Published online Jul 28, 2021. doi: 10.3748/wjg.v27.i28.4667
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
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.
To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC.
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).
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.
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.
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.