title: The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines.
abstract: GPBAR1 (also known as TGR5) is a bile acid activated receptor expressed in several adenocarcinomas and its activation by secondary bile acids increases intestinal cell proliferation. Here, we have examined the expression of GPBAR1 in human gastric adenocarcinomas and investigated whether its activation promotes the acquisition of a pro-metastatic phenotype. By immunohistochemistry and RT-PCR analysis we found that expression of GPBAR1 associates with advanced gastric cancers (Stage III-IV). GPBAR1 expression in tumors correlates with the expression of N-cadherin, a markers of epithelial-mesenchymal transition (EMT) (r=0.52; P<0.01). Expression of GPBAR1, mRNA and protein, was detected in cancer cell lines, with MKN 45 having the higher expression. Exposure of MKN45 cells to GPBAR1 ligands, TLCA, oleanolic acid or 6-ECDCA (a dual FXR and GPBAR1 ligand) increased the expression of genes associated with EMT including KDKN2A, HRAS, IGB3, MMP10 and MMP13 and downregulated the expression of CD44 and FAT1 (P<0.01 versus control cells). GPBAR1 activation in MKN45 cells associated with EGF-R and ERK1 phosphorylation. These effects were inhibited by DFN406, a GPBAR1 antagonist, and cetuximab. GPBAR1 ligands increase MKN45 migration, adhesion to peritoneum and wound healing. Pretreating MKN45 cells with TLCA increased propensity toward peritoneal dissemination in vivo. These effects were abrogated by cetuximab. In summary, we report that GPBAR1 is expressed in advanced gastric cancers and its expression correlates with markers of EMT. GPBAR1 activation in MKN45 cells promotes EMT. These data suggest that GPBAR1 antagonist might have utility in the treatment of gastric cancers.
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Carino
authors.affiliation: Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Luigina
authors.initials: L
authors.lastname: Graziosi
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.affiliation: Dipartimento di Medicina, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchianò
authors.affiliation: Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marino
authors.affiliation: Dipartimento di Farmacia, Università di Napoli, Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Rende
authors.affiliation: Dipartimento di Medicina Veterinaria, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mosci
authors.affiliation: Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Annibale
authors.initials: A
authors.lastname: Donini
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009828:Oleanolic Acid / Q000737:chemistry; D010537:Peritoneum / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D015703:Antigens, CD; C497483:CD44 protein, human; C050361:CDH2 protein, human; D015820:Cadherins; C473772:GPBAR1 protein, human; D018960:Hyaluronan Receptors; D043562:Receptors, G-Protein-Coupled; C464660:obeticholic acid; D002635:Chenodeoxycholic Acid; D009828:Oleanolic Acid
keywords: TGR5; bile acids; epithelial-mesenchymal transition; gastric cancer