title: Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression.
abstract: Thrombospondin-2 (TSP-2) is a secreted matricellular glycoprotein that is found to mediate cell-to-extracellular matrix attachment and participates in many physiological and pathological processes. The expression profile of TSP-2 on tumors is controversial, and it up-regulates in some cancers, whereas it down-regulates in others, suggesting that the functional role of TSP-2 on tumors is still uncertain.
  
  
  
  The expression of TSP-2 on prostate cancer progression was determined in the tissue array by the immunohistochemistry. The molecular mechanism of TSP-2 on prostate cancer (PCa) metastasis was investigated through pharmaceutical inhibitors, siRNAs, and miRNAs analyses. The role of TSP-2 on PCa metastasis in vivo was verified through xenograft in vivo imaging system.
  
  
  
  Based on the gene expression omnibus database and immunohistochemistry, we found that TSP-2 increased with the progression of PCa, especially in metastatic PCa and is correlated with the matrix metalloproteinase-2 (MMP-2) expression. Additionally, through binding to CD36 and integrin ανβ3, TSP-2 increased cell migration and MMP-2 expression. With inhibition of p38, ERK, and JNK, the TSP-2-induced cell migration and MMP-2 expression were abolished, indicating that the TSP-2's effect on PCa is MAPK dependent. Moreover, the microRNA-376c (miR-376c) was significantly decreased by the TSP-2 treatment. Furthermore, the TSP-2-induced MMP-2 expression and the subsequent cell motility were suppressed upon miR-376c mimic stimulation. On the other hand, the animal studies revealed that the bone metastasis was abolished when TSP-2 was stably knocked down in PCa cells.
  
  
  
  Taken together, our results indicate that TSP-2 enhances the migration of PCa cells by increasing MMP-2 expression through down-regulation of miR-376c expression. Therefore, TSP-2 may represent a promising new target for treating PCa.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Pharmacology, China Medical University, Taichung, Taiwan.|Department of Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
authors.forename: Liang-Wei
authors.initials: LW
authors.lastname: Lin
authors.affiliation: Department of Orthopedic Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Chu
authors.affiliation: Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan.
authors.forename: Tien-Huang
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Department of Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan. yuanli@asia.edu.tw.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. yuanli@asia.edu.tw.
authors.forename: Yuan-Li
authors.identifier: 0000-0002-3405-8863
authors.initials: YL
authors.lastname: Huang
mesh_terms: D001859:Bone Neoplasms / Q000556:secondary*; D002460:Cell Line; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000473:pathology*; D019699:Thrombospondins / Q000502:physiology*; D000099262:Thrombospondin 2
chemical_list: D020778:Matrix Metalloproteinase 2; D035683:MicroRNAs; D019699:Thrombospondins; D000099262:Thrombospondin 2; C573498:MIRN376C microRNA, human; C522361:MMP2 protein, human
keywords: Matrix metalloproteinase-2; Metastasis; Prostate cancer; Thrombospondin-2; microRNA