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CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells.

ABSTRACT: The changes in cancer cell surface molecules and intracellular signaling pathways during tumorigenesis make delivery of adenovirus-based cancer therapies inefficient. Here we have identified carcinoembryonic antigen- related cell adhesion molecule 6 (CEACAM6) as a cellular protein that restricts the ability of adenoviral vectors to infect cancer cells. We have demonstrated that CEACAM6 can antagonize the Src signaling pathway, downregulate cancer cell cytoskeleton proteins, and block adenovirus trafficking to the nucleus of human pancreatic cancer cells. Similar to CEACAM6 overexpression, treatment with a Src-selective inhibitor significantly reduced adenovirus replication in these cancer cells and normal human epithelial cells. In a mouse xenograft tumor model, siRNA-mediated knockdown of CEACAM6 also significantly enhanced the antitumor effect of an oncolytic adenovirus. We propose that CEACAM6-associated signaling pathways could be potential targets for the development of biomarkers to predict the response of patients to adenovirus-based therapies, as well as for the development of more potent adenovirus-based therapeutics.

SUBMITTER: Wang Y

PROVIDER: S-EPMC2689137 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells.

Wang Yaohe Y Gangeswaran Rathi R Zhao Xingbo X Wang Pengju P Tysome James J Bhakta Vipul V Yuan Ming M Chikkanna-Gowda C P CP Jiang Guozhong G Gao Dongling D Cao Fengyu F Francis Jennelle J Yu Jinxia J Liu Kangdong K Yang Hongyan H Zhang Yunhan Y Zang Weidong W Chelala Claude C Dong Ziming Z Lemoine Nick N

The Journal of clinical investigation 20090601 6

The changes in cancer cell surface molecules and intracellular signaling pathways during tumorigenesis make delivery of adenovirus-based cancer therapies inefficient. Here we have identified carcinoembryonic antigen- related cell adhesion molecule 6 (CEACAM6) as a cellular protein that restricts the ability of adenoviral vectors to infect cancer cells. We have demonstrated that CEACAM6 can antagonize the Src signaling pathway, downregulate cancer cell cytoskeleton proteins, and block adenovirus ...[more]

PMID: 19411761

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Project description:Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is abnormally expressed in various malignant tumors and thus represents a potential biomarker, although information regarding its role in gallbladder cancer (GBC) is limited. This study aimed to evaluate the expression of CEACAM6 in GBC and the effect of CEACAM6 gene silencing on the proliferation, migration, invasion and apoptosis of human GBC cells. Immunochemistry was used to evaluate CEACAM6 expression in 95 GBC specimens and 40 peritumoral tissue specimens. GBC-SD and SGC-996 cell lines were used for in vitro experiments. CEACAM6 was knocked down by transfection of targeted small interfering RNA (siRNA), and reverse-transcription quantitative PCR and western blot analysis were used to detect knockdown efficiency. Cell Counting Kit-8 and colony formation assays were undertaken to evaluate cell proliferation. Variations in cell migration and invasion were detected by wound-healing and Transwell assays, respectively. Flow cytometry was applied to measure cell apoptosis and cell cycle distribution. CEACAM6 gene expression was significantly greater in GBC tissues than in peritumoral tissues, and its positive expression was associated with poor prognosis. CEACAM6 mRNA and protein expression in the CEACAM6 siRNA treatment group was significantly lower than that in the negative control group and the blank group. CEACAM6 knockdown inhibited GBC cell proliferation, migration and invasion but promoted cell apoptosis. Western blot analysis of invasion- and apoptosis-related proteins matrix metalloproteinase-2, Vimentin, BCL-2 and BAX further confirmed CEACAM6 mRNA depletion promoted cell apoptosis and inhibited invasion. Additionally, CEACAM6 mRNA depletion affected the progression of the GBC cell cycle to increase cell distribution in G0/G1 phase, and to reduce it in G2/M phase and S phase. These findings indicated that CEACAM6 overexpression may be related to the tumorigenesis and development of GBC. In summary, depletion of CEACAM6 mRNA suppressed the malignant biological behaviors of human gallbladder cancer cells.

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CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells.

Publications

CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells.

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