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LINE-1 ORF-1p enhances the transcription factor activity of pregnenolone X receptor and promotes sorafenib resistance in hepatocellular carcinoma cells

Authors Chen Y, Zeng Q, Liu X, Fu J, Zeng Z, Zhao Z, Liu Z, Bai W, Dong Z, Liu H, Lu X, Zhu Y, Lu Y

Received 1 June 2018

Accepted for publication 2 August 2018

Published 10 October 2018 Volume 2018:10 Pages 4421—4438

DOI https://doi.org/10.2147/CMAR.S176088

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Raphael Catane


Yan Chen,1,2,* Qinglei Zeng,3,* Xiufang Liu,4 Junliang Fu,1 Zhen Zeng,1 Zhiqin Zhao,1 Ze Liu,1 Wenlin Bai,1 Zheng Dong,1 Hongjin Liu,1 Xiaoxia Lu,1 Yunfeng Zhu,2,5 Yinying Lu1

1Comprehensive Liver Cancer Center, Beijing 302 Hospital, Beijing 100039, P.R. China; 2College of Life Sciences and Bio-Engineering, Beijing Jiaotong University, Beijing 100044, P.R. China; 3Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zheng Zhou 450052, Henan Province, P.R. China; 4Department of Oncology, Chinese PLA 251 Hospital, Zhangjiakou 075000, P.R. China; 5Cancer Center in Division of Internal Medicine, Chinese PLA General Hospital, Beijing 100853, P.R. China

*These authors contributed equally to this work

Background: LINE-1 ORF-1p is encoded by the human pro-oncogene LINE-1. Our previous work showed that LINE-1 ORF-1p could enhance the resistance of hepatocellular carcinoma (HCC) cells to antitumor agents. However, the mechanisms involved in LINE-1 ORF-1p-mediated drug resistance remain largely unknown.
Materials and methods: The endogenous mRNA level of LINE-1 ORF-1p in clinical HCC specimens was examined using quantitative PCR (qPCR). The prognosis of HCC patients was assessed using time to progression and overall survival. The transcription factor activity of pregnenolone X receptor (PXR) was examined using luciferase gene reporter assays, qPCR, chromatin immunoprecipitation assays and cellular subfraction assays. Protein interaction between LINE-1 ORF-1p and PXR was detected by co-immunoprecipitation. The effect of LINE-1 ORF-1p on sorafenib resistance in HCC cells was studied using in vitro and in vivo models.
Results: A high level of LINE-1 ORF-1p in clinical specimens was related to poor prognosis in patients who received sorafenib treatment. LINE-1 ORF-1p increased the transcription factor activity of PXR by interacting with PXR and enhancing its cytoplasmic/nuclear translocation, and recruiting PXR to its downstream gene promoter, in turn enhancing the expression of the sorafenib resistance-related genes, CYP3A4 and mdr-1. LINE-1 ORF-1p enhanced the resistance to and clearance of sorafenib in HCC cells.
Conclusion: LINE-1 ORF-1p enhances the transcription factor activation of PXR and promotes the clearance of and resistance to sorafenib in HCC cells.

Keywords: LINE-1 ORF-1p, sorafenib resistance, pregnenolone X receptor, hepatocellular carcinoma, transcription factor activation

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