Expression of μ-protocadherin is negatively regulated by the activation of the β-catenin signaling pathway in normal and cancer colorectal enterocytes.
Mu-protocadherin (MUCDHL) is an adhesion molecule predominantly expressed by colorectal epithelial cells which is markedly downregulated upon malignant transformation. Notably, treatment of colorectal cancer (CRC) cells with mesalazine lead to increased expression of MUCDHL, and is associated with sequestration of β-catenin on the plasma membrane and inhibition of its transcriptional activity. To better characterize the causal relationship between β-catenin and MUCDHL expression, we performed various experiments in which CRC cell lines and normal colonic organoids were subjected to culture conditions inhibiting (FH535 treatment, transcription factor 7-like 2 siRNA inactivation, Wnt withdrawal) or stimulating (LiCl treatment) β-catenin activity. We show here that expression of MUCDHL is negatively regulated by functional activation of the β-catenin signaling pathway. This finding was observed in cell culture systems representing conditions of physiological stimulation and upon constitutive activation of β-catenin in CRC. The ability of MUCDHL to sequester and inhibit β-catenin appears to provide a positive feedback enforcing the effect of β-catenin inhibitors rather than serving as the primary mechanism responsible for β-catenin inhibition. Moreover, MUCDHL might have a role as biomarker in the development of CRC chemoprevention drugs endowed with β-catenin inhibitory activity.
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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0000-0002-8791-5603
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Montorsi
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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Parenti
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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Losi
SOFAR S.p.A., Milano, Italy.
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Ferrarini
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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Gemelli
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.
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Rossi
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.
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Manco
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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Ferrari
Department of Clinical and Diagnostic Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.|Department of Cancer Biology and SKKC, Thomas Jefferson University, Philadelphia, PA, USA.
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Calabretta
Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.|Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy.
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Tagliafico
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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Zanocco-Marani
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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Grande
D018938:Caco-2 Cells; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D046509:Tissue Culture Techniques; D058118:Transcription Factor 7-Like 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C413024:CDHR5 protein, human; C495270:CTNNB1 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; C575430:FH535; D034741:RNA, Small Interfering; D013449:Sulfonamides; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D018021:Lithium Chloride