Discs large homolog 5 decreases formation and function of invadopodia in human hepatocellular carcinoma via Girdin and Tks5

Abstract

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.

PABPC1-induced stabilization of BDNF-AS inhibits malignant progression of glioblastoma cells through STAU1-mediated decay

“…Overexpression of DLG5 inhibited glioma cells malignant biological behaviors of glioblastoma cells. Similar results were reported in many human cancers, such as bladder cancer, prostate cancer, breast cancer, and hepatocellular carcinoma 19,20,58 . We also found that knockdown of RAX2 could increase DLG5 expression.…”

“…DLG5 belongs to the membrane associated guanylate kinase (MAGUK) family, participates in epithelial cell polarity maintenance and cancer development 18 . DLG5 expression was downregulated in many human cancers, such as bladder cancer, prostate cancer, breast cancer, and hepatocellular carcinoma, not only that, knockdown of DLG5 significantly increased cell migration and invasion in these cancers 19,20 .…”

Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer

“…SH3PXD2A-AS1 is an antisense transcript transcribed from SH3PXD2A and located on chromosome 10 with 2023 bp length. And SH3PXD2A has been identified to exert oncogenic roles in multiple cancers [31-34]. In this study, we found that dysregulation of SH3PXD2A-AS1 is correlated with clinicopathological factors in CRC patients.…”

Novel Significant Stage-Specific Differentially Expressed Genes in Liver Hepatocellular Carcinoma

“…DLG5 is a cell polarity gene and its downregulation has been implicated in the malignancy of breast , prostate (Tomiyama et al, 2015) and bladder cancers (Zhou et al, 2015). It has been recently found that lower DLG5 expression is correlated with advanced stages of HCC and essential for invadopodium formation, an event critical to cancer metastasis (Ke et al, 2017). It is surprising that our study has identified a stage-III specific upregulation in DLG5.…”