ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2023; 19(14):4511-4524. doi:10.7150/ijbs.83862 This issue Cite
Research Paper
Integrative analysis of multi-omics data reveals inhibition of RB1 signaling promotes apatinib resistance of hepatocellular carcinoma
1. Minimally Invasive Tumor Therapies Center, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.
2. Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.
3. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
4. Department of Critical Care Medicine, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
*The first two authors contributed equally to this article.
Abstract
Although apatinib is a promising drug for the treatment of liver cancer, the underlying drug resistance mechanism is still unclear. Here, we constructed apatinib-resistant HepG2 cells. We then characterized the epigenomic, transcriptomic, and proteomic landscapes both in apatinib-resistant and non-resistant HepG2 cells. Differential expression, ATAC-seq, and proteomic data analyses were performed. We found that the cell cycle related protein RB1 may play an essential role in the process of apatinib resistant to hepatocarcinoma. Moreover, there were extensive variations at the transcriptome, epigenetic, and proteomic level. Finally, quantitative PCR (qPCR) and western blot analysis showed that expression level of RB1 in apatinib-resistant cell as well as the samples of patients in progressive disease were significantly lower than that in controls. Those results also showed that the RB1 pathway inhibitors CDK2-IN-73 and Palbociclib could relieve the resistance of apatinib resistant cells. Our results further enhance our understanding of the anti-tumorigenic and anti-angiogenic efficacy of apatinib in liver cancer and provide a novel perspective regarding apatinib resistance. Furthermore, we proved that CDKN2B inhibition of RB1 signaling promoted apatinib resistance in hepatocellular carcinoma. Those findings have greatly important biological significance for the resistance of apatinib and the treatment of liver cancer.
Keywords: Apatinib-resistance, Hepatocarcinoma, ATAC-seq, Multi-omics data
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