Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling
Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling
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DOI：
10.1172/jci38012
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发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
Han, Ze-Guang
中科院分区：
文献类型：
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作者：
Huang, Jian;Zheng, Da-Li;Han, Ze-Guang
抑癌基因的表观遗传沉默是肿瘤发生和转移过程中的重要事件。在此，在人类全基因组调查中，我们确定清道夫受体A类成员5(SCARA5)是位于染色体8p上的一个候选抑癌基因。我们发现，在人肝细胞癌中，SCARA5的表达经常是由于启动子高甲基化和等位基因失衡而下调，并与血管侵袭有关。此外，通过RNAi的SCARA5基因敲除显著促进了肝癌细胞的体外生长、软琼脂集落形成以及体内的侵袭性、致瘤性和肺转移。相比之下，SCARA5的过表达抑制了这些恶性行为。有趣的是，SCARA5被发现物理上与粘着斑激酶(FAK)结合，并抑制FAK-Src-Cas信号通路的酪氨酸磷酸化级联。相反，沉默SCARA5通过增加FAK、Src和p130Cas的某些酪氨酸残基的磷酸化来刺激信号通路；它也与肿瘤转移相关酶MMP9的激活有关。综上所述，这些数据表明质膜蛋白SCARA5可能通过激活FAK信号通路参与肝癌的发生和转移。
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.