Colonic mixed adenoneuroendocrine carcinoma (MANEC) is an aggressive neoplasm with worse prognosis compared with adenocarcinoma. To gain a better understanding of the molecular features of colonic MANEC, we characterized the genome-wide copy number aberrations of 14 MANECs and 5 neuroendocrine carcinomas using the OncoScan FFPE (Affymetrix, Santa Clara, CA) assay. Compared with 269 colonic adenocarcinomas, 19 of 42 chromosomal arms of MANEC exhibited a similar frequency of major aberrant events as adenocarcinomas, and 13 chromosomal arms exhibited a higher frequency of copy number gains. Among them, the most significant chromosomal arms were 5p (77% versus 13%, P = .000012) and 8q (85% versus 33%, P = .0018). The Genomic Identification of Significant Targets in Cancers algorithm identified 7 peaks that drive the tumorgenesis of MANEC. For all except 5p13.1, the peaks largely overlapped with those of adenocarcinoma. Two tumors exhibited MYC amplification localized in 8q24.21, and 2 tumors exhibited PTGER4 amplification localized in 5p13.1. A total of 8 tumors exhibited high copy number gain of PTGER4 and/or MYC. Whereas the frequency of MYC amplification was similar to adenocarcinoma (10.5% versus 4%, P = .2), the frequency of PTGER4 amplification was higher than adenocarcinoma (10.5% versus 0.3%, P = .01). Our study demonstrates similar, but also distinct, copy number aberrations in MANEC compared with adenocarcinoma and suggests an important role for the MYC pathway of colonic carcinoma with neuroendocrine differentiation. The discovery of recurrent PTGER4 amplification implies a potential of exploring targeting therapy to the prostaglandin synthesis pathways in a subset of these tumors.

OBJECTIVE: Prostaglandins have been shown to mediate the gastro-protective effect of sodium hydrosulfide (NaHS) but effect of NaHS on mRNA expression of prostaglandin E2 receptors (EP1, 3-4; EPs) has not been investigated. Therefore, this study designed to evaluate the effect of NaHS on mRNA expression of EPs receptors in response to mucosal acidification and distention-induced gastric acid secretion in rats.
METHODS: Fasted rats were randomly assigned into 4 groups (n=6/group). They were control, and NaHS-treated groups. To evaluate the effect of NaHS on mucosal mRNA expression of EPs receptors, the gastric mucosa exposed to stimulated gastric acid output and mucosal acidification. The pylorus sphincter catheterized for instillation of isotonic neutral saline or acidic solution. Ninety min after beginning the experiments, animals sacrificed and the gastric mucosa collected to determine the pH, mucus secretion and to quantify the mRNA expression of EPs receptors by quantitative real-time PCR.
RESULTS: present results showed that a) NaHS increased the mucus secretion, mRNA expression of EP3 and EP4 receptors in response to distention-induced expression; b) The mRNA expression of EP1 receptors increased while EP4 mRNA receptors decreased in response to mucosal acidification in NaHS-pretreated rats; and c) NaHS increased pH of gastric contents both in response to distention-induced gastric acid secretion and mucosal acidification.
CONCLUSIONS: NaHS behaves in a different manner. It effectively only increased the pH of gastric contents to reinforce the gastric mucosa against a highly acidic solution but modulated both acid and mucus secretion when the rate of acid increase in the stomach was slower.

PGE2 exerts its biological effect through binding to various EP receptors that result inactivation of various signal transduction pathways. It also plays an important role in mice glomerular mesangial cells (MCs) damage induced by transforming growth factor-β1 (TGF-β1); however, the molecular mechanisms remain unknown. In the present study, we tested the efficacy of four selective agonists of PGE2 receptor, EP1A (17-phenyl trinor prostaglandin E2 ethyl amid), EP2A (butaprost), EP3A (sulprostone) and EP4A (cay10580), on mice MCs. Compared with the cAMP produced by TGF-β1, additional pretreatment of EP3A decreased the cAMP level. MCs treated with EP1A and EP3A augmented PGE2, cyclooxygenase-2 (COX-2), membrane-bound PGE synthase 1 (mPGES1), laminin (LN), connective tissue growth factor (CTGF) and cyclin D1 expression stimulated by TGFβ1. EP1A and EP3A increased the number of cells in S+G2/M phase and reduced cells in G0/G1 phase. EP1 and EP3 agonists also strengthened TGFβ1-induced mitogen-activated protein kinase (p38MAPK) and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Whereas MCs treated with EP2A and EP4A weakened PGE2, COX-2, mPGES1, LN, CTGF and cyclin D1 expression stimulated by TGFβ1. EP2A and EP4A decreased the number of cells in S+G2/M phase and increased cells in G0/G1 phase. EP2 and EP4 agonists weakened TGFβ1-induced p38MAPK and ERK1/2 phosphorylation. These findings suggest that PGE2 has an important role in the progression of kidney disease via the EP1/EP3 receptor, whereas EP2 and EP4 receptors are equally important in preserving the progression of chronic kidney failure. Thus, agonists of EP2 and EP4 receptors may provide a basis for treating kidney damage induced by TGF-β1.

OBJECTIVE: The goal of this study was to functionally compare prostaglandin E2 (PGE2)-sensitive receptors in human primary cells involved in conventional outflow.
METHODS: The expression profile of prostaglandin (PG) receptors in primary cultures of human trabecular meshwork (TM) and Schlemm\'s canal (SC) cells were determined by quantitative-PCR. The functional activities of endogenous PGE2-sensitive receptors were evaluated using subtype-selective agonists and antagonists with cell impedance technology.
RESULTS: Agonist-sensitive EP1, EP2, and EP4 receptors were present in TM cells, all increasing cell stiffness (or contractility) in a dose-dependent manner. Rank order of efficacy (Emax) for agonists in TM cells were EP1 greater than EP2 greater than EP4 with EC50 1.1 μM, 0.56 μM, and 0.1 μM, respectively, and no functional EP3 receptors were found. Of the four EP receptor subtypes active in SC cells, EP1 and EP3 receptor activation increased cell stiffness, while EP2 and EP4 agonists dose-dependently decreased cell stiffness 47% and 23% with EC50 values of 170 nM and 69 nM, respectively. Consistent with these observations, the Rho kinase inhibitor Y-27632 decreased cell impedance (stiffness) of TM and SC cells (∼60%), while Rho GTPase activator thrombin caused cell impedance to increase in both cell types (168%-190%).
CONCLUSIONS: Cell impedance positively correlates with cellular stiffness/contractility. Because EP2/4 receptors caused decreased cell stiffness in SC, but not in TM cells, both receptors appear to mediate IOP lowering via changes in SC cell stiffness in the conventional outflow pathway.