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. 2022 Jun 20;24(2):269.
doi: 10.3892/ol.2022.13389. eCollection 2022 Aug.

Polo-like kinase 4 is associated with advanced TNM stages and reduced survival and its inhibition improves chemosensitivity in colorectal cancer

Zhengang Duan  1 , Lei Cai  2 , Jin Cao  3 , Wei Wu  4
Affiliations

Polo-like kinase 4 is associated with advanced TNM stages and reduced survival and its inhibition improves chemosensitivity in colorectal cancer

Zhengang Duan et al. Oncol Lett. .

Abstract

High expression of polo-like kinase 4 (PLK4) promotes tumorigenesis and is correlated with poor prognosis in several kinds of cancer. However, the prognostic value of PLK4 in colorectal cancer (CRC) has not been elucidated. The aim of the present study was to investigate the association between PLK4 and the prognosis and effect of PLK4 inhibition on chemosensitivity in CRC. A total of 142 patients with CRC were enrolled, and 142 pairs of CRC and para-carcinoma tissues were used to measure PLK4 protein expression using immunohistochemistry (IHC). Among them, 69 pairs were used to detect PLK4 mRNA expression using reverse transcription-quantitative PCR. In addition, PLK4-small interfering RNA (siRNA) was transfected into CRC cells, followed by 5-fluorouracil (5-FU) treatment for it was a fundamental chemotherapy for CRC. In addition, western blotting was used to detect PLK4 protein expression among human colonic epithelial cell and human CRC cell lines, including HCT-116, LoVo, SW480 and HT-29, as well as nuclear translocation of β-catenin. The IHC score and mRNA expression of PLK4 were higher in CRC tissues compared with para-carcinoma tissues (both P<0.001). Furthermore, the IHC score of tumor PLK4 was not correlated with pathological grade (P=0.585), T stage (P=0.357), N stage (P=0.107225) or tumor-node-metastasis (TNM) stage (P=0.093). The mRNA expression of tumor PLK4 was positively correlated with N stage (P=0.019) and TNM stage (P=0.004), but not with pathological grade (P=0.498) or T stage (P=0.112). Of note, the high protein expression of tumor PLK4 was an independent factor for poor overall survival (OS; P=0.048). In addition, PLK4 was elevated in CRC cell lines; PLK4-siRNA reduced the 50% inhibitory concentration value of 5-FU in HCT-116 (4.4±0.1 µM vs. 7.6±1.4 µM) and LoVo cells (5.5±0.6 µM vs. 9.9±1.8 µM) (both P<0.05). Besides, PLK4-siRNA decreased nuclear translocation of β-catenin. In conclusion, the high expression of tumor PLK4 was associated with advanced TNM stage and shorter OS in patients with CRC. In addition, targeting PLK4 improved chemosensitivity in CRC cells.

Keywords: chemosensitivity; colorectal cancer; overall survival; polo-like kinase 4; tumor-node-metastasis stage.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Comparison of PLK4 between para-carcinoma and CRC tissues. (A) IHC staining for PLK4 in the negative control, para-carcinoma and CRC tissues. (B) PLK4 IHC score in para-carcinoma and CRC tissues. Paired-samples t-test was applied. (C) Distribution of CRC patients with a different PLK4 expression in para-carcinoma and CRC tissues. P-value representing the difference of the proportion of PLK4 protein high and low expressions between para-carcinoma and CRC tissues. McNamar's test was applied. (D) PLK4 mRNA expression in para-carcinoma and CRC tissues. Wilcoxon signed-rank test was applied. PLK4, polo-like kinase 4; CRC, colorectal cancer; IHC, immunohistochemistry.
Figure 2.
Figure 2.
Correlation between tumor PLK4 expression and tumor features. Association between tumor PLK4 protein expression and (A) pathological grade, (B) T stage, (C) N stage or (D) TNM stage; the relationship of tumor PLK4 mRNA expression with (E) pathological grade, (F) T stage, (G) N stage or (H) TNM stage. Kruskal-Wallis followed by Dunn's test was applied. PLK4, polo-like kinase 4; IHC, immunohistochemistry; TNM, tumor-node metastases.
Figure 3.
Figure 3.
Correlation between tumor PLK4 and OS. Association between tumor (A) protein and (B) mRNA PLK4 expression and OS. Kaplan-Meier method by log-rank test was applied. PLK4, polo-like kinase 4; OS, overall survival.
Figure 4.
Figure 4.
Multivariate Cox-regression analysis for OS. OS, overall survival; PLK4, polo-like kinase 4; HR, hazard ratio; CI, confidence interval; LYN, lymph node.
Figure 5.
Figure 5.
PLK4 expression in HCoEpic and CRC cells. (A) Representative images of PLK4 detection by western blot. (B) Comparison of PLK4 expression between HCoEpic and CRC cells. One-way ANOVA followed by Dunnett's multiple comparisons test was applied among HCoEpic, HT-29, HCT-116, LoVo and SW480 cells. PLK4, polo-like kinase 4; CRC, colorectal cancer.
Figure 6.
Figure 6.
Effect of PLK4-siRNA on 5-FU sensitivity in CRC cell lines. (A) Comparison of the mRNA expression of PLK4 among blank control, NC-siRNA and PLK4-siRNA-treated HCT-116 cells. One-way ANOVA followed by Tukey's multiple comparisons test was applied. (B) Comparison of cell viability among blank control, NC-siRNA and PLK4-siRNA-treated HCT-116 cells groups. One-way ANOVA followed by Dunnett's multiple comparisons test was applied. (C) Changes in the IC50 value of 5-FU between NC-siRNA and PLK4-siRNA-treated HCT-116 cells. Student's t-test was applied. (D) Comparison of the mRNA expression of PLK4 among blank control, NC-siRNA and PLK4-siRNA-treated LoVo cells. One-way ANOVA followed by Tukey's multiple comparisons test was applied. (E) Comparison of cell viability among blank control, NC-siRNA and PLK4-siRNA-treated LoVo cell groups. One-way ANOVA followed by Dunnett's multiple comparisons test was applied. (F) Changes in the IC50 value of 5-FU between NC-siRNA and PLK4-siRNA-treated LoVo cells. Student's t-test was applied. PLK4, polo-like kinase 4; 5-FU, 5-fluorouracil; CRC, colorectal cancer; IC50, 50% inhibitory concentration; siRNA, short interfering RNA; NC, negative control.
Figure 7.
Figure 7.
Effect of PLK4-siRNA on β-catenin nuclear translocation in CRC cell lines. (A) Detection of β-catenin in the nuclei of CRC cells. (B) Comparison of β-catenin in the nuclei of CRC cells. One-way ANOVA followed by Tukey's multiple comparisons test was applied. PLK4, polo-like kinase 4; CRC, colorectal cancer; siRNA, short interfering RNA; NC, negative control.
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