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, 2020https://doi.org/10.18632/aging.104028
How 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.
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.