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

Cell Death Dis. 2018 Sep 20;9(10):955. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • CCN Intercellular Signaling Proteins / genetics
  • CCN Intercellular Signaling Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Chondrosarcoma / metabolism*
  • Chondrosarcoma / pathology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NF-kappa B / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • CCN Intercellular Signaling Proteins
  • CCN6 protein, human
  • CCN6 protein, mouse
  • NF-kappa B
  • Matrix Metalloproteinase 9