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Carcinogenesis Advance Access originally published online on October 8, 2008
Carcinogenesis 2008 29(12):2298-2305; doi:10.1093/carcin/bgn226
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells

Mei Chung Moh, Ting Zhang, Lay Hoon Lee and Shali Shen*

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore 117597, Singapore

* To whom correspondence should be addressed. Tel: +65 6516 6406; Fax: +65 6778 8161; Email: phsssl{at}nus.edu.sg

Previously, we reported the identification of a novel immunoglobulin-like cell adhesion molecule hepaCAM that is frequently downregulated and inhibits cell growth in hepatocellular carcinoma. In this study, we show that the expression of hepaCAM is suppressed in diverse human cancers. Aiming to evaluate the biological role of hepaCAM in breast cancer, we stably transfected the MCF7 cell line with either wild-type hepaCAM or its mutant hCAM-tailless that lacked the cytoplasmic domain. We found that hepaCAM inhibited colony formation and cell proliferation and arrested cells in the G2/M phase. Intriguingly, hepaCAM was capable of inducing cellular senescence as defined by the enlarged cell morphology and increased β-galactosidase activity. Furthermore, hepaCAM elevated the expression levels of senescence-associated proteins including p53, p21 and p27. In contrast, cell growth inhibition and senescence were less apparent in cells overexpressing hCAM-tailless mutant. To determine if the p53-mediated pathway was involved in hepaCAM-induced senescence, we used the small-interfering RNA system to knock down endogenous p53 expression. In the presence of hepaCAM, downregulation of p53 resulted in a clear reduction of p21, insignificant change in p27 and alleviated senescence. Together, the results suggest that the expression of hepaCAM in MCF7 cells not only inhibits cell growth but also induces cellular senescence through the p53/21 pathway.

Abbreviations: CAM, cell adhesion molecule; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; cdc2, cell division cycle 2; cdk, cyclin-dependent kinase; HCC, hepatocellular carcinoma; siRNA, small-interfering RNA

Received March 3, 2008; revised September 15, 2008; accepted September 28, 2008.


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