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Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma.

Abstract：

:The protein MENIN is the product of the multiple endocrine neoplasia type I (MEN1) gene. Altered MENIN expression is one of the few events that are clearly associated with foregut neuroendocrine tumours (NETs), classical oncogenes or tumour suppressors being not involved. One of the current challenges is to understand how alteration of MENIN expression contributes to the development of these tumours. We hypothesised that MENIN might regulate factors maintaining endocrine-differentiated functions. We chose the insulinoma model, a paradigmatic example of well-differentiated pancreatic NETs, to study whether MENIN interferes with the expression of v-MAF musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA), a master glucose-dependent transcription factor in differentiated β-cells. Immunohistochemical analysis of a series of human insulinomas revealed a correlated decrease in both MENIN and MAFA. Decreased MAFA expression resulting from targeted Men1 ablation was also consistently observed in mouse insulinomas. In vitro analyses using insulinoma cell lines showed that MENIN regulated MAFA protein and mRNA levels, and bound to Mafa promoter sequences. MENIN knockdown concomitantly decreased mRNA expression of both Mafa and β-cell differentiation markers (Ins1/2, Gck, Slc2a2 and Pdx1) and, in parallel, increased the proliferation rate of tumours as measured by bromodeoxyuridine incorporation. Interestingly, MAFA knockdown alone also increased proliferation rate but did not affect the expression of candidate proliferation genes regulated by MENIN. Finally, MENIN variants with missense mutations detected in patients with MEN1 lost the WT MENIN properties to regulate MAFA. Together, our findings unveil a previously unsuspected MENIN/MAFA connection regarding control of the β-cell differentiation/proliferation balance, which could contribute to tumorigenesis.

journal_name

Endocr Relat Cancer

journal_title

Endocrine-related cancer

authors

Hamze Z,Vercherat C,Bernigaud-Lacheretz A,Bazzi W,Bonnavion R,Lu J,Calender A,Pouponnot C,Bertolino P,Roche C,Stein R,Scoazec JY,Zhang CX,Cordier-Bussat M

doi

10.1530/ERC-13-0164

subject

Has Abstract

pub_date

2013-10-24 00:00:00

pages

833-48

issue

eissn

1351-0088

issn

1479-6821

pii

20/6/833

journal_volume

pub_type

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Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma.