Abstract
Inactivating MEN1 mutations are the most common genetic defects present in sporadic and inherited pancreatic neuroendocrine tumours (PNETs). The lack of interventional therapies prompts us to explore the therapeutic approach of targeting β-catenin signalling in MEN1-mutant PNETs. Here we show the MEN1-encoded scaffold protein menin regulates phosphorylation of β-catenin. β-catenin signalling is activated in MEN1-mutant human and mouse PNETs. Conditional knockout of β-catenin suppresses the tumorigenesis and growth of Men1-deficient PNETs, and significantly prolongs the survival time in mice. Suppression of β-catenin signalling by genetic ablation or a molecular antagonist inhibits the expression of proproliferative genes in menin-null PNETs and potently improves hyperinsulinemia and hypoglycemia in mice. Blockade of β-catenin has no adverse effect on physiological function of pancreatic β-cells. Our data demonstrate that β-catenin signalling is an effective therapeutic target for MEN1-mutant PNETs. Our findings may contribute to individualized and combined medication treatment for PNETs.
Highlights
Inactivating multiple endocrine neoplasia type 1 (MEN1) mutations are the most common genetic defects present in sporadic and inherited pancreatic neuroendocrine tumours (PNETs)
To evaluate the effect of menin on b-catenin phosphorylation, we examined the phosphob-catenin levels in MEN1-mutant PNETs
The active b-catenin is detected by the antibody specific for the dephosphorylated b-catenin on Ser[37] or Thr[41]
Summary
Inactivating MEN1 mutations are the most common genetic defects present in sporadic and inherited pancreatic neuroendocrine tumours (PNETs). The lack of interventional therapies prompts us to explore the therapeutic approach of targeting b-catenin signalling in MEN1-mutant PNETs. Here we show the MEN1-encoded scaffold protein menin regulates phosphorylation of b-catenin. Inactivating MEN1 mutations are the dominant genetic defects present in benign and malignant, sporadic and inherited PNETs. Germline mutations in MEN1 are the main cause of familial PNETs. A loss of heterozygosity, which was observed in PNETs with inactivating mutations in MEN1, results in the deficiency of the encoded protein menin in tumours[5,6]. The development of potent therapeutic approaches for MEN1-deficient tumours is the greatest challenge in reducing the morbidity and mortality of patients with PNETs. Menin, a highly conserved and ubiquitously distributed scaffold protein, plays functional roles in multiple physiological and pathological processes. The systematic in vivo evaluation of targeting Wnt/b-catenin signalling in Men1-deficient PNETs might contribute to the development of novel therapeutics
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