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. 2022 Jun 6:2022:2922832.
doi: 10.1155/2022/2922832. eCollection 2022.

High Expression of PDLIM2 Predicts a Poor Prognosis in Prostate Cancer and Is Correlated with Epithelial-Mesenchymal Transition and Immune Cell Infiltration

Songzhe Piao  1   2 , Lan Zheng  3 , Haihong Zheng  4 , Mengya Zhou  4 , Qin Feng  1 , Suna Zhou  5 , Mang Ke  1 , Haihua Yang  6 , Xuequan Wang  6
Affiliations

High Expression of PDLIM2 Predicts a Poor Prognosis in Prostate Cancer and Is Correlated with Epithelial-Mesenchymal Transition and Immune Cell Infiltration

Songzhe Piao et al. J Immunol Res. .

Abstract

Purpose: To elucidate the clinical and prognostic role of PDZ and LIM domain protein (PDLIM) genes and the association to epithelial-mesenchymal transition (EMT) and immune cell infiltration in patients with prostate cancer (PRAD).

Methods: The data of RNA-seq, DNA methylation, and clinical features of PRAD patients were collected from The Cancer Genome Atlas (TCGA) database to define the prognostic value of PDLIM gene expression and the association with EMT and immune cell infiltration. A tissue microarray including 134 radical prostatectomy specimens was served as validation by immunohistochemistry (IHC) staining analysis.

Results: The mRNA levels of PDLIM1/2/3/4/6/7 were significantly downregulated, while PDLIM5 was upregulated in PRAD (P < 0.05). High expression of PDLIM2 mRNA suggests poor progression free interval in PRAD patients. DNA methylation of PDLIM2 was correlated with its mRNA expression level, and that the cg22973076 methylation site in PDLIM2 was associated with shorter PFI (P < 0.05) in PRAD. Single-sample gene-set enrichment and gene functional enrichment results showed that PDLIM2 was correlated with EMT and immune processes. Spearman's test showed a significant correlation with six reported EMT signatures and several EMT signature-related genes. Tumor microenvironment analysis revealed that the PDLIM2 mRNA expression was positively correlated with the immune score, stromal score, and various tumor infiltrating immune cells. Additionally, the results showed that patients in the high-PDLIM2 mRNA expression group may be more sensitive to immune checkpoint blockade therapy. Finally, IHC analysis further implicated the protein level of PDLIM2 was upregulated in PRAD and acts as a novel potential biomarker in predicting tumor progression.

Conclusion: Our study suggests that PDLIM family genes might be significantly correlated with oncogenesis and the progression of PRAD. PDLIM2 correlated with EMT and immune cell infiltration by acting as an oncogene in PRAD, which may serve as a potential prognostic biomarker for PRAD patients.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1
Figure 1
Expression patterns of PDLIMs in prostate cancer. (a) The expression of PDLIM family genes in prostate cancer tissues (n = 499) compared to normal adjacent tissues (n = 42) in in TCGA-PRAD cohort. (b) Expression of PDLIM family genes in paired prostate cancer tissues and normal tissues (52 vs. 52). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.0001.
Figure 2
Figure 2
High-PDLIM2 expression was an independent predictor of poor prognosis in prostate cancer. (a, b) Kaplan–Meier survival plots of overall survival (OS) and progression free interval (PFI). (c) Univariate and multivariate Cox proportional analyses for PFI.
Figure 3
Figure 3
Correlation between PDLIM2 mRNA expression and mutation frequencies of prostate cancer-associated genes. (a) Gene mutation frequencies in TCGA-PRAD. (b) TMB scores of the high- and low-PDLIM2 groups using data from TCGA database. (c–e) Violin plots examining the effect of PTEN, FOXA1, and TTN gene mutations on PDLIM2 mRNA expression in prostate cancer.
Figure 4
Figure 4
DNA methylation of PDLIM2 in TCGA-PRAD cohort. (a) The correlation between PDLIM2 methylation sites and PDLIM2 expression in patients with prostate cancer. Blue represents a negative correlation; red represents a positive correlation; “×” represents no statistical significance. (b) Kaplan–Meier survival analysis showed that the cg22973076 methylation site in PDLIM2 was correlated with poor PFI in prostate cancer patients (P < 0.05). (c–g) Spearman's correlation analysis showed a correlation between the PDLIM2 mRNA expression level and PDLIM2 methylation sites in prostate cancer patients.
Figure 5
Figure 5
Enrichment analysis of the coexpression genes of PDLIM2. (a) Spearman's correlation analysis showed a correlation between PDLIM2 and differentially expressed genes in prostate cancer. (b, c) Heatmap showing the top 50 significant genes negatively and positively correlated with PDLIM2 in TCGA-PRAD. (d) Enrichment analysis revealed the biological processes involved in the PDLIM2-related coexpressed genes.
Figure 6
Figure 6
PDLIM2 mRNA is involved in EMT process in prostate cancer patients. (a) The mRNA expression level of PDLIM2 was correlated with various EMT signatures and EMT-related genes. EMT_1, Chen et al. 2013; EMT_2, Klarmann et al. 2009; EMT_3, Mathews et al. 2010; EMT_4, Schell et al. 2016; EMT_5, Sethi et al. 2010; EMT_6, Stylilanou et al. 2019. (b) Heatmap showing the relationship between EMT signature-related genes and PDLIM2 expression. (c) Kaplan–Meier survival analysis showed the EMT signature reported by Mathews et al. was significantly associated with poor PFI in patients with prostate cancer. (d–i) The correlation between PDLIM2 mRNA expression land EMT biomarkers, including TJP1, DSP, VIM, CDH1, OCLN, and MMP2 in prostate cancer patients.
Figure 7
Figure 7
PDLIM2 mRNA was involved in immune infiltration in patients with prostate cancer. (a) The mRNA expression level of PDLIM2 was correlated with immune infiltration levels in prostate cancer patients. Blue represents a negative correlation; red represents a positive correlation; “×” represents no statistical significance. (b) The relationship between PDLIM2 mRNA expression and MMR genes. (c) Relationships between PDLIM2 mRNA expression and immune checkpoints. (d–h) Spearman's correlation analysis showed the correlation between PDLIM2 mRNA expression and microenvironment score, cancer-associated fibroblast, immune score, hematopoietic stem cell, and stroma score. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.0001.
Figure 8
Figure 8
IHC staining of PDLIM2 in prostate cancer samples. (a) Protein expression of PDLIM2 in normal prostate tissues; (b) weak, (c) moderate, and (d) strong positive expression of PDLIM2 protein in prostate cancer tissues.
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