title: PKD1 negatively regulates cell invasion, migration and proliferation             ability of human osteosarcoma.
abstract: Osteosarcoma (OS) is a primary malignancy of the bone, with a tendency to metastasize early. Despite intensive chemotherapy and surgical resection, more than 30% of patients develop distant metastases, and the prognosis of patients with metastases is essentially poor. Members of the protein kinase D (PKD) family are serine/threonine kinases, and have been studied in various cancers. Among the three different isoforms of this family, PKD1 is one of the best understood for its role in human malignancies; however, its role in musculoskeletal tumors has not been studied. In the present study, we investigated the role of PKD1 in human OS. We first analyzed PKD1 mRNA expression in human musculoskeletal tumor tissue samples by quantitative real-time PCR. PKD1 expression in OS samples was significantly lower than that in benign schwannoma samples, and this was correlated with metastatic potential. In in vitro studies, overexpression of PKD1 by plasmid transfection decreased OS cell invasion, migration and proliferation, and significantly decreased matrix metalloproteinase (MMP)2 mRNA expression. Conversely, siRNA knockdown of PKD1 increased invasion, migration and proliferation of OS cells, and MMP2 expression was markedly increased. Furthermore, overexpression of PKD1 significantly reduced in vivo tumor growth of OS cells. These results demonstrated that low expression of PKD1 may contribute to increased cell invasion, migration and proliferation ability of human OS. Taken together, our findings strongly suggest that PKD1 may negatively regulate the malignant potential of human OS, and may be a therapeutic target for human OS in the clinical setting.
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School                     of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Onishi
authors.forename: Teruya
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Kenta
authors.initials: K
authors.lastname: Kishimoto
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hara
authors.forename: Naomasa
authors.initials: N
authors.lastname: Fukase
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Toda
authors.forename: Risa
authors.initials: R
authors.lastname: Harada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Akisue
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009442:Neurilemmoma / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D020778:Matrix Metalloproteinase 2; D050396:TRPP Cation Channels; C522361:MMP2 protein, human