title: HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase.
abstract: Dysregulation of cell surface proteolysis has been strongly implicated in tumorigenicity and metastasis. In this study, we delineated the role of hepatocyte growth factor activator inhibitor-2 (HAI-2) in prostate cancer (PCa) cell migration, invasion, tumorigenicity and metastasis using a human PCa progression model (103E, N1, and N2 cells) and xenograft models. N1 and N2 cells were established through serial intraprostatic propagation of 103E human PCa cells and isolation of the metastatic cells from nearby lymph nodes. The invasion capability of these cells was revealed to gradually increase throughout the serial isolations (103E<N1<N2). In this series of cells, the expression of HAI-2 but not HAI-1 was significantly decreased throughout the progression and occurred in parallel with increased activation of matriptase. The expression level and activity of matriptase increased whereas the HAI-2 protein level decreased over the course of orthotopic tumor growth in mice, which was consistent with the immunohistochemical profiles of matriptase and HAI-2 in archival PCa specimens. Knockdown of matriptase reduced the PCa cell invasion induced by HAI-2 knockdown. HAI-2 overexpression or matriptase silencing in N2 cells downregulated matriptase activity and significantly decreased tumorigenicity and metastatic capability in orthotopically xenografted mice. These results suggest that during the progression of human PCa, matriptase activity is primarily controlled by HAI-2 expression. The imbalance between HAI-2 and matriptase expression led to matriptase activation, thereby increasing cell migration, invasion, tumorigenicity and metastasis.
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Teng
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Tu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: T-S
authors.initials: TS
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: S-R
authors.initials: SR
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Ko
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan [2] Investigation Bureau, Ministry of Justice, Taipei, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Shyu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: S-W
authors.initials: SW
authors.lastname: Lan
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-P
authors.initials: HP
authors.lastname: Huang
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: S-F
authors.initials: SF
authors.lastname: Tzeng
authors.affiliation: Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: P-W
authors.initials: PW
authors.lastname: Hsiao
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: M-S
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D008562:Membrane Glycoproteins; C109148:SPINT2 protein, human; D012697:Serine Endopeptidases; C485596:ST14 protein, human