Role of Clostridium perfringens Enterotoxin on YAP Activation in Colonic Sessile Serrated Adenoma/Polyps with Dysplasia
Open Access
- 28 May 2020
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (11), 3840
- https://doi.org/10.3390/ijms21113840
Abstract
Sessile serrated adenoma/polyp with dysplasia (SSA/P-D) is an SSA/P with cellular dysplasia and has a higher risk of progressing to colon carcinogenesis. Previously, we reported that tight junction impairment by Clostridium perfringens enterotoxin (CPE) leads to activation of the transcriptional co-activator yes-associated protein (YAP) in oral squamous cell carcinoma. Here, we investigated whether CPE activates YAP to promote the malignant progression of SSA/P. E-cadherin expression was lower in the 12 cases with SSA/P-D examined than that in normal mucosa, SSA/P, or tubular adenoma (TA). Furthermore, intracellular translocation of claudin-4 (CLDN4) and nuclear translocation of YAP were observed. The CPE gene was detected in DNA extracted from SSA/P-D lesions, but not in SSA/P or TA. Treatment of the rat intestinal epithelial cell line IEC6 with low-dose CPE resulted in intracellular translocation of CLDN4 to the cytoplasmic membrane. Cytoplasmic CLDN4 showed co-precipitation with transcriptional co-activator with PDZ-binding motif, zonula occludens (ZO)-1, large tumor suppressor, and mammalian Ste20-like. Additionally, YAP co-precipitated with ZO-2 under CPE treatment led to decreased YAP phosphorylation and nuclear translocation. YAP activation promoted increase in nuclear TEA domain family member level, expression of cyclin D1, snail, vimentin, CD44, NS and decrease in E-cadherin levels, thereby inducing stemness and epithelial-mesenchymal-transition (EMT). The Hippo complex with the incorporation of CLDN4 increased stability. Upon low-dose CPE treatment, HT29 cells with BRAFV600E gene mutation showed increased growth, enhanced invasive potential, stemness, and induced EMT phenotype, whereas HCT116 cells, which carry KRASG13D gene mutation, did not show such changes. In an examination of 10 colorectal cancers, an increase in EMT and stemness was observed in CPE (+) and BRAF mutation (+) cases. These findings suggest that C. perfringens might enhance the malignant transformation of SSA/P-D via YAP activation. Our findings further highlight the importance of controlling intestinal flora using probiotics or antibiotics.Funding Information
- Ministry of Education, Culture, Sports, Science and Technology (16H05164, 17K19923, 19K16564)
- National Natural Science Foundation of China (81702723)
This publication has 63 references indexed in Scilit:
- RAF kinase inhibitor-independent constitutive activation of Yes-associated protein 1 promotes tumor progression in thyroid cancerOncogenesis, 2013
- Growth Control by Committee: Intercellular Junctions, Cell Polarity, and the Cytoskeleton Regulate Hippo SignalingDevelopmental Cell, 2012
- Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAPOncogene, 2011
- Yap1 Acts Downstream of α-Catenin to Control Epidermal ProliferationCell, 2011
- C Terminus of Clostridium perfringens Enterotoxin Downregulates CLDN4 and Sensitizes Ovarian Cancer Cells to Taxol and CarboplatinClinical Cancer Research, 2011
- Specificity of Interaction between Clostridium perfringens Enterotoxin and Claudin-Family Tight Junction ProteinsToxins, 2010
- The Hippo–YAP pathway: new connections between regulation of organ size and cancerCurrent Opinion in Cell Biology, 2008
- Altered localization and expression of tight-junction proteins in a rat model with chronic acid reflux esophagitisThe Esophagus, 2005
- θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of PermeabilityThe Journal of pharmacology and experimental therapeutics, 2005
- Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of PermeabilityThe Journal of pharmacology and experimental therapeutics, 2005