Targeting β-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours

Xiuli Jiang; Yanan Cao; Feng Li; Yutong Su; Yanli Li; Ying Peng; Yulong Cheng; Changxian Zhang; Weiqing Wang; Guang Ning

doi:10.1038/ncomms6809

Targeting β-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours

Nat Commun. 2014 Dec 17:5:5809. doi: 10.1038/ncomms6809.

Authors

Xiuli Jiang¹, Yanan Cao¹, Feng Li¹, Yutong Su¹, Yanli Li¹, Ying Peng¹, Yulong Cheng¹, Changxian Zhang², Weiqing Wang¹, Guang Ning³

Affiliations

¹ Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China.
² Laboratoire Génétique Moléculaire, Signalisation et Cancer, CNRS, UMR5201, Faculté de Médecine, Université Claude Bernard Lyon1, Centre LEON-BERARD, 69373 Lyon, France.
³ 1] Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China [2] Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) &Shanghai Jiao-Tong University School of Medicine (SJTUSM), Shanghai 200025, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / genetics
Carcinogenesis / metabolism*
Carcinogenesis / pathology
Gene Deletion
Gene Expression Regulation, Neoplastic*
Humans
Hyperinsulinism / genetics
Hyperinsulinism / metabolism
Hyperinsulinism / pathology
Hypoglycemia / genetics
Hypoglycemia / metabolism
Hypoglycemia / pathology
Insulin-Secreting Cells / metabolism
Insulin-Secreting Cells / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiple Endocrine Neoplasia Type 1 / genetics
Multiple Endocrine Neoplasia Type 1 / metabolism*
Multiple Endocrine Neoplasia Type 1 / mortality
Multiple Endocrine Neoplasia Type 1 / pathology
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / mortality
Pancreatic Neoplasms / pathology
Phosphorylation
Precision Medicine
Proto-Oncogene Proteins / deficiency
Proto-Oncogene Proteins / genetics*
Signal Transduction*
Survival Analysis
beta Catenin / deficiency
beta Catenin / genetics*

Substances

CTNNB1 protein, human
MEN1 protein, human
Proto-Oncogene Proteins
beta Catenin