Sex hormones in the modulation of irritable bowel syndrome

Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of “microgenderome” related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.

Central role of Yes-associated protein and WW-domain-containing transcriptional co-activator with PDZ-binding motif in pancreatic cancer development

Pancreatic ductal adenocarcinoma(PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC.Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network.Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein(YAP) and WW-domaincontaining transcriptional co-activator with PDZ-binding motif(TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.

Yes-associated protein(YAP)in pancreatic cancer:at the epicenter of a targetable signaling network associated with patient survival

Pancreatic ductal adenocarcinoma(PDAC)is generally a fatal disease with no efficacious treatment modalities.Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed.Here,we review the role of Yes-associated protein(YAP)and WW-domain-containing Transcriptional co-Activator with a PDZbinding motif(TAZ)in the development of PDAC.These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes.We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database(www.proteinatlas.org/pathology)that allows genome-wide exploration of the impact of individual proteins on survival outcomes.Multiple YAP/TEAD-regulated genes,including AJUBA,ANLN,AREG,ARHGAP29,AURKA,BUB1,CCND1,CDK6,CXCL5,EDN2,DKK1,FOSL1,FOXM1,HBEGF,IGFBP2,JAG1,NOTCH2,RHAMM,RRM2,SERP1,and ZWILCH,are associated with unfavorable survival of PDAC patients.Similarly,components of AP-1 that synergize with YAP(FOSL1),growth factors(TGFα,EPEG,and HBEGF),a specific integrin(ITGA2),heptahelical receptors(P2Y2R,GPR87)and an inhibitor of the Hippo pathway(MUC1),all of which stimulate YAP activity,are associated with unfavorable survival of PDAC patients.By contrast,YAP inhibitory pathways(STRAD/LKB-1/AMPK,PKA/LATS,and TSC/mTORC1)indicate a favorable prognosis.These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients.We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease.