title: Ras activation mediates WISP-1-induced increases in cell motility and matrix metalloproteinase expression in human osteosarcoma.
abstract: WISP-1 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matrix cellular proteins. Osteosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. However, the effect of WISP-1 on migration activity in human osteosarcoma cells is mostly unknown. In this study, we first found that the expression of WISP-1 in osteosarcoma patients was significantly higher than that in normal bone and corrected with tumor stage. Exogenous treatment of osteosarcoma cells with WISP-1 promoted cell motility and matrix metalloproteinase (MMP)-2 and MMP-9 expression. In addition, the Ras and Raf-1 inhibitor or siRNA abolished WISP-1-induced cell migration and MMP expression. On the other hand, activation of the Ras, Raf-1, MEK, ERK, and NF-κB signaling pathway after WISP-1 treatment was demonstrated, and WISP-1-induced expression of MMPs and migration activity were inhibited by the specific inhibitor, and mutant of MEK, ERK, and NF-κB cascades. Taken together, our results indicated that WISP-1 enhances the migration of osteosarcoma cells by increasing MMP-2 and MMP-9 expression through the integrin receptor, Ras, Raf-1, MEK, ERK, and NF-κB signal transduction pathway.
authors.affiliation: Department of Physical Medicine and Rehabilitation, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Chien-Lin
authors.initials: CL
authors.lastname: Wu
authors.forename: Hsiao-Chi
authors.initials: HC
authors.lastname: Tsai
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Chen
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Wu
authors.forename: Te-Mao
authors.initials: TM
authors.lastname: Li
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D039302:Integrin alphaVbeta3; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019908:Proto-Oncogene Proteins c-raf; D020782:Matrix Metalloproteinases; D018631:ras Proteins
keywords: Migration; Osteosarcoma; Raf-1; Ras; WISP-1