Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2021; 27(28): 4667-4686
Published online Jul 28, 2021. doi: 10.3748/wjg.v27.i28.4667
Y-box binding protein 1 augments sorafenib resistance via the PI3K/Akt signaling pathway in hepatocellular carcinoma
Ting Liu, Xiao-Li Xie, Xue Zhou, Sheng-Xiong Chen, Yi-Jun Wang, Lin-Ping Shi, Shu-Jia Chen, Yong-Juan Wang, Shu-Ling Wang, Jiu-Na Zhang, Shi-Ying Dou, Xiao-Yu Jiang, Ruo-Lin Cui, Hui-Qing Jiang
Ting Liu, Xiao-Li Xie, Xue Zhou, Yi-Jun Wang, Yong-Juan Wang, Shu-Ling Wang, Jiu-Na Zhang, Xiao-Yu Jiang, Ruo-Lin Cui, Hui-Qing Jiang, Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Sheng-Xiong Chen, Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Lin-Ping Shi, Department of Gastroenterology, Hebei General Hospital, Shijiazhuang 050000, Hebei Province, China
Shu-Jia Chen, Department of Gastroenterology, Shijiazhuang People’s Hospital, Shijiazhuang 050000, Hebei Province, China
Shi-Ying Dou, Department of Infectious Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Author contributions: Liu T, Xie XL and Jiang HQ conceived, designed the study; Liu T, Xie XL, Zhou X, Chen SX and Wang YJ performed most experiments, analyzed the data, wrote the manuscript and edited the paper; Xie XL and Jiang HQ helped to supervised the study; Shi LP, Chen SJ, Wang YJ, Wang SL, Zhang JN, Dou SY, Cui RL and Jiang XY helped to perform the experiments and analyzed the data; Xie XL and Jiang HQ helped to edited the paper.
Supported by National Natural Science Foundation of China, No. 81770601, No. 81702324, and No. 81602529; Natural Science Foundation of Hebei Province, No. H2018206176 and No. H2017206141; and Post-graduate’s Innovation Fund Project of Hebei Province, No. CXZZBS2019121.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of the Second Hospital of Hebei Medical University (approval letter No.: 2020-P025).
Institutional animal care and use committee statement: All animal procedures were approved by the ethics committee of the Second Hospital of Hebei Medical University (approval letter No.: 2020-AE002).
Conflict-of-interest statement: The authors declare that there are no conflicts of interest in our study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hui-Qing Jiang, MD, Professor, Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang 050000, Hebei Province, China. jianghq@aliyun.com
Received: March 19, 2021
Peer-review started: March 19, 2021
First decision: June 3, 2021
Revised: June 4, 2021
Accepted: June 22, 2021
Article in press: June 22, 2021
Published online: July 28, 2021
Processing time: 129 Days and 7.7 Hours
Abstract
BACKGROUND

Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown.

AIM

To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC.

METHODS

The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq).

RESULTS

YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance.

CONCLUSION

Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.

Keywords: Y-box binding protein 1; Hepatocellular carcinoma; Sorafenib; Drug resistance; Phosphoinositide-3-kinase/protein kinase B

Core Tip: Y-box binding protein 1 (YB-1) was significantly increased in hepatocellular carcinoma (HCC), and it could increase the IC50 values of sorafenib in HCC cell lines. Meanwhile, YB-1 suppressed apoptosis and cell proliferation inhibition induced by sorafenib. Furthermore, we screened the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway to explore the molecular mechanism of sorafenib resistance by the KEGG pathway enrichment analysis of the digital gene expression profiling-seq. And the blockade of PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. Given that sorafenib is the first-line treatment for patients with advanced HCC, we proposed that the down-regulation of YB-1 is of great significance for the application of sorafenib in advanced HCC.