title: CCN3 increases cell motility and MMP-13 expression in human chondrosarcoma through integrin-dependent pathway.
abstract: Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. CCN3, also called nephroblastoma overexpressed gene (NOV), regulates proliferation and differentiation of cancer cells. However, the effect of CCN3 on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that CCN3 increased the migration and expression of matrix metalloproteinase (MMP)-13 in human chondrosarcoma cells (JJ012 cells). αvβ3 or αvβ5 monoclonal antibody (mAb), phosphatidylinositol 3-kinase (PI3K) inhibitors (Ly294002 and wortmannin) and Akt inhibitor inhibited the CCN3-induced increase of the migration and MMP-13 upregulation of chondrosarcoma cells. CCN3 stimulation increased the phosphorylation of focal adhesion kinase (FAK), PI3K, and Akt. In addition, NF-κB inhibitors also suppressed the cell migration and MMP-13 expression enhanced by CCN3. Moreover, CCN3 increased NF-κB luciferase activity and binding of p65 to the NF-κB element on the MMP-13 promoter. Taken together, our results indicate that CCN3 enhances the migration of chondrosarcoma cells by increasing MMP-13 expression through the αvβ3/αvβ5 integrin receptor, FAK, PI3K, Akt, p65, and NF-κB signal transduction pathway.
authors.affiliation: Division of Hematology/Oncology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Huey-En
authors.initials: HE
authors.lastname: Tzeng
authors.forename: Jui-Ching
authors.initials: JC
authors.lastname: Chen
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Kuo
authors.forename: Horng-Chaung
authors.initials: HC
authors.lastname: Hsu
authors.forename: Wen-Lee
authors.initials: WL
authors.lastname: Hwang
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001665:Binding Sites; D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002813:Chondrosarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000276:immunology / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009361:Neoplasm Invasiveness; D055514:Nephroblastoma Overexpressed Protein / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D019030:Receptors, Vitronectin / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; C526319:CCN3 protein, human; D039302:Integrin alphaVbeta3; D055514:Nephroblastoma Overexpressed Protein; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C498143:RELA protein, human; D019030:Receptors, Vitronectin; D051996:Transcription Factor RelA; C064660:integrin alphaVbeta5; D058539:Phosphatidylinositol 3-Kinase; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13