Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis

Yu, Ji Hee; Li, Shan; Guo, Jing; Xu, Zhengshui; Zheng, Jianbao; Sun, Xuejun

doi:10.1038/s41419-020-02819-w

Cited by 51 publications

(45 citation statements)

References 60 publications

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“…The would-healing assays were carried out as described previously. 33 Cells were cultured in six-well plates until 90% confluence. Pipette tips (10 µL) were then utilised to scratch artificial vertical lines.…”

Section: Methodsmentioning

confidence: 99%

“…The transwell assays were carried out as described previously. 33 Briefly, cells, suspended in FBS-free medium, were seeded into Transwell (Corning, New York, NY, USA) inserts coated with Matrigel (BD Biosciences, Franklin Lakes, NJ, USA) or not. The lower chamber contained 600 μl of RPMI-1640 medium with 20% FBS.…”

Section: Methodsmentioning

confidence: 99%

“…The IF assay was carried out as described previously. 33 The sample was observed using a fluorescence microscope to measure E-cadherin and vimentin expression and β-catenin subcellular localisation.…”

Section: Methodsmentioning

confidence: 99%

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CDX2 inhibits epithelial–mesenchymal transition in colorectal cancer by modulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression

et al. 2020

Br J Cancer

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Background Emerging evidence suggests the involvement of caudal-related homoeobox transcription factor 2 (CDX2) in tumorigenesis of various cancers. Although CDX2 functions in cancer invasion and metastasis, fewer studies focus on the role of CDX2 during the induction of epithelial–mesenchymal transition (EMT) in colorectal cancer (CRC). Methods Immunohistochemical analysis of CDX2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of CDX2 in the invasion and metastasis of CRC. Results CDX2 was downregulated in CRC tissues and reduced CDX2 correlated with poor prognosis. Knockdown of CDX2 promoted colon cancer cell invasion in vitro and facilitated liver metastasis in vivo with inducing EMT phenotypes. Further investigation indicated that CDX2 retarded Akt and GSK-3β phosphorylation, and thereby diminished Snail expression, β-catenin stabilisation and nuclear translocation. The depletion of β-catenin neutralised the regulation of Slug and ZEB1 by CDX2 knockdown. Mechanistically, CDX2 antagonised PI3K/Akt activity in CRC by modulating PTEN expression. CDX2 directly bound to the promoter of PTEN and transactivated its expression. Conclusions Our study first uncovered that CDX2 inhibits EMT and metastasis of CRC by regulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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CDX2 inhibits epithelial–mesenchymal transition in colorectal cancer by modulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression

et al. 2020

Br J Cancer

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“…These data revealed that abnormal bile acid metabolism was involved in CAC development. Several studies have found that the FXR mRNA expression is inversely correlated with CRC progression, and FXR deficiency increased the tumor load in Apc min/+ mice and xenograft tumor model [47][48][49]. Moreover, mice lacking FXR showed disrupted intestinal epithelium integrity and an overgrowth of intestinal bacteria [50].…”

Section: Discussionmentioning

confidence: 99%

Gut Dysbiosis and Abnormal Bile Acid Metabolism in Colitis-Associated Cancer

Liu

Yang

Dong

et al. 2021

Gastroenterology Research and Practice

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Background. Patients with prolonged inflammatory bowel disease (IBD) can develop into colorectal cancer (CRC), also called colitis-associated cancer (CAC). Studies have shown the association between gut dysbiosis, abnormal bile acid metabolism, and inflammation process. Here, we aimed to investigate these two factors in the CAC model. Methods. C57BL/6 mice were randomly allocated to two groups: azoxymethane/dextran sodium sulfate (AOM/DSS) and control. The AOM/DSS group received AOM injection followed by DSS drinking water. Intestinal inflammation, mucosal barrier, and bile acid receptors were determined by real-time PCR and immunohistochemistry. Fecal microbiome and bile acids were detected via 16S rRNA sequencing and liquid chromatography-mass spectrometry. Results. The AOM/DSS group exhibited severe mucosal barrier impairment, inflammatory response, and tumor formation. In the CAC model, the richness and biodiversity of gut microbiota were decreased, along with significant alteration of composition. The abundance of pathogens was increased, while the short-chain fatty acids producing bacteria were reduced. Interestingly, Clostridium XlV and Lactobacillus, which might be involved in the bile acid deconjugation, transformation, and desulfation, were significantly decreased. Accordingly, fecal bile acids were decreased, accompanied by reduced transformation of primary to secondary bile acids. Given bile acid receptors, the ileum farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) axis was downregulated, while Takeda G-protein receptor 5 (TGR5) was overexpressed in colonic tumor tissues. Conclusion. Gut dysbiosis might alter the metabolism of bile acids and promote CAC, which would provide a potential preventive strategy of CAC by regulating gut microbiota and bile acid metabolism.

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“…Intriguingly, the activation of FXR by GW4064 decreased the expression of HER2, the upstream of JAK/STAT3 pathway 47 . Besides JAK/STAT signalling, OCA might exert tumour suppressor role by directly regulating FXR target genes SHP 31 and MMP7 48 or suppressing Wnt/β‐catenin 49 and EGFR/ERK signalling 50 . Hence, OCA exerts its tumour suppressor functions via multiple molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X receptor activation induces antitumour activity in colorectal cancer by suppressing JAK2/STAT3 signalling via transactivation of SOCS3 gene

Guo

et al. 2020

J Cellular Molecular Medi

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Colorectal cancer (CRC) is the second most common cause of cancer-related death. 1 Globally, approximately 1 800 000 new cases are diagnosed as CRC every year. Due to distant metastasis and relapse, most advanced-stage CRC indicates a poor prognosis. 2,3 The 5-year survival rate of stage I CRC in patients exceeds 90%; however, the rate of stage IV CRC in patients is slightly higher than 10%. 4 There has recently been substantial progress in multimodality therapy for CRC. Chemotherapy is the second major treatment type for CRC after surgical treatment. However, there are many problems with chemotherapy, such as drug resistance and side effects. 5 Thus, more effective strategies and novel targets for chemotherapy in this malignancy are urgently required.

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Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis

Cited by 51 publications

References 60 publications

CDX2 inhibits epithelial–mesenchymal transition in colorectal cancer by modulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression

CDX2 inhibits epithelial–mesenchymal transition in colorectal cancer by modulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression

Gut Dysbiosis and Abnormal Bile Acid Metabolism in Colitis-Associated Cancer

Farnesoid X receptor activation induces antitumour activity in colorectal cancer by suppressing JAK2/STAT3 signalling via transactivation of SOCS3 gene

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