Multiple Endocrine Neoplasia Type I Syndrome (MEN 1) is a monogenic autosomal dominantly inherited cancer syndrome caused by a heterozygous loss of the MEN1 gene, predisposing for endocrine cell proliferation and tumor formation. MEN 1 carriers classically develop tumors in endocrine organs; the parathyroids, the endocrine pancreas, and the pituitary. Other organs, endocrine and non-endocrine, may also be affected. The most common cause of death in MEN 1 is pancreatic endocrine tumor (PNET), which exhibit inactivation of both MEN1 alleles. The increased proliferation prior to loss of the wild-type allele indicates haploinsufficiency, and little is known concerning the mechanisms behind MEN 1 PNET development. The MEN1 protein, menin, lacking homology with other known proteins, is involved in several aspects of transcriptional regulation and chromatin organization. We report differential expression and subcellular localization of transcription factors important in pancreatic development, in human and mouse MEN 1 pancreas, compared to non-MEN 1 pancreas. A predominantly cytoplasmic localization of Neurogenin3 and NeuroD1 was observed in tumors as well as in MEN 1 non-tumorous pancreas. Notch signaling factor expression and localization were examined in the pancreas of a heterozygous Men1 mouse model, and compared with that of wild-type littermates. Nuclear Hes1 was lost in tumors, concomitant to weaker Notch1 NICD expression, and further, analyzed using qPCR, it was shown that Notch1 was less expressed in heterozygous islets compared to wild-type islets. Performing a global gene expression array, we identified differential gene expression in five-week-old heterozygous Men1 mouse islets, compared to islets from wild-type littermates. The array results for a subset of the differentially regulated genes were corroborated using qPCR, western blotting and in situ PLA. We additionally observed significantly accelerated proliferation in islets from young heterozygous animals. It is often problematic to determine prognosis for individual patients with PNET. This is especially true in the group of patients with well differentiated endocrine carcinomas. In the absence of metastases, morphological signs of malignancy are frequently lacking. We evaluated the expression of nuclear and cytoplasmic survivin in a clinically characterized patient material (n=111), and a high nuclear survivin expression proved to be a significant negative prognostic factor for survival.

Prostaglandin E₂ (PGE₂), the most abundant prostaglandin in mouse skin, has been shown to promote skin tumor development. EP1 is one of four PGE₂ receptors. EP1 mRNA levels analyzed by a quantitative real-time polymerase chain reaction were increased after treatments of 12-O-tetradecanoylphorbol 13-acetate (TPA) or ultraviolet light on skin as well as in 7,12 dimethylbenz[a]anthracene (DMBA)/TPA or UV-induced skin tumors. To determine whether the EP1 receptor levels affect skin tumor development, we generated BK5.EP1 transgenic mice which overexpress EP1 in the basal layer of the epidermis. The skins of these mice are histologically indistinguishable from wild type mice. To determine the role of EP1 in skin tumor development, a DMBA/TPA skin carcinogenesis protocol was used. EP1 transgenic mice had a reduced tumor multiplicity and a reduced tumor incidence compared to wild type mice, but had a higher papilloma to carcinoma conversion rate. In a DMBA-only skin carcinogenesis protocol, EP1 transgenic mice developed more tumors than wild type mice. The effect of EP1 on cell proliferation was measured in vivo. After TPA treatment, cell proliferation was induced in both EP1 transgenic mice and wild type mice to a similar extent. However, 5 days after DMBA treatment, there were about 2-fold more proliferating cells in the basal layer of the epidermis of EP1 transgenic mouse skin than in wild type mice. To confirm that the enhanced tumor formation in transgenic mice is in fact PGE₂ dependent, EP1 transgenic mice were administered the selective cyclooxygenase-2 inhibitor Celecoxib or a control diet starting 1 week before DMBA treatment. Surprisingly, there was no lesion development on mice that were fed Celecoxib. Histological sections of skin from Celecoxib-fed mice showed a fairly normal skin histology 2 weeks after DMBA treatment compared to the pronounced pseudocarcinomatous hyperplasia observed in control diet mice. Therefore, it can be concluded that EP1 signaling increases PGE₂ production through COX-2 induction and promotes tumor development. / text

Le récepteur D de l'interleukine-17 (IL-17RD), également connu sous le nom d'expression similaire aux gènes FGF (SEF), est un membre de la famille des récepteurs de l'IL-17 et une protéine carrefour qui régule principalement négativement les voies de signalisation mitogènes, comme la voie des MAP kinases ERK1/2 et la signalisation immunitaire innée. Au vu du nombre grandissant d’évidences montrant que l'expression d’IL-17RD est régulée à la baisse dans une variété de tumeurs solides, nous et d'autres équipes avons émis l'hypothèse qu'elle pourrait exercer des fonctions de suppression de tumeur. Cependant, le rôle d’IL-17RD dans la biologie tumorale reste à étudier in vivo. Dans une première étude, en combinant l’analyse d’une cohorte longitudinale de vieillissement et d’un modèle de cancer colorectal associé à la colite, nous avons découvert qu’IL-17RD est un véritable gène suppresseur de tumeur in vivo. Nous avons constaté que la perturbation génétique d’Il17rd entraîne une augmentation de la formation de tumeurs dans les deux modèles. De manière intéressante, le développement d'une tumeur dans le modèle de cancer colorectal associé à la colite a été associé à une réponse inflammatoire exacerbée. Parce qu'il est désormais généralement admis que l'inflammation et le cancer sont liés et que nous n’avons observé aucun changement dans la prolifération et l'activation de la voie des MAP kinases ERK1/2 dans les cellules épithéliales intestinales normales ou tumorales lors de l'inactivation génétique de l'IL-17RD, nos résultats établissent l'IL-17RD comme suppresseur de tumeur qui exerce sa fonction en limitant l'étendue et la durée de l'inflammation. Nous avons en outre montré que la perte d’IL-17RD accroît les signalisations du récepteur de type Toll et de l'IL-17A dans les cellules d'adénocarcinome du côlon. Dans une deuxième étude, nous avons évalué l'étendue du potentiel régulateur d'IL-17RD dans l'inflammation. Notre étude révèle qu'IL-17RD régule non seulement l'immunité innée médiée par le TLR et l'IL-17, mais inhibe également l'immunité innée antivirale médiée par les capteurs d'acide nucléique, à savoir la signalisation induite par RIG-I. Ces résultats établissent IL-17RD comme un nouveau régulateur de la réponse immunitaire innée antivirale. En conclusion, nos études sur le rôle d'IL-17RD dans la cancérogenèse et la signalisation immunitaire innée ont établi une fonction suppresseur de tumeur liée à une inflammation accrue in vivo et ont étendu sa fonction inhibitrice à la réponse cytoplasmique antivirale. / Interleukin-17 receptor D (IL-17RD), also known as Similar expression to FGF genes (SEF) is a member of the IL-17 receptor family and a signaling hub that negatively regulates mitogenic signaling pathways, such as the ERK1/2 MAP kinase pathway, and innate immune signaling. With the growing evidence that IL-17RD expression is down-regulated in a variety of solid tumors, we and others hypothesized that it may exert tumor suppressor functions. However, the role of IL-17RD in tumor biology remained to be studied in vivo. In a first study, combining analysis of a longitudinal aging cohort and a colitisassociated colorectal cancer model, we uncovered that IL-17RD is as a bona fide tumor suppressor gene in vivo. We found that genetic disruption of Il17rd leads to increased tumor formation in both models. Interestingly, tumor development in the model of colitisassociated colorectal cancer was associated with an exacerbated inflammatory response. Because it is now generally accepted that inflammation and cancer are linked, and because no change in the proliferation and ERK1/2 MAP kinase activation of normal or tumor intestinal epithelial cells was observed upon genetic inactivation of IL-17RD, our findings establish IL-17RD as a tumor suppressor that exerts its function by limiting the extent and duration of inflammation. We further showed that depletion of IL-17RD enhances Toll-like receptor and IL-17A signaling in colon adenocarcinoma cells. In a second study, we have evaluated the extent of the regulatory potential of IL-17RD in inflammation. Our study reveals that IL-17RD not only regulates TLR and IL-17 mediated innate immunity but also inhibits antiviral innate immunity mediated by nucleic acid sensors, namely RIG-I signaling. Our findings establish IL-17RD as a new regulator of antiviral innate immune response mediated by RIG-I. Altogether, our studies on the role of IL-17RD in carcinogenesis and innate immune signaling have uncovered a tumor suppressor function linked to increased inflammation in vivo and extended its inhibitory function to the antiviral cytoplasmic response.

Dysregulation of PI3K-AKT-mTOR pathway has been reported in various pathologies, such as cancer and insulin resistance. The proline-rich AKT substrate of 40-kDa (PRAS40), also known as AKT substrate 1 (AKT1S1), lies at the crossroads of these cascades and inhibits the activity of the mTOR complex 1 (mTORC1) kinase. Firstly, our findings showed that disruption of PRAS40, a substrate of AKT and component of mTORC1, alters glucose homeostasis and prevent hyperglycemia in the streptozotocin (STZ)-induced diabetes mouse model. PRAS40 ablation resulted in a mild lowering of blood glucose levels and glycated hemoglobin (HbA1C), a lowered insulin requirement, and improved glucose tolerance in untreated PRAS40 gene knockout (PRAS40 (-/-)) as compared to wild-type (PRAS40 (+/+)) mice. PRAS40 deletion significantly attenuates hyperglycemia in STZ-induced PRAS40 (-/-) mice through increased hepatic AKT and mTORC1 signaling, a lowered serum insulin requirement, and altered hepatic GLUT4 levels. Furthermore, we investigated the role of PRAS40 in possible feedback mechanisms, and altered AKT/PRAS40/mTOR signaling in the pathogenesis of tumor progression. For this we probed new datasets extracted from Oncomine, a cancer microarray database containing datasets derived from patient samples, to further understand the role of PRAS40 (AKT1S1). These data strongly supports the previous findings that PRAS40 may serve as a potential therapeutic target for various cancers. Elevated levels of HER2 and PRAS40 are found in some human breast cancers. To directly test the importance of these genetic events in mammary tumorigenesis, we assessed whether disruption of PRAS40 could alter mammary tumor occurrence in HER2 overexpressing mice. HER2 overexpressing mice expressing the activated rat Erbb2 (c-neu) oncogene under the direction of the MMTV promoter was bred with Cre-recombined homozygous (PRAS40-/-) mice. We examined mammary tumor development in the presence (PRAS40+/+) or absence (PRAS40-/-) of PRAS40 using this double transgenic mouse mammary tumor model. Loss of PRAS40 resulted in a delayed mammary tumor onset, improved tumor-free survival, and reduced mammary pre-cancerous lesions in PRAS40-/- versus PRAS40+/+ HER2 overexpressing mice. These results suggest that PRAS40 knockdown could be an attractive target and adjuvant therapy in HER2-positive breast cancers.