Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6188112 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Chen Yan Y Zeng Qinglei Q Liu Xiufang X Fu Junliang J Zeng Zhen Z Zhao Zhiqin Z Liu Ze Z Bai Wenlin W Dong Zheng Z Liu Hongjin H Lu Xiaoxia X Zhu Yunfeng Y Lu Yinying Y

Cancer management and research 20181010

<h4>Background</h4>LINE-1 ORF-1p is encoded by the human pro-oncogene <i>LINE-1</i>. 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.<h4>Materials and methods</h4>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 assess ...[more]

PMID: 30349375

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Project description:The present study aimed to investigate the anticancer effect of sorafenib combined with silencing of activating transcription factor 2 (ATF2) in hepatocellular carcinoma (HCC) cells and to assess the underlying molecular mechanisms. Huh?7 HCC cell line was selected for the present study. Small interfering RNA (siRNA)?ATF2 sequence was constructed to silence ATF2 expression. The experiment was divided into 6 groups: i) Control; ii) vector; iii) sorafenib (6.8 µM); iv) vector+sorafenib; v) siRNA?ATF2; and vi) siRNA?ATF2+sorafenib groups. Cell proliferation, apoptosis, migration and invasion were detected following treatments with sorafenib and/or ATF2 silencing. Additionally, expression of tumor necrosis factor (TNF)?? and c?Jun N?terminal kinase 3 (JNK3) was detected using reverse transcription?quantitative polymerase chain reaction and western blotting. The current findings revealed that siRNA?ATF2 significantly reduced ATF2 expression. Cell proliferation, migration and invasion abilities in the sorafenib and siRNA?ATF2 groups were significantly reduced compared with the control group (P<0.05). Apoptotic rate in the sorafenib and siRNA?ATF2 groups was significantly increased compared with the control group (P<0.05). The mRNA and protein expression levels of ATF2 in the sorafenib or siRNA?ATF2 groups was significantly reduced when compared with control group. The phosphorylation of ATF2 was also reduced following sorafenib treatment or ATF2 silence. Although JNK3 mRNA expression level was not affected, the phosphorylation level of JNK3 was significantly promoted following sorafenib treatment or ATF2 silencing. Additionally, TNF?? mRNA and protein expression levels were increased following sorafenib treatment or ATF2 silencing. It is of note that siRNA?ATF2 treatment promoted the anticancer activity of sorafenib in Huh?7 cells. Additionally, siRNA?ATF2+sorafenib treatment combined additionally promoted TNF?? expression and phosphorylation of JNK3. Combined siRNA?ATF2 and sorafenib treatment had a greater anticancer effect compared with sorafenib or ATF2 silencing alone. The possible mechanism involved in the anticancer effect of sorafenib and ATF2 silencing may be associated with the activation of the TNF??/JNK3 signaling pathway.

Dataset Information

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

Background

Materials and methods

Results

Conclusion

Publications

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

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