Discs large homolog 5 decreases formation and function of invadopodia in human hepatocellular carcinoma via Girdin and Tks5
Discs large homolog 5 decreases formation and function of invadopodia in human hepatocellular carcinoma via Girdin and Tks5
复制标题
Discs Large 同源物 5 通过 Girdin 和 Tks5 降低人肝细胞癌侵袭伪足的形成和功能
DOI：
10.1002/ijc.30730
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发表时间：
2017-07-15
影响因子：
6.4
通讯作者：
Wang, Lin
中科院分区：
文献类型：
--
作者：
Ke, Yang;Bao, Tianhao;Wang, Lin
浸润样腺形成是肝细胞癌（HCC）侵袭和转移的重要早期事件。然而，侵殖畸形调控的分子机制仍不清楚。本研究旨在探讨椎间盘大同源物5 （disc large homolog 5, Dlg5）在肝细胞癌（HCC）中侵入性隔形成和功能中的潜在作用。我们发现Dlg5在人类HCC组织和细胞系中的表达明显低于邻近的非肿瘤组织和肝细胞。较低的Dlg5表达与HCC晚期、HCC患者较差的总生存期和无病生存期相关。Dlg5‐沉默促进了上皮-间质转化、内殖泡形成、明胶降解功能和内殖泡相关的HepG2细胞侵袭。相比之下，Dlg5过表达抑制了上皮-间质转化、功能性侵样细胞形成和SK‐Hep1细胞的侵袭。Girdin和Tks5，而不是Tks5非磷酸化突变体，都对Dlg5沉默的HepG2细胞的侵入性形成和侵袭负责。此外，Dlg5与Girdin相互作用并干扰Girdin与Tks5的相互作用。Dlg5的沉默促进了Girdin和Tks5的磷酸化，而Girdin的沉默消除了这一磷酸化，并通过诱导shRNA抗性Girdin的表达来恢复。此外，Dlg5过表达在体内显著抑制肝癌肝内和肺转移。综上所述，我们的数据表明，Dlg5通过Girdin和干扰Girdin与Tks5之间的相互作用，作为一种新的侵袭性调节因子，这可能对HCC细胞中Tks5的磷酸化很重要。可以想象，Dlg5可能作为HCC患者预后的一种新的生物标志物。
Invadopodium formation is a crucial early event of invasion and metastasis of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying regulation of invadopodia remain elusive. This study aimed to investigate the potential role of discs large homolog 5 (Dlg5) in invadopodium formation and function in HCC. We found that Dlg5 expression was significantly lower in human HCC tissues and cell lines than adjacent nontumor tissues and liver cells. Lower Dlg5 expression was associated with advanced stages of HCC, and poor overall and disease‐free survival of HCC patients. Dlg5‐silencing promoted epithelial–mesenchymal transition, invadopodium formation, gelatin degradation function, and invadopodium‐associated invasion of HepG2 cells. In contrast, Dlg5 overexpression inhibited epithelial–mesenchymal transition, functional invadopodium formation, and invasion of SK‐Hep1 cells. Both Girdin and Tks5, but not the Tks5 nonphosphorylatable mutant, were responsible for the enhanced invadopodium formation and invasion of Dlg5‐silenced HepG2 cells. Furthermore, Dlg5 interacted with Girdin and interfered with the interaction of Girdin and Tks5. Dlg5 silencing promoted Girdin and Tks5 phosphorylation, which was abrogated by Girdin silencing and rescued by inducing shRNA‐resistant Girdin expression. Moreover, Dlg5 overexpression significantly inhibited HCC intrahepatic and lung metastasis in vivo. Taken together, our data indicate that Dlg5 acts as a novel regulator of invadopodium‐associated invasion via Girdin and by interfering with the interaction between Girdin and Tks5, which might be important for Tks5 phosphorylation in HCC cells. Conceivably, Dlg5 may act as a new biomarker for prognosis of HCC patients.