Endoplasmic reticulum stress promotes sorafenib resistance via miR-188-5p/hnRNPA2B1-mediated upregulation of PKM2 in hepatocellular carcinoma

Bei Zhou,Donghui Lu,Anqi Wang,Jie Cui,Li Zhang,Jian Li,Lulu Fan,Wei Wei,Jiatao Liu,Guoping Sun

doi:10.1016/j.omtn.2021.09.014

Abstract

Emerging evidence has shown that endoplasmic reticulum (ER) stress promotes sorafenib resistance in hepatocellular carcinoma (HCC). However, the underlying mechanisms are poorly understood. The purpose of this study was to explore the mechanism by which ER stress promotes sorafenib resistance in HCC. We found that pyruvate kinase isoform M2 (PKM2) was highly expressed in human HCC tissues and co-related with worse clinicopathologic features and overall survival. Activation of ER stress positively correlated with PKM2 expression both in HCC tissue samples and tunicamycin (TM)-induced HCC cell lines. PKM2 knockdown increased sorafenib-induced apoptosis and decreased the ability of colony formation, while upregulation of PKM2 reverses this phenomenon. Furthermore, high-throughput sequencing identified that activation of ER stress significantly downregulated the expression of miR-188-5p in HCC cells. According to bioinformatics analysis and dual-luciferase assays, we further confirmed that hnRNPA2B1 is the target gene of miR-188-5p. Downregulating the expression of hnRNPA2B1 with siRNA could decrease the expression of PKM2 and enhance sorafenib-induced apoptosis in HepG2 cells. Our study demonstrated that ER stress could promote sorafenib resistance through upregulating PKM2 via miR-188-5p/hnRNPA2B1. Therefore, targeting the miR-188-5p/hnRNPA2B1/PKM2 pathway and ER stress may prove instrumental in overcoming sorafenib resistance in HCC treatment.

Highlights

Hepatocellular carcinoma (HCC) is one of the most malignant tumors that seriously endanger human health
Studies have demonstrated that sorafenib resistance of HCC is associated with special tumor microenvironments, including hypoxia, inflammation, and oxidative stress, and malignant biological behaviors of tumor cells involve epithelial-mesenchymal transitions, autophagy, apoptosis resistance, and energy metabolism reprogramming.[28,29]
We revealed that the therapeutic mechanism of endoplasmic reticulum (ER) stress promoting sorafenib resistance may be related to Pyruvate kinase isoform M2 (PKM2) upregulation via miR-188-5p/hnRNPA2B1

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most malignant tumors that seriously endanger human health. Different from normal cells, most tumor cells tend to obtain energy from a higher glycolysis rate, even in the condition of sufficient oxygen supply This kind of energy metabolism reprogramming is called. Molecular Therapy: Nucleic Acids the Warburg effect.[9] Pyruvate kinase isoform M2 (PKM2) is an essential enzyme that mediates glycolysis and is mainly expressed in tumor cells and embryonic cells Another translation product of PKM gene, PKM1, is elementarily expressed in normally differentiated tissues.[10] Méndez-Lucas et al.[11] showed that PKM2 mediated the reprogramming of glucose metabolism, enabling tumor cells to obtain energy quickly and directly, which is beneficial for tumor cells to acquire advantageous survival conditions and apoptosis resistance. Both ER stress and PKM2 are involved in the pro-survival mechanism and apoptosis resistance of tumor cells; the relationship between them aroused our great research interest

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