β-Catenin signaling controls tumorigenesis in menin-deficient insulinoma
G. Ning, Y. Cao, X. Jiang, F. Li, J. Lu, X. Li & W. Wang
Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumour syndrome characterized by the development of tumours of the parathyroid, anterior pituitary and pancreatic islets, etc. Heterozygous germ line mutations of MEN1 gene are responsible for the onset of MEN1. Here We reported totally 87 patients from 24 unrelated Chinese families associated with MEN1 and identified five novel mutations and several previously reported mutations. Furthermore, we detected a loss of heterozygosity (LOH) at chromosome11q in the removed tumours, including gastrinoma, insulinoma and parathyroid adenoma. After that, we try to explain how the mutated MEN1 genes induced the tumours in multiple endocrine neoplasia type 1 syndrome. Menin is able to interact with β-catenin, and regulates translocation and transcriptional activity of β-catenin via nuclear-cytoplasmic shuttling. To determine the role of β-catenin signaling in β-cells and menin-deficient insulinoma, we established pancreatic β-cell specific ctnnb1 knockout mice (BBKO) and Men1/ctnnb1 double-knockout mice (DBKO). BBKO mice were phenotypically normal compared to WT mice under a chow diet or challenged with a high fat diet, indicated that β-catenin is not crucial for β-cell development and physiological proliferation. Double-knockout of menin and β-catenin rescued the hypoglycemia phenotype and exhibit elevated survival rate compared with Men1 conditional knockout mice. Loss of β-catenin reduced the expression of a series of proproliferative genes, which were up-regulated in menin-deficient islets, including ccna2, pbk, mcm5, mcm6 and Mki67. These results indicate that β-catenin signaling is critical for tumorigenesis of menin-deficient β-cells.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.