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Expression of human carcinoembryonic antigen-related cell adhesion molecule 6 and alveolar progenitor cells in normal and injured lungs of transgenic mice.

ABSTRACT: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is expressed in the epithelium of various primate tissues, including lung airway and alveoli. In human lung, CEACAM6 is developmentally and hormonally regulated, protects surfactant function, has anti-apoptotic activity and is dysregulated in cancers. We hypothesized that alveolar CEACAM6 expression increases in lung injury and promotes cell proliferation during repair. Studies were performed in CEABAC transgenic mice-containing human CEACAM genes. The level of CEACAM6 in adult CEABAC lung was comparable to that in human infants; expression occurred in epithelium of airways and of some alveoli but rarely co-localized with markers of type I or type II cells. Ten days after bleomycin instillation, both the number of CEACAM6(+) cells and immunostaining intensity were elevated in injured lung areas, and there was increased co-localization with type I and II cell markers. To specifically address type II cells, we crossed CEABAC mice with animals expressing EGFP driven by the SP-C promoter. After bleomycin injury, partially flattened, elongated epithelial cells were observed that expressed type I cell markers and were primarily either EGFP(+) or CEACAM6(+). In cell cycle studies, mitosis was greater in CEACAM6(+) non-type II cells versus CEACAM6(+)/EGFP(+) cells. CEACAM6 epithelial expression was also increased after hyperoxic exposure and LPS instillation, suggesting a generalized response to acute lung injuries. We conclude that CEACAM6 expression is comparable in human lung and the CEABAC mouse. CEACAM6 in this model appears to be a marker of a progenitor cell population that contributes to alveolar epithelial cell replenishment after lung injury.

SUBMITTER: Lin SE

PROVIDER: S-EPMC4760449 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Expression of human carcinoembryonic antigen-related cell adhesion molecule 6 and alveolar progenitor cells in normal and injured lungs of transgenic mice.

Lin Shin-E SE Barrette Anne Marie AM Chapin Cheryl C Gonzales Linda W LW Gonzalez Robert F RF Dobbs Leland G LG Ballard Philip L PL

Physiological reports 20151222 12

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is expressed in the epithelium of various primate tissues, including lung airway and alveoli. In human lung, CEACAM6 is developmentally and hormonally regulated, protects surfactant function, has anti-apoptotic activity and is dysregulated in cancers. We hypothesized that alveolar CEACAM6 expression increases in lung injury and promotes cell proliferation during repair. Studies were performed in CEABAC transgenic mice-containing ...[more]

PMID: 26702074

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Project description:Objective We have previously shown that expression of the CEACAM1 long isoform (CC1-L) in metastatic colorectal cancer (CRC) cells results in significant inhibition of liver metastasis via Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Yet, despite recent advances in identifying molecules involved in the CC1-L inhibition of metastasis, much remains to be elucidated regarding the molecular mechanisms orchestrating this pathway. Design We performed an untargeted transcript profiling and a phosphokinase screen between CC1-L-expressing and non-expressing (CT) CRC cells. Identified targets were validated in vitro and in vivo for their involvement in signaling and invasion or metastasis. We validated our conclusions in CRC patient cohorts for time to metastasis development and long-term survival. Results Untargeted transcript profiling revealed high Decorin (Dcn) expression in CC1-L-expressing cells versus CT cells. Decorin was detected at the peri-endothelial layers of large blood vessels and in liver stellate cells. In metastatic lesions, it was expressed in pericyte-like cells covering capillary endothelium. Phosphokinase differential screening revealed reduced Ephrin type-A receptor 2 (EphA2) expression and activity in CC1-L- versus CT-expressing cells. Treatment of CT cells with recombinant Dcn led to decreased migration and invasion and decreased EphA2-mediated Erk and Akt signaling. CRC patients exhibiting high CC1 and DCN expression, in combination with low EPHA2 expression, benefit from longer 10-year survival than those with high EPHA2 expression. Conclusion CC1-L expression in poorly differentiated CRC inhibits liver metastasis through increased Decorin expression and EphA2-mediated signaling. Quadriplicate samples of each mouse colon cancer cell lines (control cells versus those expressing either short or long isoform of CEACAM1) have been used for RNA extraction

Project description:Patients with nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) commonly develop atherosclerosis through a mechanism that is not well delineated. These diseases are associated with steatosis, inflammation, oxidative stress, and fibrosis. The role of insulin resistance in their pathogenesis remains controversial. Albumin (Alb)Cre+ Cc1flox ( fl ) /fl mice with the liver-specific null deletion of the carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1; alias Cc1) gene display hyperinsulinemia resulting from impaired insulin clearance followed by hepatic insulin resistance, elevated de novo lipogenesis, and ultimately visceral obesity and systemic insulin resistance. We therefore tested whether this mutation causes NAFLD/NASH and atherosclerosis. To this end, mice were propagated on a low-density lipoprotein receptor (Ldlr) -/- background and at 4 months of age were fed a high-cholesterol diet for 2 months. We then assessed the biochemical and histopathologic changes in liver and aortae. Ldlr-/-AlbCre+Cc1fl/fl mice developed chronic hyperinsulinemia with proatherogenic hypercholesterolemia, a robust proinflammatory state associated with visceral obesity, elevated oxidative stress (reduced NO production), and an increase in plasma and tissue endothelin-1 levels. In parallel, they developed NASH (steatohepatitis, apoptosis, and fibrosis) and atherosclerotic plaque lesions. Mechanistically, hyperinsulinemia caused down-regulation of the insulin receptor followed by inactivation of the insulin receptor substrate 1-protein kinase B-endothelial NO synthase pathway in aortae, lowering the NO level. This also limited CEACAM1 phosphorylation and its sequestration of Shc-transforming protein (Shc), activating the Shc-mitogen-activated protein kinase-nuclear factor kappa B pathway and stimulating endothelin-1 production. Thus, in the presence of proatherogenic dyslipidemia, hyperinsulinemia and hepatic insulin resistance driven by liver-specific deletion of Ceacam1 caused metabolic and vascular alterations reminiscent of NASH and atherosclerosis. Conclusion: Altered CEACAM1-dependent hepatic insulin clearance pathways constitute a molecular link between NASH and atherosclerosis.

Dataset Information

Expression of human carcinoembryonic antigen-related cell adhesion molecule 6 and alveolar progenitor cells in normal and injured lungs of transgenic mice.

Publications

Expression of human carcinoembryonic antigen-related cell adhesion molecule 6 and alveolar progenitor cells in normal and injured lungs of transgenic mice.

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