Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma.
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.
['Hamze|Z|Z|', 'Vercherat|C|C|', 'Bernigaud-Lacheretz|A|A|', 'Bazzi|W|W|', 'Bonnavion|R|R|', 'Lu|J|J|', 'Calender|A|A|', 'Pouponnot|C|C|', 'Bertolino|P|P|', 'Roche|C|C|', 'Stein|R|R|', 'Scoazec|J Y|JY|', 'Zhang|C X|CX|', 'Cordier-Bussat|M|M|']
D000328:Adult D000368:Aged D000818:Animals D017209:Apoptosis D015153:Blotting, Western D018278:Carcinoma, Neuroendocrine D002454:Cell Differentiation D049109:Cell Proliferation D047369:Chromatin Immunoprecipitation D005260:Female D005947:Glucose D006801:Humans D007124:Immunoenzyme Techniques D050417:Insulin-Secreting Cells D007340:Insulinoma D051473:Maf Transcription Factors, Large D008297:Male D051379:Mice D018345:Mice, Knockout D008875:Middle Aged D010190:Pancreatic Neoplasms D011518:Proto-Oncogene Proteins D012333:RNA, Messenger D034741:RNA, Small Interfering D051381:Rats D060888:Real-Time Polymerase Chain Reaction D020133:Reverse Transcriptase Polymerase Chain Reaction D014407:Tumor Cells, Cultured
MENIN MAFA differentiation insulinoma MEN1 endocrine tumour