Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling
Jian Huang, … , Hua-Sheng Xiao, Ze-Guang Han
Jian Huang, … , Hua-Sheng Xiao, Ze-Guang Han
Published December 14, 2009
Citation Information: J Clin Invest. 2010;120(1):223-241. https://doi.org/10.1172/JCI38012.
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Research Article Oncology

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

Abstract

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.

Authors

Jian Huang, Da-Li Zheng, Feng-Song Qin, Na Cheng, Hui Chen, Bing-Bing Wan, Yu-Ping Wang, Hua-Sheng Xiao, Ze-Guang Han

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Figure 7

SCARA5 modulates HCC cell migration, invasion, and metastasis.

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SCARA5 modulates HCC cell migration, invasion, and metastasis. (A) The m...
(A) The migration of YY-8103 cells transfected with shRNA-489 in wound-healing experiment. (B) Cell invasion of MHCC-M3 cells infected with an adenovirus vector containing SCARA5 was evaluated with Matrigel assay. (C) The same approach was used for 2 stable YY-8103 subclones (shRNA-489-2 and shRNA-489-11) with SCARA5 knockdown. Counts of trespassed cells represent mean values per field (from at least 5 fields) from 3 independent experiments (right) (mean ± SD). (D–F) Effect of SCARA5 overexpression on liver metastasis of MHCC-LM3 cells with adenovirus-SCARA5, from spleen through the portal vein. No metastatic nodules were found in livers of any of SCID mice (n = 8) at 2 weeks after injection (D), but a small metastatic nodule formed at 4 weeks (n = 3). (E). However, cells with empty vector formed metastatic nodules (n = 6) at 2 weeks and larger ones at 4 weeks (n = 3). Representative images show livers and H&E-stained sections. (F) Tumors were weighed at 4 weeks; the weight is indicated (mean ± SD). (G) Representative images of metastases that formed in lungs of each nude mouse (n = 7) at 16 weeks after tail vein injection of YY-8103 cells with shRNA-489-2 or shRNA-NC. The sections show the lung tissues of mice injected with these cells. N, normal lung; M, metastatic nodule. White and black arrows indicate metastatic tumors in liver and lung, respectively. Original magnification, ×100 (A–C); ×400 (D and E, right panels); ×200 (G, right panels).