The interplay between AR, EGF receptor and MMP-9 signaling pathways in invasive prostate cancer

Anna Mandel,Azharuddin Sajid Syed Khaja,Jenny L Persson,Julius Semenas,Per Larsson,Martuza Sarwar

doi:10.1186/s10020-018-0035-4

Abstract

BackgroundMetastatic Prostate cancer (PCa) cells have gained survival and invasive advantages. Epidermal growth factor (EGF) receptor is a receptor tyrosine kinase, which may mediate signalling to promote progression and invasion of various cancers. In this study, we uncovered the molecular mechanisms underlying the interconnection among the androgen receptor (AR), matrix metalloproteinase-9 (MMP9) and EGFR in promoting PCa progression.MethodsImmunohistochemical analysis of the tissue microarrays consisting of primary and metastatic PCa tissues was performed. The clinical importance of EGFR and its association with survivals were analyzed using three cohorts from MSKCC Prostate Oncogenome Project dataset (For primary tumors, n = 181; for metastatic tumors n = 37) and The Cancer Genome Atlas Prostate Adenocarcinoma Provisional dataset (n = 495). Targeted overexpression or inhibition of the proteins of interests was introduced into PCa cell lines. Treatment of PCa cell lines with the compounds was conducted. Immunoblot analysis was performed.ResultsWe showed that AR, MMP-9 and EGFR are interconnect factors, which may cooperatively promote PCa progression. Altered EGFR expression was associated with poor disease-free survival in PCa patients. Induced overexpression of AR led to an increase in the expression of EGFR, p-GSK-3β and decrease in p27 expression in PCa cell lines in the presence of androgen stimulation. Overexpression of MMP9 significantly induced EGFR expression in PCa cells. Inhibition of PIP5K1α, a lipid kinase that acts upstream of PI3K/AKT greatly reduced expressions of AR, MMP-9 and EGFR.ConclusionsOur findings also suggest that PCa cells may utilize AR, EGFR and MMP-9 pathways in androgen-dependent as well as in castration-resistant conditions. Our data suggest a new therapeutic potential to block cancer metastasis by targeting AR, EGFR and MMP-9 pathways in subsets of PCa patients.

Highlights

Metastatic Prostate cancer (PCa) cells have gained survival and invasive advantages
Clinical importance of Epidermal growth factor receptor (EGFR) expression and its correlation with androgen receptor (AR) in primary and metastatic PCa tissues from patients To evaluate clinical importance of EGFR and its correlation with AR expression in PCa patients, we used Tissue microarrays (TMAs) consisting of primary PCa (n = 17), and PCa metastatic tissues (n = 43)
In order to further examine the clinical relevance of EGFR expression, we compared EGFR mRNA expression between normal prostate tissues adjacent to the prostate tumor tissues, primary PCa tissues, as well as PCa metastatic lesions

Summary

Introduction

Metastatic Prostate cancer (PCa) cells have gained survival and invasive advantages. Epidermal growth factor (EGF) receptor is a receptor tyrosine kinase, which may mediate signalling to promote progression and invasion of various cancers. EGFR and HER-2 have been revealed to play a significant role in metastasis to the bone marrow (Day et al 2017; Lu and Kang 2010), and these factors exhibited elevated activity in tumour initiating cells (TICs) and circulating tumour cells (CTCs) (Day et al 2017) Taken together these data suggest a role of EGFR in the development and progression of PCa. Since excess levels of EGF and EGFR are produced by both PCa cells and tumor-specific stromal/fibroblasts, it is likely that EGFR signalling in cancer cells is activated via the production of binding ligands by both cancer cells and tumor-specific stromal/fibroblasts through paracrine and autocrine loops, leading to the growth and survival of PCa cells in the absence of androgens (Di Lorenzo et al 2002; Traish and Wotiz 1987)

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