Leptin modulated microRNA-628-5p targets Jagged-1 and inhibits prostate cancer hallmarks.

MicroRNAs (miRNAs) are single-stranded non-coding RNA molecules that play a regulatory role in gene expression and cancer cell signaling. We previously identified miR-628-5p (miR-628) as a potential biomarker in serum samples from men with prostate cancer (PCa) (Srivastava et al. in Tumour Biol 35:4867-4873, 10.1007/s13277-014-1638-1, 2014). This study examined the detailed cellular phenotypes and pathways regulated by miR-628 in PCa cells. Since obesity is a significant risk factor for PCa, and there is a correlation between levels of the obesity-associated hormone leptin and PCa development, here we investigated the functional relationship between leptin and miR-628 regulation in PCa. We demonstrated that exposure to leptin downregulated the expression of miR-628 and increased cell proliferation/migration in PCa cells. We next studied the effects on cancer-related phenotypes in PCa cells after altering miR-628 expression levels. Enforced expression of miR-628 in PCa cells inhibited cell proliferation, reduced PCa cell survival/migration/invasion/spheroid formation, and decreased markers of cell stemness. Mechanistically, miR-628 binds with the JAG1-3'UTR and inhibits the expression of Jagged-1 (JAG1). JAG1 inhibition by miR-628 downregulated Notch signaling, decreased the expression of Snail/Slug, and modulated epithelial-mesenchymal transition and invasiveness in PC3 cells. Furthermore, expression of miR-628 in PCa cells increased sensitivity towards the drugs enzalutamide and docetaxel by induction of cell apoptosis. Collectively our data suggest that miR-628 is a key regulator of PCa carcinogenesis and is modulated by leptin, offering a novel therapeutic opportunity to inhibit the growth of advanced PCa.

Association between anemia and postoperative complications in infants undergoing pyloromyotomy.

BACKGROUND: Although preoperative anemia has been suggested to predict postsurgical morbidity and mortality among infants <1 year of age, the data were drawn from heterogeneous patient cohorts including severely ill infants undergoing complex, high-risk procedures. We aimed to determine whether untreated preoperative anemia was associated with increased risk of postoperative complications in infants <1 year of age who underwent pyloromyotomy, a common and relatively simple surgery. METHODS: Infants <1 year of age undergoing pyloromyotomy were identified from the American College of Surgeons (ACS) National Surgical Quality Improvement Program-Pediatric database. Preoperative anemia was defined as a hematocrit ≤40% for infants 0-30 days of age and ≤30% for infants more than 30 days of age. Patients who received pre- or postoperative blood transfusions were excluded. RESULTS: We identified 2948 patients who met our inclusion criteria, of whom 843 were anemic (29%). The overall rate of complications in this cohort was 6%. The most common postoperative complications were readmission (97 cases), surgical site infection (43), reoperation (39), prolonged hospital stay (24), urinary tract infection (3), 30-day mortality (3) and cardiac arrest (2). We found no differences in the incidence of complications in anemic versus nonanemic patients on bivariate analysis or multivariable logistic regression (adjusted odds ratio = 1.2; 95% confidence interval: 0.8-1.7; P = 0.319). CONCLUSIONS: In relatively healthy infants undergoing pyloromyotomy, untreated preoperative anemia was not associated with postoperative compilations and should not be considered a significant risk factor. Level of evidence III.

Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway.

BACKGROUND: Besides its neurotransmitter and vasoconstriction functions, serotonin is an important mediator of numerous biological processes in peripheral tissues including cell proliferation, steatosis, and fibrogenesis. Recent reports indicate that serotonin may promote tumor growth in liver cancer, however, the molecular mechanisms remain elusive. n this study, we investigated the role and molecular signaling mechanisms mediated by serotonin in liver cancer cell survival, drug resistance, and steatosis. METHODS: Effect of serotonin on modulation of cell survival/proliferation was determined by MTT/WST1 assay. Effect of serotonin on the regulation of autophagy biomarkers and lipid/fatty acid proteins expression, AKT/mTOR and Notch signaling was evaluated by immunoblotting. The role of serotonin in normal human hepatocytes and liver cancer cell steatosis was analyzed by Oil Red O staining. The mRNA expression levels of lipid/fatty acid proteins and serotonin receptors were validated by qRT-PCR. The important roles of autophagy, Notch signaling, serotonin receptors and serotonin re-uptake proteins on serotonin-mediated cell steatosis were investigated by using selective inhibitors or antagonists. The association of peripheral serotonin, autophagy, and hepatic steatosis was also investigated using chronic EtOH fed mouse model. RESULTS: Exposure of liver cancer cells to serotonin induced Notch signaling and autophagy, independent of AKT/mTOR pathway. Also, serotonin enhanced cancer cell proliferation/survival and drug resistance. Furthermore, serotonin treatment up-regulated the expression of lipogenic proteins and increased steatosis in liver cancer cells. Inhibition of autophagy or Notch signaling reduced serotonin-mediated cell steatosis. Treatment with serotonin receptor antagonists 5-HTr1B and 5-HTr2B reduced serotonin-mediated cell steatosis; in contrast, treatment with selective serotonin reuptake inhibitors (SSRIs) increased steatosis. In addition, mice fed with chronic EtOH resulted in increased serum serotonin levels which were associated with the induction of hepatic steatosis and autophagy. CONCLUSIONS: Serotonin regulates liver cancer cell steatosis, cells survival, and may promote liver carcinogenesis by activation of Notch signaling and autophagy.

TNFAIP8 promotes prostate cancer cell survival by inducing autophagy.

Tumor necrosis factor-α-inducible protein 8 (TNFAIP8) is a TNF-α inducible anti-apoptotic protein with multiple roles in tumor growth and survival. Mechanisms of cell survival by TNFAIP8 remain elusive. We investigated the role of TNFAIP8 in the regulation of the cell cycle, autophagy, cell survival and neuroendocrine differentiation in prostate cancer cells. We showed that TNFAIP8 dysregulates cell-cycle-related proteins, in PC3 cells. Oncogenic cell survival, drug resistance and dysregulation of cell cycle-related proteins are often associated with autophagy. We demonstrated that TNFAIP8 induces autophagy by increasing expression of autophagy effectors such as LC3ß I/II, Beclin1, 4EBP1, p62, and SIRT1. We also demonstrated that TNFAIP8 interacts with autophagy-related protein 3 (ATG3). TNFα treatment increased the expression of TNFAIP8, which was associated with increased autophagy and decreased apoptosis. We also observed an increase in expression of neuroendocrine differentiation markers, synaptophysin and chromogranin A, and drug resistance to anticancer drugs, docetaxel and doxorubicin, in cells transfected with TNFAIP8. Collectively, our findings reveal that by the creation of cellular autophagy events, TNFAIP8 promotes cell survival and drug resistance in prostate cancer cells.

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics.

Glioblastoma multiforme (GBM) is the most common and lethal cancer of the adult brain, remaining incurable with a median survival time of only 15 months. In an effort to identify new targets for GBM diagnostics and therapeutics, recent studies have focused on molecular phenotyping of GBM subtypes. This has resulted in mounting interest in microRNAs (miRNAs) due to their regulatory capacities in both normal development and in pathological conditions such as cancer. miRNAs have a wide range of targets, allowing them to modulate many pathways critical to cancer progression, including proliferation, cell death, metastasis, angiogenesis, and drug resistance. This review explores our current understanding of miRNAs that are differentially modulated and pathologically involved in GBM as well as the current state of miRNA-based therapeutics. As the role of miRNAs in GBM becomes more well understood and novel delivery methods are developed and optimized, miRNA-based therapies could provide a critical step forward in cancer treatment.

Autophagy inhibitor 3-methyladenine potentiates apoptosis induced by dietary tocotrienols in breast cancer cells.

INTRODUCTION: Tocomin® represents commercially available mixture of naturally occurring tocotrienols (T3s) and tocopherols extracted from palm oil/palm fruits that possess powerful antioxidant, anticancer, neuro/cardioprotective and cholesterol-lowering properties. Cellular autophagy represents a defense mechanism against oxidative stress and several anticancer compounds. Recently, we reported that T3s induce apoptosis and endoplasmic reticulum stress in breast cancer cells. METHODOLOGY: We studied the effects of Tocomin® on MCF-7 and MDA-MB 231 breast cancer cells and non-tumor MCF-10A cells. RESULTS: Tocomin® inhibited cell proliferation and induced apoptosis in both MCF-7 and MDA-MB 231 breast cancer cell lines without affecting the viability of MCF-10A cells. We also showed that Tocomin® negatively modulates phosphoinositide 3-kinase and mTOR pathways and induces cytoprotective autophagic response in triple negative MDA-MB 231 cells. Lastly, we demonstrate that autophagy inhibitor 3-methyladenine (3-MA) potentiated the apoptosis induced by Tocomin® in MDA-MB 231 cells. CONCLUSION: Together, our data indicate anticancer effects of Tocomin® in breast cancer cells, which is potentiated by the autophagy inhibitor 3-MA.