Mechanisms of transcriptional regulation and prognostic significance of activated leukocyte cell adhesion molecule in cancer

Molecular Cancer

Research

Fang Tan¹  Diego Alvarez²  Sarah Cantrell²  Hairu Chen²  Zachariah Chambers²  Judy A King³  Flaubert Mbeunkui⁴  Solomon F Ofori-Acquah⁵  Lalita A Shevde⁶ 

[1] Aflac Cancer Center and Blood Disorders Service, Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, 30322, Atlanta, GA, USA;Center for Lung Biology, University of South Alabama, 307 N. University Boulevard, 36688, Mobile, AL, USA;Center for Lung Biology, University of South Alabama, 307 N. University Boulevard, 36688, Mobile, AL, USA;Center of Excellence in Healthy Communities, University of South Alabama, 307 N. University Boulevard, 36688, Mobile, AL, USA;Center of Excellence in Healthy Communities, University of South Alabama, 307 N. University Boulevard, 36688, Mobile, AL, USA;Center of Excellence in Healthy Communities, University of South Alabama, 307 N. University Boulevard, 36688, Mobile, AL, USA;Aflac Cancer Center and Blood Disorders Service, Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, 30322, Atlanta, GA, USA;Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, 36604, Mobile, AL, USA;

关键词: Breast Cancer;    Circulate Tumor Cell;    Melanoma Cell Line;    Pulmonary Vasculature;    Activate Leukocyte Cell Adhesion Molecule;   

DOI  :  10.1186/1476-4598-9-266

 received in 2010-03-17, accepted in 2010-10-07,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundActivated leukocyte cell adhesion molecule (ALCAM) is implicated in the prognosis of multiple cancers with low level expression associated with metastasis and early death in breast cancer. Despite this significance, mechanisms that regulate ALCAM gene expression and ALCAM's role in adhesion of pre-metastatic circulating tumor cells have not been defined. We studied ALCAM expression in 20 tumor cell lines by real-time PCR, western blot and immunochemistry. Epigenetic alterations of the ALCAM promoter were assessed using methylation-specific PCR and bisulfite sequencing. ALCAM's role in adhesion of tumor cells to the vascular wall was studied in isolated perfused lungs.ResultsA common site for transcription initiation of the ALCAM gene was identified and the ALCAM promoter sequenced. The promoter contains multiple cis-active elements including a functional p65 NF-κB motif, and it harbors an extensive array of CpG residues highly methylated exclusively in ALCAM-negative tumor cells. These CpG residues were modestly demethylated after 5-aza-2-deoxycytidine treatment. Restoration of high-level ALCAM expression using an ALCAM cDNA increased clustering of MDA-MB-435 tumor cells perfused through the pulmonary vasculature of ventilated rat lungs. Anti-ALCAM antibodies reduced the number of intravascular tumor cell clusters.ConclusionOur data suggests that loss of ALCAM expression, due in part to DNA methylation of extensive segments of the promoter, significantly impairs the ability of circulating tumor cells to adhere to each other, and may therefore promote metastasis. These findings offer insight into the mechanisms for down-regulation of ALCAM gene expression in tumor cells, and for the positive prognostic value of high-level ALCAM in breast cancer.

【 授权许可】

Unknown   
© King et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.