherapeutic agents and radiotherapy
This result was confirmed by immunohistochemical staining for protein tyrosine phosphatase non-receptor type 14 (PTPN14) in sections of tissue taken from patients with Hepatocellular carcinoma (HCC) (Fig. 1C, D)
We found that PTPN14 expression was significantly lower in HCC lines than in the normal hepatic cell line

Summary

Introduction

Tumor microenvironments are characterized by resistance to chemotherapeutic agents and radiotherapy. YAP participates in the regulation of hypoxia-mediated chemoresistance, and is negatively regulated by protein tyrosine phosphatase non-receptor type 14 (PTPN14). Despite substantial progress in cancer therapeutics, prognosis in patients with HCC remains low [3, 4]. Solid tumors such as HCC are characterized by areas of hypoxia, for various reasons including the absence of access to a blood supply [7, 8]. Tumor hypoxia is associated with radioresistance, chemoresistance and metastasis, eventually leading to cancer progression and poor prognosis [9, 10]. Nuclear translocation and activation of yes-associated protein (YAP) by hypoxia contributes to chemoresistance in hepatocellular carcinoma cells [11, 12].

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Discussion

Conclusion