CCN6-mediated MMP-9 activation enhances metastatic potential of human chondrosarcoma

Huey-En Tzeng,Sz-Hua Wu,Hsien-Te Chen,Yi-Chin Fong,Wei-Cheng Chen,Chih-Yang Lin,Shih-Wei Wang,Chih-Hsin Tang,Hsien-Da Huang,Yung-Chang Lu

doi:10.1038/s41419-018-1008-9

Abstract

Chondrosarcomas are primary malignant bone tumors that have a poor prognosis. WNT1-inducible signaling pathway protein-3 (WISP-3, also termed CCN6) belongs to the CCN family of proteins and is implicated in the regulation of various cellular functions, such as cell proliferation, differentiation, and migration. It is unknown as to whether CCN6 affects human chondrosarcoma metastasis. We show how CCN6 promotes chondrosarcoma cell migration and invasion via matrix metallopeptidase-9 (MMP)-9 expression. These effects were abolished by pretreatment of chondrosarcoma cells with PI3K, Akt, mTOR, and NF-κB inhibitors or short interfering (si)RNAs. Our investigations indicate that CCN6 facilitates metastasis through the PI3K/Akt/mTOR/NF-κB signaling pathway. CCN6 and MMP-9 expression was markedly increased in the highly migratory JJ012(S10) cell line compared with the primordial cell line (JJ012) in both in vitro and in vivo experiments. CCN6 knockdown suppressed MMP-9 production in JJ012(S10) cells and attenuated cell migration and invasion ability. Importantly, CCN6 knockdown profoundly inhibited chondrosarcoma cell metastasis to lung. Our findings reveal an important mechanism underlying CCN6-induced metastasis and they highlight the clinical significance between CCN6 and MMP-9 in regard to human chondrosarcoma. CCN6 appears to be a promising therapeutic target in chondrosarcoma metastasis.

Highlights

Chondrosarcomas are common primary malignant bone tumors that are difficult to diagnose and treat[1]
Using the Transwell assay, we found that CCN6 dose-dependently stimulated the migratory and invasion activity of human chondrosarcoma cells (Fig. 1a, b)
Transfecting cells with matrix metallopeptidase-9 (MMP)-9 siRNA markedly inhibited MMP-9 expression, CCN6-induced cell migration and invasion activity (Fig. 1e–g), which implies that CCN6-induced migration and invasion activity occurs via activation of MMP-9 expression

Summary

Introduction

Chondrosarcomas are common primary malignant bone tumors that are difficult to diagnose and treat[1]. Patients are mostly aged between 30 and 60 years, with a peak between 40 and 50 years. The male: female ratio for chondrosarcoma is ~2:11,2. Chondrosarcomas most frequently involve the scapula, sternum, ribs, and pelvic bones[3] and their prognosis is poor, as they do not respond well to conventional treatments such as chemotherapy or radiotherapy[4]. Surgical resection is the cornerstone of treatment[5].

Methods

Results

Conclusion