Bei Wang1, Ping Feng, Ziwei Xiao, Ee-Chee Ren. 1. Laboratory of Immunogenetics and Viral Host-Pathogen Genomics, Singapore Immunology Network, 8A Biomedical Grove, Immunos, Singapore.
Abstract
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with poor prognosis associated with tumor invasion and metastasis. The tumor suppressor p53 plays critical roles in tumor development, but there is increasing evidence for its involvement in tumor metastasis with the underlying mechanisms largely unexplored. METHODS: Using combinatorial analysis of a p53 binding database with HCC microarray expression profile, we identified a novel metastasis-related gene Lasp1 as a potential p53 target. RESULTS: In this study, we demonstrate that Lasp1 is indeed a bona fide p53 target by validating the functional repression effect of p53 on Lasp1 via a p53 response element. Transient transfection of wild-type p53 but not the mutant form suppressed Lasp1 in Hep3B (p53-/-) cells, while p53 siRNA up-regulated its expression in HepG2 (p53+/+) cells. p53 mutations at key residues involved in DNA binding abrogates the p53-mediated suppression of Lasp1 expression. In addition, Lasp1 regulates HCC cell growth as well as cell migration and invasion ability. CONCLUSIONS: p53 transcriptionally represses Lasp1, which is a partner protein in affecting HCC cell motility. This suggests that p53 may play a role in influencing tumor metastasis through Lasp1.
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with poor prognosis associated with tumor invasion and metastasis. The tumor suppressor p53 plays critical roles in tumor development, but there is increasing evidence for its involvement in tumor metastasis with the underlying mechanisms largely unexplored. METHODS: Using combinatorial analysis of a p53 binding database with HCC microarray expression profile, we identified a novel metastasis-related gene Lasp1 as a potential p53 target. RESULTS: In this study, we demonstrate that Lasp1 is indeed a bona fide p53 target by validating the functional repression effect of p53 on Lasp1 via a p53 response element. Transient transfection of wild-type p53 but not the mutant form suppressed Lasp1 in Hep3B (p53-/-) cells, while p53 siRNA up-regulated its expression in HepG2 (p53+/+) cells. p53 mutations at key residues involved in DNA binding abrogates the p53-mediated suppression of Lasp1 expression. In addition, Lasp1 regulates HCC cell growth as well as cell migration and invasion ability. CONCLUSIONS:p53 transcriptionally represses Lasp1, which is a partner protein in affecting HCC cell motility. This suggests that p53 may play a role in influencing tumor metastasis through Lasp1.
Authors: J J Frietsch; T G P Grunewald; S Jasper; U Kammerer; S Herterich; M Kapp; A Honig; E Butt Journal: Br J Cancer Date: 2010-05-11 Impact factor: 7.640