Research Paper Volume 12, Issue 22 pp 22975—23003
Silencing KIF14 reverses acquired resistance to sorafenib in hepatocellular carcinoma
- 1 Department of Surgical Oncology and Hepatobiliary Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, China
- 2 Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, China
Received: May 4, 2020 Accepted: August 1, 2020 Published: November 16, 2020
https://doi.org/10.18632/aging.104028How to Cite
Copyright: © 2020 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
For nearly a decade, sorafenib has served as a first-line chemotherapeutic drug for the treatment of hepatocellular carcinoma (HCC), but it displays only limited efficacy against advanced drug-resistant HCC. Regorafenib, the first second-line drug approved for treatment after sorafenib failure, can reverse resistance to sorafenib. We used bioinformatics methods to identify genes whose expression was differentially induced by sorafenib and regorafenib in HCC. We identified KIF14 as an oncogene involved in the acquired resistance to sorafenib in HCC and investigated its potential as a target for reversing this resistance. Sustained exposure of resistant HCC cells to sorafenib activated the AKT pathway, which in turn upregulated KIF14 expression by increasing expression of the transcription factor ETS1. Silencing KIF14 reversed the acquired resistance to sorafenib by inhibiting AKT activation and downregulating ETS1 expression by blocking the AKT–ETS1–KIF14 positive feedback loop. Moreover, injection of siKIF14 with sorafenib suppressed growth of sorafenib-resistant HCC tumors in mice. These results demonstrate that targeting KIF14 could be an effective means of reversing sorafenib failure or strengthening sorafenib’s antitumor effects.
Abbreviations
Abs: antibodies; BSA: bovine serum albumin; CDI: coefficient of drug interaction; DAVID: Database for Annotation, Visualization and Integrated Discovery; DEGs: differentially expressed genes; DMEM: Dulbecco’s modified Eagle’s medium; EMT: epithelial–mesenchymal transition; ERK: extracellular signaling-regulated kinase; ETS1: transcription factor E26 transformation-specific sequence 1; FGFR1: fibroblast growth factor receptor 1; GEO: Gene Expression Omnibus; HCC: hepatocellular carcinoma; KEGG: Kyoto Encyclopedia of Genes and Genomes; KIF14: kinesin family member 14; MAPK: mitogen-activated protein kinase; MK-2206: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one dihydrochloride; OD: optical density; OS: overall survival; PDGFR-β: platelet-derived growth factor receptor beta; PI: propidium iodide; PI3K: phosphoinositide 3-kinase; PPI: protein–protein interaction; PVDF: polyvinylidene difluoride; qRT-PCR: quantitative reverse transcription-polymerase chain reaction; Raf-1: serine/threonine kinases c-Raf; RFA: radiofrequency ablation; SD: standard deviation; TCGA: The Cancer Genome Atlas; TIE2: tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VEGFRs: vascular endothelial growth factor receptors.