Differential expressions of integrin-linked kinase, β-parvin and cofilin 1 in high-fat diet induced prostate cancer progression in a transgenic mouse model

Abstract

High-fat diet induced obesity was associated with more aggressive prostate cancer. Recent research has demonstrated that integrin-linked kinase (ILK), β-parvin and downstream cofilin 1 jointly affected cancer progression. Meanwhile, these proteins were also involved in energy metabolism. Therefore, the present study was conducted to investigate the potential function of ILK, β-parvin and cofilin 1 in the high-fat diet-induced progression of prostate cancer. Transgenic mice with prostate cancer were employed, fed with different diets and sacrificed at 20 and 28 weeks. Tumor differentiation, extracapsular extension and metastasis were compared between the groups. Expression levels of ILK, β-parvin and cofilin 1 in prostate were evaluated by immunohistochemical analysis and determined by an immunoreactivity score. Public databases were applied for analysis and validation. It was detected that high-fat diet feeding promoted cancer progression in transgenic mice with prostate cancer, with increased expressions of β-parvin (P=0.038) and cofilin 1 (P=0.018). Higher expressions of ILK, β-parvin and cofilin 1 were also associated with poorer cancer differentiation. Additionally, higher mRNA levels of CFL1 were correlated with a worse disease-free survival in patients of certain subgroups from The Cancer Genome Atlas database. Further studies were warranted in discussing the potential roles of ILK, β-parvin and cofilin 1 in high-fat diet feeding induced progression of prostate cancer.

Keywords: cofilin 1; high-fat diet; integrin-linked kinase; prostate carcinoma; β-parvin.

Figure 1.

Representative IHC staining demonstrating ILK expression of different IRS category in TRAMP prostate and ILK levels compared among different prostate tissue and between different diet feeding. (A-D) Representatives images showing (A) negative (IRS category=0), (B) weak (IRS category=1), (C) moderate (IRS category=2) and (D) strong (IRS category=3) expressions of ILK in prostate specimens (magnification, ×400). (E and F) Boxplots graphs showing the IRS category of ILK expression across benign prostate tissue, well-differentiated, moderately-differentiated and poorly-differentiated prostate cancer in 20-week and 28-week TRAMP mice, respectively. The horizontal line indicates the median and the central box indicates the inter-quartile range, with whiskers indicate the lowest and highest results. *P<0.05, significant differences are indicated as compared with benign subgroup. (G) Boxplots graphs showing the IRS category of ILK expression in prostate cancer between CD-fed and HFD-fed TRAMP mice of 20 and 28 weeks of age. The horizontal line and central box shows the median and inter-quartile range, with whiskers indicating the lowest and highest result. ILK, integrin-linked kinase; TRAMP, transgenic adenocarcinoma of mouse prostate; IHC, immunochemistry; CD, control diet; HFD, high-fat diet; IRS, immunoreactivity score.

Figure 2.

Representative IHC staining demonstrating β-parvin expression of different IRS category in TRAMP prostate and β-parvin levels compared among different prostate tissue and between different diet feeding. (A-D) Representatives images showing (A) negative (IRS category=0), (B) weak (IRS category=1), (C) moderate (IRS category=2) and (D) strong (IRS category=3) expressions of β-parvin in prostate specimens (magnification, ×400). (E and F) Boxplots graphs showing the IRS category of β-parvin expression across benign prostate tissue, well-differentiated, moderately-differentiated and poorly-differentiated prostate cancer in 20-week and 28-week TRAMP mice, respectively. The horizontal line indicates the median and the central box indicates the inter-quartile range, with whiskers indicate the lowest and highest results. *P<0.05, **P<0.01, significant difference is indicated as compared with benign subgroup. (G) Boxplots graphs showing the IRS category of β-parvin expression in prostate cancer between CD-fed and HFD-fed TRAMP mice of 20 and 28 weeks of age. The horizontal line and central box shows the median and inter-quartile range, with whiskers indicating the lowest and highest result. *P<0.05, significant difference is indicated as compared with control-diet fed mice of the same week subgroup. TRAMP, transgenic adenocarcinoma of mouse prostate; IHC, immunochemistry; CD, control diet; HFD, high-fat diet; IRS, immunoreactivity score.

Figure 3.

Representative IHC staining demonstrating cofilin 1 expression of different IRS category in TRAMP prostate and cofilin 1 levels compared among different prostate tissue and between different diet feeding. (A-D) Representatives images showing (A) negative (IRS category=0), (B) weak (IRS category=1), (C) moderate (IRS category=2) and (D) strong (IRS category=3) expression of cofilin 1 in prostate specimens (magnification, ×400). (E and F) Boxplots graphs showing the IRS category of cofilin 1 expressions across benign prostate tissue, well-differentiated, moderately-differentiated and poorly-differentiated prostate cancer in 20-week and 28-week TRAMP mice, respectively. The horizontal line indicates the median and the central box indicates the inter-quartile range, with whiskers indicate the lowest and highest results. *P<0.05, significant differences are indicated as compared with benign subgroup. (G) Boxplots graphs showing the IRS category of cofilin 1 expression in prostate cancer between CD-fed and HFD-fed TRAMP mice of 20 and 28 weeks of age. The horizontal line and central box shows the median and inter-quartile range, with whiskers indicating the lowest and highest result. *P<0.05, significant difference is indicated as compared with control-diet fed mice of the same week subgroup. TRAMP, transgenic adenocarcinoma of mouse prostate; IHC, immunochemistry; CD, control diet; HFD, high-fat diet; IRS, immunoreactivity score.

Figure 4.

Protein and genetic expression profiles of ILK, PARVB, CFL1 in prostate adenocarcinoma from TCGA database. (A) Oncoprint of ILK, PARVB and CFL1 genetic alterations, with the specific alteration categories presented in the lower panel. (B) The tendency towards co-occurrence among ILK, PARVB and CFL1. (C) Plots showing the associations between DNA copy number alterations and related mRNA abundance in the gene ILK (left panel), PARVB (middle panel) and CFL1 (right panel) in prostate adenocarcinoma. Blue dots indicate individual cases. (D) Plots demonstrating the mRNA expression correlations in PARVB vs. ILK (left panel), CFL1 vs. ILK (middle panel) and CFL1 vs. PARVB (right panel). Correlations are determined by Pearson coefficient with P-value. Blue dots indicate individual cases. TCGA, The Cancer Genome Atlas.

Figure 5.

Effects of mRNA expression of ILK, PARVB and CFL1 on the disease-free survival in TCGA prostate adenocarcinoma cohort. (A) Kaplan-Meier plots with log-rank test demonstrating the disease-free survival in patients expressing high vs. low mRNA levels of ILK (left panel), PARVB (middle panel) and CFL1 (right panel). (B) Disease-free survival curves for stage III and stage IV cancer patients with high vs. low mRNA expression in ILK (left panel), PARVB (middle panel) and CFL1 (right panel). (C) Disease-free survival curves for Gleason score ≥7 cancer patients with high vs. low mRNA expression in ILK (left panel), PARVB (middle panel) and CFL1 (right panel). TCGA, The Cancer Genome Atlas.