title: NHERF1/EBP50 Suppresses Wnt-β-Catenin Pathway-Driven Intestinal Neoplasia.
abstract: NHERF1/EBP50, an adaptor molecule that interacts with β-catenin, YAP, and PTEN, has been recently implicated in the progression of various human malignancies, including colorectal cancer. We report here that NHERF1 acts as a tumor suppressor in vivo for intestinal adenoma development. NHERF1 is highly expressed at the apical membrane of mucosa intestinal epithelial cells (IECs) and serosa mesothelial cells. NHERF1-deficient mice show overall longer small intestine and colon that most likely could be attributed to a combination of defects, including altered apical brush border of absorbtive IECs and increased number of secretory IECs. NHERF1 deficiency in Apc(Min/+) mice resulted in significantly shorter animal survival due to markedly increased tumor burden. This resulted from a moderate increase of the overall tumor density, more pronounced in females than males, and a massive increase in the number of large adenomas in both genders. The analysis of possible pathways controlling tumor size showed upregulation of Wnt-β-catenin pathway, higher expression of unphosphorylated YAP, and prominent nuclear expression of cyclin D1 in NHERF1-deficient tumors. Similar YAP changes, with relative decrease of phosphorylated YAP and increase of nuclear YAP expression, were observed as early as the adenoma stages in the progression of human colorectal cancer. This study discusses a complex role of NHERF1 for intestinal morphology and presents indisputable evidence for its in vivo tumor suppressor function upstream of Wnt-β-catenin and Hippo-YAP pathways.
authors: Department of Pathology and Translational Pathobiology, Louisiana State University, Shreveport, LA, 71103, USA. Electronic address: mmgeorgescu@yahoo.com.
authors: Maria-Magdalena
authors: MM
authors: Georgescu
authors: Department of Veterinary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Mihai
authors: M
authors: Gagea
authors: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Gilbert
authors: G
authors: Cote
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D017491:Genes, APC; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; D051153:Wnt Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051176:beta Catenin; C093376:sodium-hydrogen exchanger regulatory factor; D019938:Cyclin D1