BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/..
OBJECTIVE: Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD.
DESIGN: We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves-/- and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels.
RESULTS: BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves-/- mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves-/- tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction.
CONCLUSION: Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Gut - 66(2017), 5 vom: 13. Mai, Seite 852-862 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Parang, Bobak [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.07.2017 Date Revised 21.05.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1136/gutjnl-2015-310255 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM27077209X |
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| 041 | |a eng | ||
| 100 | 1 | |a Parang, Bobak |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis |
| 264 | 1 | |c 2017 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 10.07.2017 | ||
| 500 | |a Date Revised 21.05.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/. | ||
| 520 | |a OBJECTIVE: Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD | ||
| 520 | |a DESIGN: We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves-/- and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels | ||
| 520 | |a RESULTS: BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves-/- mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves-/- tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction | ||
| 520 | |a CONCLUSION: Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CANCER | |
| 650 | 4 | |a COLONIC NEOPLASMS | |
| 650 | 4 | |a COLORECTAL CANCER | |
| 650 | 4 | |a IBD | |
| 650 | 4 | |a ULCERATIVE COLITIS | |
| 650 | 7 | |a BVES protein, human |2 NLM | |
| 650 | 7 | |a Biomarkers, Tumor |2 NLM | |
| 650 | 7 | |a Bves protein, mouse |2 NLM | |
| 650 | 7 | |a Cell Adhesion Molecules |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Muscle Proteins |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-myc |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 650 | 7 | |a Dextran Sulfate |2 NLM | |
| 650 | 7 | |a 9042-14-2 |2 NLM | |
| 650 | 7 | |a Ppp2r5a protein, mouse |2 NLM | |
| 650 | 7 | |a EC 3.1.3.16 |2 NLM | |
| 650 | 7 | |a Protein Phosphatase 2 |2 NLM | |
| 650 | 7 | |a EC 3.1.3.16 |2 NLM | |
| 700 | 1 | |a Kaz, Andrew M |e verfasserin |4 aut | |
| 700 | 1 | |a Barrett, Caitlyn W |e verfasserin |4 aut | |
| 700 | 1 | |a Short, Sarah P |e verfasserin |4 aut | |
| 700 | 1 | |a Ning, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Keating, Cody E |e verfasserin |4 aut | |
| 700 | 1 | |a Mittal, Mukul K |e verfasserin |4 aut | |
| 700 | 1 | |a Naik, Rishi D |e verfasserin |4 aut | |
| 700 | 1 | |a Washington, Mary K |e verfasserin |4 aut | |
| 700 | 1 | |a Revetta, Frank L |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, J Joshua |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Keith T |e verfasserin |4 aut | |
| 700 | 1 | |a Brand, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Bader, David M |e verfasserin |4 aut | |
| 700 | 1 | |a Tansey, William P |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ru |e verfasserin |4 aut | |
| 700 | 1 | |a Brentnall, Teresa A |e verfasserin |4 aut | |
| 700 | 1 | |a Grady, William M |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Christopher S |e verfasserin |4 aut | |
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