title: GPR54 is a target for suppression of metastasis in endometrial cancer.
abstract: Invasion into deep myometrium and/or lymphovascular space is a well-known risk factor for endometrial cancer metastasis, resulting in poor prognosis. It is therefore clinically important to identify novel molecules that suppress tumor invasion. Reduced expression of the metastasis suppressor, kisspeptin (KISS1), and its endogenous receptor, GPR54, has been reported in several cancers, but the significance of the KISS1/GPR54 axis in endometrial cancer metastasis has not been clarified. Metastin-10 is the minimal bioactive sequence of genetic products of KISS1. Clinicopathological analysis of 92 endometrial cancers revealed overall survival is improved in cancers with high expression of GPR54 (P < 0.05) and that GPR54 expression is associated with known prognostic factors including FIGO stage, grade, and deep myometrial invasion. Through RNAi and microarray analyses, metastin-10 was predicted to suppress metastasis of GPR54-expressing endometrial cancers in vivo. Methylation analysis revealed GPR54 is epigenetically regulated. Metastin-GPR54 axis function was restored following treatment with the DNA hypomethylating agent 5-aza-DC. These data suggest that metastin-10 may be effective at inhibiting the metastatic spread of endometrial cancers in combination with demethylating agents to induce GPR54 expression.
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Kang
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Baba
authors.forename: Masaki
authors.initials: M
authors.lastname: Mandai
authors.forename: Noriomi
authors.initials: N
authors.lastname: Matsumura
authors.forename: Junzo
authors.initials: J
authors.lastname: Hamanishi
authors.forename: Budiman
authors.initials: B
authors.lastname: Kharma
authors.forename: Eiji
authors.initials: E
authors.lastname: Kondoh
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D059648:Kisspeptins; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; C106628:KISS1 protein, human; C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D001374:Azacitidine