Dataset Information

LGALS3 and AXIN1 gene variants playing role in the Wnt/ ?-catenin signaling pathway are associated with mucinous component and tumor size in colorectal cancer.

ABSTRACT: The Wnt pathway alterations have been identified in colorectal and many other cancer types. It has been reported that galectin-3 (which is encoded by the LGALS3 gene) alters the signaling mechanism in the Wnt/ ?-catenin pathway by binding to ?-catenin in colon and other cancers. AXIN1 is mainly responsible for the assembly of the ?-catenin destruction complex in the Wnt pathway. This study investigated the relationship of rs4644 and rs4652 variants of the LGALS3 gene and rs214250 variants of the AXIN1 gene to histopathological and clinical properties. Our study included a total of 236 patients, of whom 119 had colorectal cancer (42 women, 77 men) and 117 were healthy controls. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and allele-specific oligonucleotide (ASO) PCR methods were used. In addition, the serum galectin-3 level was studied with the enzyme-linked immunosorbent assay (ELISA) method. For the rs4644 variant of the LGALS3 gene, the CC genotype a mucinous component was significantly more common than those without a mucinous component (p=0.026). C allele frequency of the rs214250 variant of the AXIN1 gene was significantly correlated to tumor size in the advanced tumor stage (p=0.022). The CCAACT haplotype was more common in colorectal cancer patients (p=0.022). Serum galectin-3 level was higher in the patient group compared to the control group (5.9± 0.69 ng/ml vs. 0.79±0.01 ng/ml; p<0.001). In conclusion, variants of LGALS3 and AXIN1 genes affect tumor sizes and the mucinous component via Wnt/ ?-catenin pathway in the pathogenesis of colorectal cancer.

SUBMITTER: Korkmaz G

PROVIDER: S-EPMC4852991 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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LGALS3 and AXIN1 gene variants playing role in the Wnt/ β-catenin signaling pathway are associated with mucinous component and tumor size in colorectal cancer.

Korkmaz Gurbet G Horozoglu Cem C Arıkan Soykan S Gural Zeynep Z Sağlam Esra Kaytan EK Turan Saime S Özkan Nazlı Ezgi NE Kahraman Ozlem Timirci OT Yenilmez Ezgi Nurdan EN Düzköylü Yigit Y Doğan Mehmet Baki MB Zeybek Umit U Ergen Arzu A Yaylım İlhan İ

Bosnian journal of basic medical sciences 20160204 2

The Wnt pathway alterations have been identified in colorectal and many other cancer types. It has been reported that galectin-3 (which is encoded by the LGALS3 gene) alters the signaling mechanism in the Wnt/ β-catenin pathway by binding to β-catenin in colon and other cancers. AXIN1 is mainly responsible for the assembly of the β-catenin destruction complex in the Wnt pathway. This study investigated the relationship of rs4644 and rs4652 variants of the LGALS3 gene and rs214250 variants of the ...[more]

PMID: 26894286

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Project description:Colorectal cancer exhibits aberrant activation of Wnt/β-catenin signaling. Many inhibitors of the Wnt/β-catenin pathway have been tested for Wnt-dependent cancers including colorectal cancer, but are unsuccessful due to severe adverse reactions. FL3 is a synthetic derivative of natural products called flavaglines, which exhibit anti-inflammatory and cytoprotective properties in intestinal epithelial cells, but has not been previously tested in cell or preclinical models of intestinal tumorigenesis. In vitro studies suggest that flavaglines target prohibitin 1 (PHB1) as a ligand, but this has not been established in the intestine. PHB1 is a highly conserved protein with diverse functions that depend on its posttranslational modifications and subcellular localization. Here, we demonstrate that FL3 combats intestinal tumorigenesis in the azoxymethane-dextran sodium sulfate and ApcMin/+ mouse models and in human colorectal cancer tumor organoids (tumoroids) by inhibiting Wnt/β-catenin signaling via induction of Axin1 expression. FL3 exhibited no change in cell viability in normal intestinal epithelial cells or human matched-normal colonoids. FL3 response was diminished in colorectal cancer cell lines and human colorectal cancer tumoroids harboring a mutation at S45 of β-catenin. PHB1 deficiency in mice or in human colorectal cancer tumoroids abolished FL3-induced expression of Axin1 and drove tumoroid death. In colorectal cancer cells, FL3 treatment blocked phosphorylation of PHB1 at Thr258, resulting in its nuclear translocation and binding to the Axin1 promoter. These results suggest that FL3 inhibits Wnt/β-catenin signaling via PHB1-dependent activation of Axin1. FL3, therefore, represents a novel compound that combats Wnt pathway-dependent cancers, such as colorectal cancer. SIGNIFICANCE: Targeting of PHB1 by FL3 provides a novel mechanism to combat Wnt-driven cancers, with limited intestinal toxicity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/17/3519/F1.large.jpg.

Dataset Information

LGALS3 and AXIN1 gene variants playing role in the Wnt/ ?-catenin signaling pathway are associated with mucinous component and tumor size in colorectal cancer.

Publications

LGALS3 and AXIN1 gene variants playing role in the Wnt/ β-catenin signaling pathway are associated with mucinous component and tumor size in colorectal cancer.

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