Unlike EP1 and EP3, EP2 and EP4 have been shown to activate the GSK3/β-catenin pathway, as well as the adenylate cyclase-triggered cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/exchange protein directly activated by cAMP pathway.46–48 Whether IDEN-PGE2 also suppresses IFN-γ and IL-4 expression via cAMP/PKA/cAMP responsive element binding protein (CREB)-dependent pathway is unknown. If IDEN-PGE2 does suppress cytokine production, also it needs to be

determined if there is cross-talk with the cAMP/PKA/CREB pathway at unidentified points to ultimately regulate the production RAD001 supplier these cytokines. Finally, the Wnt signaling pathway is known to play a crucial role in the prevention of autoimmune responses and in promotion of tumor growth. PGE2 is a potent signaling molecule that regulates immune tolerance and promotes tumor growth in addition to having a role in hematopoiesis, regulation of blood flow, renal filtration and blood pressure, regulation of mucosal integrity, and vascular permeability.49 Our findings provide a basis for further studies regarding the biological effects of PGE2 cross-talk with the Wnt/β-catenin pathway Olaparib mw on these systems as well. We thank the National Institutes of Health Tetramer Facility for providing PBS-57 ligand complexed to CD1d monomers or tetramers and Mitchell Kronenberg, who provided the NKT1.2 hybridomas. We also thank Jerald Ainsworth and Fiona Hunter for editorial

assistance. Additional Supporting Information may be found in the online version of this article. “
“The MYC oncogene is overexpressed in hepatocellular carcinoma (HCC) and has been associated with widespread microRNA (miRNA) repression; however, the underlying mechanisms are largely unknown. Here, we report that the c-Myc oncogenic transcription factor physically interacts with enhancer of zeste homolog 2 (EZH2), a core enzymatic unit of polycomb repressive complex 2 (PRC2). Furthermore, miR-101, an important tumor-suppressive miRNA in human hepatocarcinomas, is epigenetically repressed by PRC2 complex

in a c-Myc-mediated manner. miR-101, 上海皓元医药股份有限公司 in turn, inhibits the expression of two subunits of PRC2 (EZH2 and EED), thus creating a double-negative feedback loop that regulates the process of hepatocarcinogenesis. Restoration of miR-101 expression suppresses multiple malignant phenotypes of HCC cells by coordinate repression of a cohort of oncogenes, including STMN1, JUNB, and CXCR7, and further increases expression of endogenous miR-101 by inhibition of PRC2 activation. In addition, co-overexpression of c-Myc and EZH2 in HCC samples was closely associated with lower expression of miR-101 (P < 0.0001) and poorer prognosis of HCC patients (P < 0.01). Conclusions: c-Myc collaborates with EZH2-containing PRC2 complex in silencing tumor-suppressive miRNAs during hepatocarcinogenesis and provides promising therapeutic candidates for human HCC.