Published online Aug 28, 2020. doi: 10.3748/wjg.v26.i32.4786
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
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.
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.
To determine the expression pattern of PLK1 and BIRC5, as well as their correlation with mutation status of p53 and patient clinical outcome.
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.
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.
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.
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.