Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target.

We investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6-/- cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase.

Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative stress. However, the role of reactive oxygen species or specific antioxidant enzymes in its development has not been tested under physiological conditions. The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide (H(2)O(2)) in vivo, on glucose metabolism and insulin function. The GPX1-overexpressing (OE) and WT male mice (n = 80) were fed a selenium-adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE mice developed (P < 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of age. Meanwhile, these mice were heavier (37 vs. 27 g, P < 0.001) and fatter (37% vs. 17% fat, P < 0.01) than the WT mice. At 30-60 min after an insulin challenge, the OE mice had 25% less (P < 0.05) of a decrease in blood glucose than the WT mice. Their insulin resistance was associated with a 30-70% reduction (P < 0.05) in the insulin-stimulated phosphorylations of insulin receptor (beta-subunit) in liver and Akt (Ser(473) and Thr(308)) in liver and soleus muscle. Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing.

Mouse system-N amino acid transporter, mNAT3, expressed in hepatocytes and regulated by insulin-activated and phosphoinositide 3-kinase-dependent signalling.

Amino acid transporters are essential for normal cell function and physiology. In the present study, we report the identification and functional and regulatory characterization of a mouse system-N amino acid transporter, mNAT3. Expression of mNAT3 in Xenopus oocytes revealed that the strongest transport activities were preferred for L-alanine. In addition, mNAT3 is an Na(+)- and pH-dependent low-affinity transporter and it partially tolerates substitution of Na(+) by Li(+). mNAT3 has been found to be expressed predominantly in the liver, where it is localized to the plasma membrane of hepatocytes, with the strongest expression in those cells adjacent to the central vein, decreasing gradually towards the portal tract. Treatment of mouse hepatocyte-like H2.35 cells with insulin led to a significant increase in the expression of mNAT3, and this stimulation was associated closely with an increase in the uptake of L-alanine. Interestingly, this insulin-induced stimulatory effect on mNAT3 expression was attenuated by the phosphoinositide 3-kinase inhibitor LY294002, but not by the mitogen-activated protein kinase inhibitor PD98059, although both kinases were fully activated by insulin. The results suggest that insulin-mediated regulation of mNAT3 is likely to be mediated through a phosphoinositide 3-kinase-dependent signalling pathway. The unique expression pattern and insulin-mediated regulatory properties of mNAT3 suggest that this transporter may play an important role in liver physiology.