Osteoblast-derived WISP-1 increases VCAM-1 expression and enhances prostate cancer metastasis by down-regulating miR-126

Huai-Ching Tai,An-Chen Chang,Yu-Wei Lai,Hui-Lung Sun,Hong-Jeng Yu,Chao-Yuan Huang,Shih-Wei Wang,Chih-Hsin Tang,Yu-Chieh Tsai

doi:10.18632/oncotarget.2280

Abstract

Bone metastases of prostate cancer (PCa) may cause intractable pain. Wnt-1-induced secreted protein 1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV) that plays a key role in bone formation. We found that osteoblast-conditioned medium (OBCM) stimulates migration and vascular adhesion molecule-1 (VCAM)-1 expression in human PCa (PC3 and DU145) cells. Osteoblast transfection with WISP-1 shRNA reduced OBCM-mediated PCa migration and VCAM-1 expression. Stimulation of PCa with OBCM or WISP-1 elevated focal adhesion kinase (FAK) and p38 phosphorylation. Either FAK and p38 inhibitors or siRNA abolished osteoblast-derived WISP-1-induced migration and VCAM-1 expression. Osteoblast-derived WISP-1 inhibited miR-126 expression. Moreover, miR-216 mimic reversed the WISP-1-enhanced migration and VCAM-1 expression. This study suggests that osteoblast-derived WISP-1 promotes migration and VCAM-1 expression in human PCa cells by down-regulating miR-126 expression via αvβ1 integrin, FAK, and p38 signaling pathways. Thus, WISP-1 may be a new molecular therapeutic target in PCa bone metastasis.

Highlights

Prostate cancer (PCa) is the most commonly diagnosed malignancy in the United States and other Western countries [1]
We hypothesized that osteoblasts are capable of regulating PCa metastasis to the bone and we examined the effect of osteoblast-conditioned medium (OBCM) on PCa cell motility via a Transwell assay
Using Wntinduced secreted protein-1 (WISP-1) short hairpin RNA (shRNA) to knock down WISP-1 expression in osteoblasts, we identified WISP-1 as the chief factor in osteoblasts that promotes PCa migration and vascular cell adhesion molecule-1 (VCAM1) up-regulation

Summary

Introduction

Prostate cancer (PCa) is the most commonly diagnosed malignancy in the United States and other Western countries [1]. Surgery is the most frequent therapeutic intervention. Systemic intervention is required to inhibit tumor growth and prevent secondary metastases. Bone metastasis is a common complication associated with advanced PCa, often causing acute pain and bone fracture. Bone metastasis has prognostic value in PCa, since the extent of disease in the bone significantly affects survival [2,3,4]. Cancer cells yield soluble factors to stimulate osteoblast activation, proliferation, and maturation. They secrete bone matrix and growth factors, which promote malignancy and osteoblastic bone metastasis [8, www.impactjournals.com/oncotarget

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Results

Conclusion