Epigenetic Silencing of SPINT2 Promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma.
Epigenetic Silencing of SPINT2 Promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma.
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SPINT2的表观遗传沉默可通过黑素瘤中的HGF-MET途径激活促进癌细胞的运动。
DOI：
10.1038/jid.2015.160
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Ryu B
中科院分区：
文献类型：
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作者：
Hwang S;Kim HE;Min M;Raghunathan R;Panova IP;Munshi R;Ryu B
通过与肿瘤微环境中周围基质细胞相互作用而异常的 HGF-MET 信号激活在恶性肿瘤进展中发挥着重要作用。然而，受肿瘤微环境影响的 HGF 激活的细胞外蛋白水解调节及其对黑色素瘤恶性肿瘤的影响仍然未知。在这项研究中，我们发现了 SPINT2：一种肝细胞生长因子激活剂 (HGFA) 的蛋白水解抑制剂，它在抑制 HGF-MET 通路和恶性黑色素瘤进展中发挥着重要作用。与早期原发性黑色素瘤相比，转移性黑色素瘤组织中的 SPINT2 表达显着降低，这也与从组织样本中分离出的 DNA 甲基化水平相对应。在培养的黑色素瘤细胞中使用 DNA 低甲基化剂地西他滨治疗可诱导 SPINT2 转录重新激活，表明该基因在恶性黑色素瘤中被表观遗传沉默。此外，我们发现黑色素瘤细胞中异位表达的 SPINT2 抑制 HGF 诱导的 MET-AKT 信号通路，并降低恶性表型潜力，例如细胞运动和黑色素瘤细胞的侵袭性生长。这些结果表明，SPINT2 通过抑制 HGF 的细胞外信号调节因子而与黑色素瘤的肿瘤抑制功能相关，而 HGF 通常由肿瘤-基质相互作用激活。这些发现表明，肿瘤微环境中严格调节的细胞因子受体通讯的表观遗传损伤可能导致恶性肿瘤进展。
Aberrant HGF-MET signaling activation via interactions with surrounding stromal cells in tumor microenvironment plays significant roles in malignant tumor progression. However, extracellular proteolytic regulation of HGF activation which is influenced by the tumor microenvironment and its consequential effects on melanoma malignancy remain uncharacterized. In this study we identified SPINT2: a proteolytic inhibitor of hepatocyte growth factor activator (HGFA), which plays a significant role in the suppression of the HGF-MET pathway and malignant melanoma progression. SPINT2 expression is significantly lower in metastatic melanoma tissues compared to those in early stage primary melanomas which also corresponded with DNA methylation levels isolated from tissue samples. Treatment with the DNA hypomethylating agent decitabine in cultured melanoma cells induced transcriptional reactivation of SPINT2, suggesting that this gene is epigenetically silenced in malignant melanomas. Furthermore, we show that ectopically expressed SPINT2 in melanoma cells inhibits HGF induced MET-AKT signaling pathway and decreases malignant phenotype potential such as cell motility, and invasive growth of melanoma cells. These results suggest that SPINT2 is associated with tumor suppressive functions in melanoma by inhibiting an extracellular signal regulator of HGF which is typically activated by tumor-stromal interactions. These findings indicate that epigenetic impairment of the tightly regulated cytokine-receptor communications in tumor microenvironment may contribute to malignant tumor progression.