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), often diagnosed at advanced stages without curative therapies, is the fifth most common malignant cancer and the second leading cause of cancer-related mortality. Polo-like kinase 1 (PLK1) is activated in 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 this malignancy.
To determine the expression patterns of PLK1 and BIRC5, as well as their correlation with p53 mutation status and patient clinical outcome.
The expression patterns of PLK1 and BIRC5, and their correlation with p53 mutation status or patient clinical outcome were analyzed using a TCGA HCC dataset. Cell viability, cell apoptosis, and cell cycle arrest assays were conducted to investigate the efficacy of the PLK1 inhibitors volasertib and GSK461364 and the BIRC5 inhibitor YM155, alone or in combination. The in vivo efficacy of volasertib and YM155, alone or in combination, was assessed in p53-mutated Huh7-derived xenograft models in immune-deficient NSIG mice.
Our bioinformatics analysis using a TCGA HCC dataset revealed that PLK1 and BIRC5 were overexpressed in the same patient subset and their expression was highly correlated. The overexpression of both PLK1 and BIRC5 was more frequently detected in HCC with p53 mutations. High PLK1 or BIRC5 expression significantly correlated with poor clinical outcome. PLK1 inhibitors (volasertib and GSK461364) or a BIRC5 inhibitor (YM155) selectively targeted Huh7 cells with mutated p53, but not HepG2 cells with wild-type p53. The combination treatment of volasertib and YM155 synergistically inhibited the viability of Huh7 cells via apoptotic pathway. The efficacy of volasertib and YM155, alone or in combination, was validated in vivo in a Huh7-derived xenograft model.
PLK1 and BIRC5 are highly co-expressed in p53-mutated HCC and inhibition of both PLK1 and BIRC5 synergistically compromises the viability of p53-mutated HCC cells in vitro and in vivo.
Core tip: A bioinformatics analysis using a TCGA hepatocellular carcinoma (HCC) dataset revealed that Polo-like kinase 1 (PLK1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) were overexpressed in the same patient subset and their expression was highly correlated. Overexpression of both PLK1 and BIRC5 was more frequently detected in HCC with p53 mutations. High PLK1 or BIRC5 expression significantly correlated with poor clinical outcome. The PLK1 inhibitors volasertib and GSK461364 or BIRC5 inhibitor YM155 selectively targeted Huh7 cells with mutated p53, but not HepG2 cells with wild-type p53. Combination treatment with volasertib and YM155 synergistically inhibited the viability of Huh7 cells by inducing apoptosis. The efficacy of volasertib and YM155, alone or in combination, was validated in vivo in a Huh7-derived xenograft model in immuno-deficient NSIG mice.