Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling

• Published in: The Journal of clinical investigation 2010-01, Vol.120 (1), p.223-241
• Main Authors: Huang, Jian, Zheng, Da-Li, Qin, Feng-Song, Cheng, Na, Chen, Hui, Wan, Bing-Bing, Wang, Yu-Ping, Xiao, Hua-Sheng, Han, Ze-Guang
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomedical research; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Care and treatment; Cell growth; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cellular signal transduction; Chromosomes; Chromosomes, Human, Pair 8; Cyclin-dependent kinases; Development and progression; DNA Methylation; Epigenetics; Focal Adhesion Protein-Tyrosine Kinases - physiology; Gene expression; Gene Silencing; Genetic aspects; Genomes; Hepatoma; Humans; Kinases; Liver cancer; Liver Neoplasms - etiology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Loss of Heterozygosity; Metastasis; Methods; Mice; Mice, SCID; Mutation; Neoplasm Invasiveness; Phosphorylation; Physiological aspects; Promoter Regions, Genetic; Proteins; Scavenger Receptors, Class A - antagonists & inhibitors; Scavenger Receptors, Class A - genetics; Scavenger Receptors, Class A - physiology; Signal Transduction - physiology; Tumorigenesis; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI38012

The epigenetic silencing of tumor suppressor genes is a crucial event during carcinogenesis and metastasis. Here, in a human genome-wide survey, we identified scavenger receptor class A, member 5 (SCARA5) as a candidate tumor suppressor gene located on chromosome 8p. We found that SCARA5 expression was frequently downregulated as a result of promoter hypermethylation and allelic imbalance and was associated with vascular invasion in human hepatocellular carcinoma (HCC). Furthermore, SCARA5 knockdown via RNAi markedly enhanced HCC cell growth in vitro, colony formation in soft agar, and invasiveness, tumorigenicity, and lung metastasis in vivo. By contrast, SCARA5 overexpression suppressed these malignant behaviors. Interestingly, SCARA5 was found to physically associate with focal adhesion kinase (FAK) and inhibit the tyrosine phosphorylation cascade of the FAK-Src-Cas signaling pathway. Conversely, silencing SCARA5 stimulated the signaling pathway via increased phosphorylation of certain tyrosine residues of FAK, Src, and p130Cas; it was also associated with activation of MMP9, a tumor metastasis-associated enzyme. Taken together, these data suggest that the plasma membrane protein SCARA5 can contribute to HCC tumorigenesis and metastasis via activation of the FAK signaling pathway.