Bile acids repress E‐cadherin through the induction of Snail and increase cancer invasiveness in human hepatobiliary carcinoma

Fukase, Koji; Ohtsuka, Hideo; Onogawa, Tohru; Oshio, Hiroshi; Takayuki,; Mutoh, Mitsuhisa; Katayose, Yu; Rikiyama, Toshiki; Oikawa, Masaya; Motoi, Fuyuhiko; Egawa, Shinichi; Abe, Takaaki; Unno, Michiaki

doi:10.1111/j.1349-7006.2008.00898.x

Cited by 30 publications

(30 citation statements)

References 48 publications

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“…CA and DCA are unconjugated forms; unconjugated hydrophobic bile acids possess higher affinities for nuclear receptors, such as the farnesoid X receptor, compared with conjugated hydrophilic bile acids (10), thus may have an effect on cancer progression. It is hypothesized that unconjugated bile acids, which can enter the cells via passive diffusion through the plasma membrane, can directly activate nuclear receptors and modulate the transcriptional activity of stimulating protein1 (Sp1) on the Snail promotor (10). Certain reports have indicated that unconjugated bile acids may induce cell apoptosis, particularly at high concentrations (>100 µM) (18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

“…The wound edges were imaged using a digital camera fitted to a light microscope with x10 objective lens. The images were captured at 0, 12 and 24 h following wounding (10). The degree of wound closure was measured at three independent wound sites per each treatment group at 0, 12 and 24 h. The percentage of cell migration was calculated according to the following formula: [Distance of edge at 0-12 h (or 24 h)/distance of edge at 0 h] x100.…”

Section: Methodsmentioning

confidence: 99%

“…Then, they were pretreated with serum-free medium containing 100 µM of each bile acid for 24 h prior to wound formation. The 'scratch' wounds were created using a sterile 10 µl pipette tip (10). The old medium was discarded and the wells were washed twice with sterile PBS.…”

Section: Methodsmentioning

confidence: 99%

“…Taurocholic acid (TCA) is known to stimulate the secretion of certain cytokines, including monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6), from cholangiocytes, which are involved in the inflammatory and fibrotic processes that occur during cholestatic diseases (9). Additionally, chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) could promote CCA invasiveness via stimulating the Snail signaling pathway, leading to the downregulation of E-cadherin (10). The present study aimed to investigate the effects of bile acids on the migration of human CCA cells.…”

Section: Introductionmentioning

confidence: 99%

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High expression of CCDC25 in cholangiocarcinoma tissue samples

et al. 2017

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Abstract. Cholangiocarcinoma (CCA) is a malignant transformation of biliary epithelial cells. It is a slow growing tumor, but is also highly metastatic with a poor prognosis. Bile acids are known to transactivate the epidermal growth factor receptor (EGFR) in cholangiocytes and induce cyclooxygenase-2 expression. The protein expression profiles of bile acid-treated CCA cells were studied using a proteomic approach. To elucidate the possible mechanisms involved in the bile acid-mediated enhancement of CCA cell migration, the effects of six bile acids, including cholic, deoxycholic, taurocholic, taurodeoxycholic, glycocholic and glycodeoxycholic acid, on the migration of CCA cells were examined in vitro using wound healing assays. Subsequently, the possible proteins involved in enhanced CCA cell migration were investigated using a proteomic approach. Changes to the protein expression profiles of CCA cells following bile acid treatment was examined using two-dimensional electrophoresis and mass spectrometry. The results demonstrated that cholic and deoxycholic acid significantly enhanced the migration of CCA cells, compared with the treated MMNK-1 control cells. CCA cells had 77 overexpressed protein spots following cholic acid treatment, and 50 protein spots following deoxycholic acid treatment, compared with the treated MMNK-1 control cells. Liquid chromatography tandem-mass spectrometry analysis revealed that coiled-coil domain containing 25 (CCDC25) was significantly overexpressed in cholic acid-treated CCA cells compared with in cholic acid-treated control cells. When the expression levels of CCDC25 were investigated using western blot analysis, CCDC25 was demonstrated to be highly expressed in CCA tissues, but not in the adjacent non-cancerous tissue samples. The identified proteins were further analyzed for protein-chemical interactions using STITCH version 3.1 software. CCDC25 protein was identified to be associated with Son of sevenless homolog 1 and growth factor receptor-bound protein 2, which are involved in EGFR signaling. The results of the present study demonstrated that following cholic acid treatment, CCDC25 is overexpressed in CCA cells, which is associated with significantly enhanced cell migration. This suggests that CCDC25 is a potential therapeutic target for the treatment of patients with CCA. IntroductionCholangiocarcinoma (CCA) is a malignant transformation of biliary epithelial cells. It is a slow growing tumor, but it is also highly metastatic with a poor prognosis (1). The highest incidence of this cancer has been identified in Asia, particularly in Northeast Thailand (2). In the majority of cases of CCA, the etiology is unknown. Chronic inflammation and cellular injury within bile ducts, together with the partial obstruction of bile flow result in high-risk conditions for CCA development (3). The tumor not only may develop mechanisms to survive in the toxic environment of bile, but may also utilize bile components to promote cell growth, survival and invasion (4-6). Bile acids are known...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High expression of CCDC25 in cholangiocarcinoma tissue samples

et al. 2017

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“…Unconjugated primary bile acid, chenodeoxycholic acid, and the secondary bile acid, lithocholic acid, induce SNAIL expression and E-cadherin down-regulation in CCA cells, at least in part, through two transcription factors, Nuclear factor-Y and Stimulating protein 1 [116]. Whether these effects involve the bile acid receptors, Farnesoid X Receptor and G protein-coupled bile acid receptor 1 (TGR5), remains to be elucidated.…”

Section: Additional Regulatory Factorsmentioning

confidence: 99%

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

126

122

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Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

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Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulate β‐catenin activity in colon cancer cells

Egan

Thompson

Vitanov

et al. 2009

Molecular Carcinogenesis

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The activity of β-catenin, commonly dysregulated in human colon cancers, is inhibited by the vitamin D receptor (VDR), and this mechanism is postulated to explain the putative anti-cancer activity of vitamin D metabolites in the colon. We investigated the effect of a common FokI restriction site polymorphism (F/f) in the human VDR gene as well as the effect of antitumorigenic 1,25-dihydroxyvitamin D 3 (1,25D) and pro-tumorigenic lithocholic acid (LCA) VDR ligands on β-catenin transcriptional activity. Furthermore, the influence of a major regulatory protein of β-catenin, the APC tumor suppressor gene, on VDR-dependent inhibition of β-catenin activity was examined. We report herein that β-catenin-mediated transcription is most effectively suppressed by the VDR FokI variant F/M4 when 1,25D is limiting. Using Caco-2 colorectal cancer cells, it was observed that VDR ligands, 1,25D and LCA, both suppress β-catenin transcriptional activity, though 1,25D exhibited significantly greater inhibition. Moreover, 1,25D, but not LCA, suppressed endogenous expression of the β-catenin target gene DKK-4 independent of VDR DNA-binding activity. These results support β-catenin sequestration away from endogenous gene targets by 1,25D-VDR. This activity is most efficiently mediated by the FokI gene variant F/M4, a VDR allele previously associated with protection against colorectal cancer. Interestingly, we found the inhibition of β-catenin activity by 1,25D-VDR was significantly enhanced by wildtype APC. These results reveal a previously unrecognized role for 1,25D-VDR in APC/β-catenin cross-talk. Collectively, these findings strengthen evidence favoring a direct effect on the Wnt-signaling molecule β-catenin as one anti-cancer target of 1,25D-VDR action in the colorectum.

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Bile acids repress E‐cadherin through the induction of Snail and increase cancer invasiveness in human hepatobiliary carcinoma

Abstract: Although some kinds of bile acids have been implicated in colorectal cancer development, the mechanism of cancer progression remains unexplored in hepatobiliary cancer. From our personal results using complementary DNA microarray, we found that chenodeoxycholic acid (

Cited by 30 publications

References 48 publications

High expression of CCDC25 in cholangiocarcinoma tissue samples

High expression of CCDC25 in cholangiocarcinoma tissue samples

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulate β‐catenin activity in colon cancer cells

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