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INSERM U1052/CNRS UMR5286/Université de Lyon, Service de Génétique Moléculaire et Clinique, UMR 3347/CNRS, Service Central d'Anatomie et Cytologie Pathologiques, Department of Molecular Physiology and Biophysics, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France
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INSERM U1052/CNRS UMR5286/Université de Lyon, Service de Génétique Moléculaire et Clinique, UMR 3347/CNRS, Service Central d'Anatomie et Cytologie Pathologiques, Department of Molecular Physiology and Biophysics, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France
INSERM U1052/CNRS UMR5286/Université de Lyon, Service de Génétique Moléculaire et Clinique, UMR 3347/CNRS, Service Central d'Anatomie et Cytologie Pathologiques, Department of Molecular Physiology and Biophysics, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France
INSERM U1052/CNRS UMR5286/Université de Lyon, Service de Génétique Moléculaire et Clinique, UMR 3347/CNRS, Service Central d'Anatomie et Cytologie Pathologiques, Department of Molecular Physiology and Biophysics, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France
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The protein MENIN is the product of the multiple endocrine neoplasia type I (MEN1) gene. Altered MENIN expression is one of the few events that are clearly associated with foregut neuroendocrine tumours (NETs), classical oncogenes or tumour suppressors being not involved. One of the current challenges is to understand how alteration of MENIN expression contributes to the development of these tumours. We hypothesised that MENIN might regulate factors maintaining endocrine-differentiated functions. We chose the insulinoma model, a paradigmatic example of well-differentiated pancreatic NETs, to study whether MENIN interferes with the expression of v-MAF musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA), a master glucose-dependent transcription factor in differentiated β-cells. Immunohistochemical analysis of a series of human insulinomas revealed a correlated decrease in both MENIN and MAFA. Decreased MAFA expression resulting from targeted Men1 ablation was also consistently observed in mouse insulinomas. In vitro analyses using insulinoma cell lines showed that MENIN regulated MAFA protein and mRNA levels, and bound to Mafa promoter sequences. MENIN knockdown concomitantly decreased mRNA expression of both Mafa and β-cell differentiation markers (Ins1/2, Gck, Slc2a2 and Pdx1) and, in parallel, increased the proliferation rate of tumours as measured by bromodeoxyuridine incorporation. Interestingly, MAFA knockdown alone also increased proliferation rate but did not affect the expression of candidate proliferation genes regulated by MENIN. Finally, MENIN variants with missense mutations detected in patients with MEN1 lost the WT MENIN properties to regulate MAFA. Together, our findings unveil a previously unsuspected MENIN/MAFA connection regarding control of the β-cell differentiation/proliferation balance, which could contribute to tumorigenesis.
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Departments of Nuclear Medicine and Endocrine Tumors, Digestive Oncology, Medical Oncology (Thoracic Group), Pathology, Radiology, Centre Antoine Lacassagne, Department of Urologic Oncology, Department of Endocrinology, Department of Biostatistics and Epidemiology, Faculté de Médecine, Gustave Roussy, 114 Rue Edouard Vaillant, F-94800 Villejuif Cedex, France
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Departments of Nuclear Medicine and Endocrine Tumors, Digestive Oncology, Medical Oncology (Thoracic Group), Pathology, Radiology, Centre Antoine Lacassagne, Department of Urologic Oncology, Department of Endocrinology, Department of Biostatistics and Epidemiology, Faculté de Médecine, Gustave Roussy, 114 Rue Edouard Vaillant, F-94800 Villejuif Cedex, France
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There is no standard for second-line chemotherapy in poorly differentiated grade 3 neuroendocrine carcinoma (G3-NEC) patients. We analyzed the antitumor efficacy of 5-fluorouracil and oxaliplatin (FOLFOX) chemotherapy in this population. A single-center retrospective analysis of consecutive G3-NEC patients treated with FOLFOX chemotherapy after failure of a cisplatinum-based regimen between December 2003 and June 2012 was performed. Progression-free survival (PFS), overall survival (OS), response rate, and safety were assessed according to RECIST 1.1 and NCI.CTC v4 criteria. Twenty consecutive patients were included (seven males and 13 females; median age 55; range 23–87 years) with a performance status of 0–1 in 75% of them. Primary location was gastroenteropancreatic in 12, thoracic in four, other in two, and unknown in two patients. There were 12 (65%) large-cell and 7 (30%) small-cell G3-NEC tumors, and 1 (5%) unknown. All patients had distant metastases. Twelve (60%) patients received FOLFOX as second-line treatment and 8 (40%) as third-line treatment or later and the median number of administered cycles was 6 (range 3–14). The median follow-up was 19 months. Median PFS was 4.5 months. Among the 17 evaluable patients, five partial responses (29%), six stable diseases (35%), and six progressive diseases (35%) were observed. Median OS was 9.9 months. Main Grade 3–4 toxicities were neutropenia (35%), thrombopenia (20%), nausea/vomiting (10%), anemia (10%), and elevated liver transaminases (10%). Our results indicate that the FOLFOX regimen could be considered as a second-line option in poorly differentiated G3-NEC patients after cisplatinum-based first-line treatment but warrant further confirmation in future larger prospective studies.