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.

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Traumatic brain injury (TBI) is an insult to the brain that results in impairments of cognitive and physical functioning. Both of human research and animal studies demonstrate that spontaneous exercise can facilitate neuronal plasticity and improve cognitive function in normal or TBI rodent models. However, the possible mechanisms underlying are still not well known. We postulated that spontaneous running wheel (RW) altered microRNA (miRNA) expressions in hippocampus of mice following TBI, which might be associated with the improvement in cognitive functions. In the present study, acquisition of spatial learning and memory retention was assessed by using the Morris water maze (MWM) test on days 15 post RW exercise. Then, microarray analyses in miRNA files were employed, and the expressional changes of miRNAs in the hippocampus of mice were detected. The results showed that spontaneous RW exercise (i) recovered the hippocampus-related cognitive deficits induced by TBI, (ii) altered hippocampal expressions of miRNAs in both of sham and TBI mice, and (iii) miR-21 or miR-34a was associated with the recovery process. The present results indicated that an epigenetic mechanism might be involved in voluntary exercise-induced cognitive improvement of mice that suffered from TBI.

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