The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines.
The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines.
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DOI：
10.18632/oncotarget.10477
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发表时间：
2016-09-20
期刊：
影响因子：
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通讯作者：
Fiorucci S
中科院分区：
文献类型：
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作者：
Carino A;Graziosi L;D'Amore C;Cipriani S;Marchianò S;Marino E;Zampella A;Rende M;Mosci P;Distrutti E;Donini A;Fiorucci S
GPBAR1（又称TGR5）是一种胆汁酸激活受体，在多种腺癌中表达，其被次级胆汁酸激活可促进肠细胞增殖。在这里，我们检测了GPBAR1在人胃腺癌中的表达，并研究了其激活是否促进了促转移表型的获得。通过免疫组织化学和RT-PCR分析，我们发现GPBAR1的表达与晚期胃癌（III-IV期）有关。GPBAR1在肿瘤中的表达与上皮-间质转化（epithelial-mesenchymal transition， EMT）标志物N-cadherin的表达相关（r=0.52； P<0.01）。GPBAR1 mRNA和蛋白在肿瘤细胞系中均有表达，其中mkn45表达量较高。MKN45细胞暴露于GPBAR1配体、TLCA、齐墩果酸或6-ECDCA（双FXR和GPBAR1配体）后，包括KDKN2A、HRAS、IGB3、MMP10和MMP13在内的EMT相关基因的表达增加，CD44和FAT1的表达下调（与对照细胞相比P<0.01）。GPBAR1在MKN45细胞中的激活与EGF-R和ERK1磷酸化相关。这些作用可被GPBAR1拮抗剂DFN406和西妥昔单抗抑制。GPBAR1配体增加MKN45迁移、腹膜粘附和伤口愈合。在体内用TLCA预处理MKN45细胞增加了向腹膜播散的倾向。西妥昔单抗消除了这些影响。总之，我们报道GPBAR1在晚期胃癌中表达，其表达与EMT标志物相关。GPBAR1在MKN45细胞中的激活促进EMT。这些数据提示GPBAR1拮抗剂可能在胃癌的治疗中具有实用价值。
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.