Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4.

Xi He,Xiaojuan Li,Junfeng Hao,Boan Li,Yantao Chai,Zhijie Wang,Shaojie Xin,Huiwei Sun,Qiyu Jiang,Shaoli You,Bing Zhu

doi:10.3389/fonc.2021.735447

Xi He, Xiaojuan Li + Show 9 more

Open Access

https://doi.org/10.3389/fonc.2021.735447

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Abstract

Increasing evidence has shown that the metabolism and clearance of molecular targeted agents, such as sorafenib, plays an important role in mediating the resistance of HCC cells to these agents. Metabolism of sorafenib is performed by oxidative metabolism, which is initially mediated by CYP3A4. Thus, targeting CYP3A4 is a promising approach to enhance the sensitivity of HCC cells to chemotherapeutic agents. In the present work, we examined the association between CYP3A4 and the prognosis of HCC patients receiving sorafenib. Using the online tool miRDB, we predicted that has-microRNA-4277 (miR-4277), an online miRNA targets the 3’UTR of the transcript of cyp3a4. Furthermore, overexpression of miR-4277 in HCC cells repressed the expression of CYP3A4 and reduced the elimination of sorafenib in HCC cells. Moreover, miR-4277 enhanced the sensitivity of HCC cells to sorafenib in vitro and in vivo. Therefore, our results not only expand our understanding of CYP3A4 regulation in HCC, but also provide evidence for the use of miR-4277 as a potential therapeutic in advanced HCC.

Highlights

Though many advances have been made in the treatment of advanced HCC, it remains a major challenge for China’s public health [1,2,3]
HCC arises from hepatocytes, and the metabolism and clearance of exogenous agents may be specific to the ability of HCC cells to tolerate sorafenib [18, 19]
Feng et al [18] showed that sorafenib can function as a ligand/agonist to induce PXR transcription factor activity and accelerate the metabolism and clearance rate of sorafenib. It does this by inducing the expression of drug resistance genes downstream of PXR, such as cyp3a4 or abcb1 (ATP-binding cassette, sub-family B, member 1), and through a similar negative feedback mechanism that induces resistance of HCC cells to sorafenib itself

Summary

Introduction

Though many advances have been made in the treatment of advanced HCC, it remains a major challenge for China’s public health [1,2,3]. In China, more than 80 million people suffer from viral liver disease or related acute and chronic liver diseases [1] These patients have a high risk of developing HCC [1, 4]. It is important to understand the mechanisms of resistance to sorafenib and other agents, and to study and explore sensitization strategies for HCC cells to molecular targeted agents. This will provide more choice for the patient, but it will help improve the efficacy of combination therapies using targeted agents and/or immune checkpoint inhibitors

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