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 3

Expression pattern of SCARA5 in HCC.

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Expression pattern of SCARA5 in HCC. (A) Endogenous SCARA5 (red) in PLC/...
(A) Endogenous SCARA5 (red) in PLC/PRF/5 cells was detected by immunofluorescence. Original magnification, ×1,000. (B) Schematic diagram of the SCARA5 membrane protein, consisting of multiple functional domains. (C) Real time RT-PCR analysis of SCARA5 was carried out on 40 paired HCC samples and adjacent noncancerous tissue. For each sample, the relative SCARA5 mRNA level was normalized to that of β-actin. The vertical line within each box represents the median –ΔCt value. The upper and lower edges of each box represent the 75th and 25th percentile, respectively. The upper and lower horizontal bars indicate the highest and lowest values determined, respectively. (D) Representative immunohistochemical staining of a pair of HCC specimens and corresponding noncancerous tissue, using the anti-SCARA5 antibody on a tissue array containing 78 pairs of HCC specimens. The nuclei were counterstained with hematoxylin. Original magnification, ×40 (left); ×400 (right). (E) Statistical analysis was performed using the GraphPad Prism 5 program to compare the relative levels of SCARA5 in HCC with PVTT with cells without PVTT (P = 0.02169, Mann-Whitney Test). Black triangles indicate the HCC sample, and the transverse lines indicate the mean.