Endoplasmic reticulum stress promotes sorafenib resistance via miR-188-5p/hnRNPA2B1-mediated upregulation of PKM2 in hepatocellular carcinoma.
Endoplasmic reticulum stress promotes sorafenib resistance via miR-188-5p/hnRNPA2B1-mediated upregulation of PKM2 in hepatocellular carcinoma.
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内质网应激通过 miR-188-5p/hnRNPA2B1 介导的肝细胞癌中 PKM2 上调促进索拉非尼耐药
DOI：
10.1016/j.omtn.2021.09.014
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发表时间：
2021-12-03
期刊：
影响因子：
--
通讯作者：
Sun G
中科院分区：
文献类型：
--
作者：
Zhou B;Lu D;Wang A;Cui J;Zhang L;Li J;Fan L;Wei W;Liu J;Sun G
越来越多的证据表明，内质网应激促进了肝细胞癌对索拉非尼的耐药。然而，人们对其潜在的机制知之甚少。本研究旨在探讨内质网应激促进肝细胞癌对索拉非尼耐药的机制。我们发现丙酮酸激酶亚型M2(PKM2)在人肝细胞癌组织中高表达，并与肝细胞癌的临床病理特征和总生存率相关。无论是在肝癌组织样本还是衣霉素(TM)诱导的肝癌细胞系中，内质网应激的激活与PKM2的表达均呈正相关。PKM2基因敲除增加了索拉非尼诱导的细胞凋亡并降低了集落形成能力，而上调PKM2则逆转了这一现象。此外，高通量测序发现，内质网应激的激活显著下调了肝癌细胞中MmiR-188-5p的表达。根据生物信息学分析和双荧光素酶分析，进一步证实hnRNPA2B1是miR-188-5p的靶基因。用siRNA下调hnRNPA2B1的表达可以减少PKM2的表达，增强索拉非尼诱导的HepG2细胞的凋亡。我们的研究表明，ER胁迫可以通过miR-188-5p/hnRNPA2B1上调PKM2来促进索拉非尼的耐药性。因此，靶向miR-188-5p/hnRNPA2B1/PKM2通路和内质网应激可能有助于克服肝癌治疗中索拉非尼的耐药性。内质网应激促进肝细胞癌对索拉非尼耐药的潜在机制尚不清楚。本研究表明，ER胁迫可通过miR-188-5P/hnRNPA2B1上调PKM2，从而促进索拉非尼的耐药性。因此，靶向miR-188-5p/hnRNPA2B1/PKM2通路和内质网应激可能有助于克服肝癌治疗中索拉非尼的耐药性。
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. The underlying mechanisms of endoplasmic reticulum (ER) stress that promote sorafenib resistance in hepatocellular carcinoma (HCC) are poorly understood. This study demonstrated that ER stress could promote sorafenib resistance by 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.
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