title: Metastin and its variant forms suppress migration of pancreatic cancer cells.
abstract: Metastin, a post-translationally modified variant of KiSS1, was recently identified as an endogenous peptide agonist for a novel G-protein coupled receptor, hOT7T175 (AXOR12, GPR54). In this study, we analyzed the role of KiSS1 and hOT7T175 in both pancreatic cancer tissues and pancreatic cancer cell lines. Furthermore, we synthesized novel short variant forms of metastin and tested the inhibitory effect of those variants on in vitro cell functions that are relevant to metastasis. Pancreatic cancer tissues showed significantly lower expression of KiSS1 mRNA than normal tissues (p=0.018), while cancer tissues showed significantly higher expression of hOT7T175 mRNA than normal pancreatic tissues (p=0.027). In human pancreatic cancer cell lines, KiSS1 mRNA was highly expressed in 2 out of 6 pancreatic cancer cell lines, while hOT7T175 mRNA was expressed in all cell lines at various degrees. PANC-1 cells showed the highest expression of hOT7T175. Exogenous metastin did not suppress cell proliferation but significantly reduced the in vitro migration of PANC-1 cells (p<0.01). Metastin induced activation of ERK1 in PANC-1 and AsPC-1 cells. Finally, we synthesized 3 novel short variant forms of metastin, FM053a2TFA, FM059a2TFA, and FM052a4TFA. These metastin variants significantly suppressed the migration of PANC-1 cells and activated ERK1. These data suggest that the metastin receptor, hOT7T175, is one of the promising targets for suppression of metastasis, and that small metastin variants could be an anti-metastatic agent to pancreatic cancer.
authors.affiliation: Department of Surgery and Surgical Basic Science, Kyoto University, Kyoto, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Masui
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Doi
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Mori
authors.forename: Eiji
authors.initials: E
authors.lastname: Toyoda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Koizumi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kami
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: James R
authors.initials: JR
authors.lastname: Broach
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Ayumu
authors.initials: A
authors.lastname: Niida
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Masayuki
authors.initials: M
authors.lastname: Imamura
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D059648:Kisspeptins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D011506:Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins
chemical_list: C106628:KISS1 protein, human; C118688:KISS1R protein, human; D059648:Kisspeptins; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide; D025521:Tumor Suppressor Proteins; D020928:Mitogen-Activated Protein Kinases