Increased Expressions of Matrix Metalloproteinases (MMPs) in Prostate Cancer Tissues of Men with Type 2 Diabetes.

Andras Franko,Andreas Peter,Arnulf Stenzl,Lucia Berti,Martin Hrabĕ De De Angelis,Steffen Rausch,Marcus O Scharpf,Andreas L Birkenfeld,Martin Heni,Stefan Z Lutz,Hans-Ulrich Häring,Jörg Hennenlotter

doi:10.3390/biomedicines8110507

Abstract

Type 2 diabetes (T2D) is associated with worse prognosis of prostate cancer (PCa). The molecular mechanisms behind this association are still not fully understood. The aim of this study was to identify key factors, which contribute to the more aggressive PCa phenotype in patients with concurrent T2D. Therefore, we investigated benign and PCa tissue of PCa patients with and without diabetes using real time qPCR. Compared to patients without diabetes, patients with T2D showed a decreased E-cadherin/N-cadherin (CDH1/CDH2) ratio in prostate tissue, indicating a switch of epithelial-mesenchymal transition (EMT), which is a pivotal process in carcinogenesis. In addition, the gene expression levels of matrix metalloproteinases (MMPs) and CC chemokine ligands (CCLs) were higher in prostate samples of T2D patients. Next, prostate adenocarcinoma PC3 cells were treated with increasing glucose concentrations to replicate hyperglycemia in vitro. In these cells, high glucose induced expressions of MMPs and CCLs, which showed significant positive associations with the proliferation marker proliferating cell nuclear antigen (PCNA). These results indicate that in prostate tissue of men with T2D, hyperglycemia may induce EMT, increase MMP and CCL gene expressions, which in turn activate invasion and inflammatory processes accelerating the progression of PCa.

Highlights

The association between prostate cancer (PCa) and type 2 diabetes (T2D) is complex [1].Many studies suggest that patients with Type 2 diabetes (T2D) may have a reduced risk for developing PCa [2,3], the underlying molecular mechanisms are not fully understood
We aimed to identify key pathways and their regulators including epithelial-mesenchymal transition (EMT), inflammation, and invasion, which could accelerate PCa progression in patients with T2D
Even though patients with T2D displayed higher CDH2 mRNA levels in both benign prostate (BEN) and PCa groups, the CDH1/CDH2 ratio was only decreased in PCa tissue of the T2D group when compared to patients without T2D (Figure 2B,C)

Summary

Introduction

The association between prostate cancer (PCa) and type 2 diabetes (T2D) is complex [1].Many studies suggest that patients with T2D may have a reduced risk for developing PCa [2,3], the underlying molecular mechanisms are not fully understood. When patients with T2D are diagnosed with PCa, they are characterized by activated carcinogenic pathways [5] and suffer from more aggressive PCa [6,7] with a markedly poorer prognosis compared to patients without T2D [8,9]. Both high insulin and glucose levels are postulated to drive PCa carcinogenesis in patients with. We aimed to identify key pathways and their regulators including epithelial-mesenchymal transition (EMT), inflammation, and invasion, which could accelerate PCa progression in patients with T2D. EMT is characterized by decreased expression of epithelial E-cadherin (encoded by the CDH1 gene) and increased level of mesenchymal N-cadherin (encoded by the CDH2 gene), which leads to a reduced

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