Oncotarget

Research Papers:

The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines

Adriana Carino, Luigina Graziosi, Claudio D’Amore, Sabrina Cipriani, Silvia Marchianò, Elisabetta Marino, Angela Zampella, Mario Rende, Paolo Mosci, Eleonora Distrutti, Annibale Donini and Stefano Fiorucci _

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Oncotarget. 2016; 7:61021-61035. https://doi.org/10.18632/oncotarget.10477

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Abstract

Adriana Carino1,*, Luigina Graziosi2,*, Claudio D’Amore1,*, Sabrina Cipriani3, Silvia Marchianò1, Elisabetta Marino2, Angela Zampella4, Mario Rende1, Paolo Mosci5, Eleonora Distrutti2, Annibale Donini1, Stefano Fiorucci1

1Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia, Perugia, Italy

2Azienda Ospedaliera di Perugia, Perugia, Italy

3Dipartimento di Medicina, Università degli Studi di Perugia, Perugia, Italy

4Dipartimento di Farmacia, Università di Napoli, Napoli, Italy

5Dipartimento di Medicina Veterinaria, Università degli Studi di Perugia, Perugia, Italy

*These authors contributed equally to this work

Correspondence to:

Stefano Fiorucci, email: [email protected]

Keywords: gastric cancer, TGR5, bile acids, epithelial-mesenchymal transition

Received: May 16, 2016    Accepted: June 09, 2016    Published: July 07, 2016

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.


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