title: Targeting β-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours.
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.
authors.affiliation: 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.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Laboratoire Génétique Moléculaire, Signalisation et Cancer, CNRS, UMR5201, Faculté de Médecine, Université Claude Bernard Lyon1, Centre LEON-BERARD, 69373 Lyon, France.
authors.forename: Changxian
authors.initials: C
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010766:Phosphorylation; D057285:Precision Medicine; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D016019:Survival Analysis; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics*
chemical_list: C495270:CTNNB1 protein, human; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D051176:beta Catenin