Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2020; 26(32): 4786-4801
Published online Aug 28, 2020. doi: 10.3748/wjg.v26.i32.4786
Dual targeting of Polo-like kinase 1 and baculoviral inhibitor of apoptosis repeat-containing 5 in TP53-mutated hepatocellular carcinoma
Yan Li, Zhen-Gang Zhao, Yin Luo, Hao Cui, Hao-Yu Wang, Yan-Fang Jia, Ying-Tang Gao
Yan Li, Zhen-Gang Zhao, Hao Cui, Hao-Yu Wang, Department of Hepatology, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
Yin Luo, Ying-Tang Gao, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Institute of Hepatobiliary Disease, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
Yan-Fang Jia, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Medical University Third Center Clinical College, Tianjin 300170, China
Author contributions: Li Y, Zhao ZG, Luo Y, and Jia YF performed the majority of experiments and analyzed the data; Cui H and Wang HY were responsible for animal experiments; Li Y and Gao YT designed and coordinated the research; Li Y, Luo Y, and Gao YT wrote the paper; all authors approved the final version of the article.
Supported by National Science and Technology Major Project, No. 2018ZX10732-202-004; Tianjin Science and Technology Plan Project, No. 17JCYBJC26100 and No. 19ZXDBSY00030.
Institutional review board statement: This study/paper was reviewed and approved by the Ethics Committee of Tianjin Third Central Hospital.
Institutional animal care and use committee statement: All animal experiments and procedures were conducted under the protocol approved by the Animal Care and Use Committee of Nankai University.
Conflict-of-interest statement: All authors have nothing to disclose.
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:
Corresponding author: Ying-Tang Gao, PhD, Professor, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Institute of Hepatobiliary Disease, Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin 300170, China.
Received: May 7, 2020
Peer-review started: May 7, 2020
First decision: May 21, 2020
Revised: June 4, 2020
Accepted: August 4, 2020
Article in press: August 4, 2020
Published online: August 28, 2020
Research background

Hepatocellular carcinoma (HCC) is the fifth most common malignant cancer and the second leading cause of cancer-related mortality. HCC is often diagnosed at advanced stages without curative therapies. Therefore, there is an unmet need of preclinical studies to develop novel therapeutic strategies to treat HCC, especially at advanced stages. Polo-like kinase 1 (PLK1) is activated at the late G2 phase of the cell cycle and is required for entry to mitosis. Interestingly, PLK1 is overexpressed in many HCC patients and is highly associated with poor clinical outcome. Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) is also highly overexpressed in HCC and plays key roles in HCC cell survival, cell proliferation, and disease progression of HCC.

Research motivation

More biomarkers are required for the diagnosis and treatment of HCC. However, how p53, PLK1, and BIRC5 interact in HCC has not been well defined.

Research objectives

To determine the expression pattern of PLK1 and BIRC5, as well as their correlation with mutation status of p53 and patient clinical outcome.

Research methods

The expression of PLK1 and BIRC5 and their correlation with the mutation status p53 were analyzed using a TCGA HCC dataset. Cell-based studies were conducted to investigate the efficacy of PLK1 and BIRC5 inhibitors, alone or in combination, the results of which were further validated in p53-mutated Huh7-derived xenografts in immune-deficient NSIG mice.

Research results

Our bioinformatic analysis using an HCC dataset from TCGA revealed that PLK1 and BIRC5 were overexpressed in the same subset of HCC patients and that their expression was highly correlated in all HCC patients. Both PLK1 and BIRC5 overexpression was more frequently detected in HCC with p53 mutations, compared to that observed in HCC with wild-type p53. High PLK1 or BIRC5 expression was significantly correlated with poor clinical outcome. Both PLK1 inhibitors volasertib and GSK461364 or the BIRC5 inhibitor YM155 selectively targeted Huh7 cells, which express Y220C-mutated p53 that is aberrantly stable and transcriptionally inactive, but not HepG2 cells, which express wild-type p53. Combination treatment with volasertib and YM155 synergistically inhibited the cell viability of Huh7 cells by promoting cell apoptosis. The efficacy of volasertib and YM155, alone or in combination, was further validated in vivo in a Huh7-derived xenograft model in immuno-deficient NSIG mice.

Research conclusions

PLK1 and BIRC5 are highly co-expressed in p53-mutated HCC and dual targeting of PLK1 and BIRC5 synergistically inhibits the cell viability of p53-mutated HCC cells in vitro through the induction of cell apoptosis as well as the tumor growth of p53-mutated HCC cells in vivo.

Research perspectives

The results of this study provides valuable insights for therapeutic development for the subset of the HCC patient population with the PLK1/BIRC5 co-expression signature in p53-mutated HCC patients as well as for other cancer models in the future.