Reactive oxygen species\u2013mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression

Chia-Ling Hsieh,Chia-Ning Shen,Fukashi Yamamichi,Koichi Kitagawa,Katsumi Shigemura,Kuan-Chou Chen,Cheng-Chieh Lin,Hsin-An Chen,Wei-Hua Lee,Shun-Tai Yang,Masato Fujisawa,Shian-Ying Sung,Yun-Ru Liu,Leland W K Chung,Che-Ming Liu

doi:10.1038/s41598-017-08835-9

Abstract

Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.

Highlights

Cancer progression is a complex process involving local invasion, micrometastasis, and intravasation
We focused on profiling the expression pattern of extracellular matrices (ECMs) remodeling-related genes associated with prostate cancer development in paired cancer-associated fibroblasts (CAFs) and normal fibroblasts derived from a coculture cell model and clinical patient samples
Numerous reports have elaborated the coevolution of prostate cancer cells with stroma in their genotypic and phenotypic characters, relatively few studies have delineated the contribution of CAFs to overall changes in gene and protein expressions in prostate cancer microenvironments

Summary

Introduction

Cancer progression is a complex process involving local invasion, micrometastasis, and intravasation. Studies of cancer gene changes have revealed MMP expressions in cancer cells that play crucial roles in cancer progression[5,6,7]; the regulation of MMP expression in cancer-associated fibroblasts (CAFs) has not been fully explored[6]. We focused on profiling the expression pattern of ECM remodeling-related genes associated with prostate cancer development in paired CAFs and normal fibroblasts derived from a coculture cell model and clinical patient samples. CAFs exhibited higher capacity to promote prostate cancer tumor formation, these cells expressed lower levels of MMP-3 than did normal fibroblasts. We provide the first evidence that hydrogen peroxide serves as a central mediator in regulating MMP-3 expression, with opposite results in the microenvironments of fibroblasts and prostate cancer cells, through the direct inhibition of mmp-3 promoter activity via nuclear factor-κB (NF-κB) signaling pathway in CAFs and downregulation of thrombospondin 2, an MMP-3 suppressor in prostate cancer cells through microRNA (miRNA) regulation

Methods

Results

Conclusion