Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma

Area of Science:

• Endocrinology
• Molecular Biology
• Oncology

Background:

• Altered MENIN protein expression is linked to neuroendocrine tumors (NETs).
• The role of MENIN in maintaining endocrine cell function and its connection to NET development is unclear.
• MENIN's interaction with transcription factors in pancreatic NETs requires further investigation.

Purpose of the Study:

• To investigate the hypothesis that MENIN regulates factors maintaining endocrine-differentiated functions.
• To determine if MENIN interferes with the expression of v-MAF musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA) in insulinomas.
• To elucidate the MENIN/MAFA connection in controlling beta-cell differentiation and proliferation balance.

Main Methods:

• Immunohistochemical analysis of human insulinomas.
• Analysis of mouse insulinomas following Men1 ablation.
• In vitro studies using insulinoma cell lines.
• MENIN knockdown and MAFA knockdown experiments.
• Analysis of MENIN variants with missense mutations.

Main Results:

• Human and mouse insulinomas showed correlated decreases in MENIN and MAFA.
• MENIN regulates MAFA at both protein and mRNA levels in vitro.
• MENIN knockdown decreased Mafa and beta-cell differentiation markers while increasing proliferation.
• MAFA knockdown increased proliferation but did not affect MENIN-regulated proliferation genes.
• MENIN variants with MEN1-associated mutations lost the ability to regulate MAFA.

Conclusions:

• MENIN directly regulates MAFA expression and is crucial for maintaining beta-cell differentiation.
• The MENIN/MAFA axis plays a significant role in controlling the balance between beta-cell differentiation and proliferation.
• Dysregulation of the MENIN/MAFA pathway may contribute to the development of pancreatic neuroendocrine tumors.