p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1α pathways

Abstract

The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular mechanisms underlying HCC progression and aggressiveness are unclear. Here, we report that increased expression of p28 GANK (Gankyrin, PSMD10, or p28) in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and intrahepatic or distant metastasis, expressed high levels of p28 GANK . Invasive tumors overexpressing p28 GANK were featured by active epithelial-mesenchymal transition (EMT), and exhibited increased angiogenesis associated with vascular endothelial growth factor overexpression, whereas silencing p28 GANK expression attenuated EMT and motility/invasion of tumor cells. The p28 GANK activates phosphoinositide 3-kinase (PI3K)-V-akt Murine Thymoma Viral Oncogene Homolog (AKT)-hypoxia-inducible factor 1a (HIF-1a) signaling to promote TWIST1, vascular endothelial growth factor, and metalloproteinase 2 expression. Suppression of the PI3K-AKT-HIF-1a pathway interfered with p28 GANK -mediated EMT and invasion. Consistently, we detected a significant correlation between p28GANK expression and p-AKT levels in a cohort of HCC biopsies, and the combination of these two parameters is a more powerful predictor of poor prognosis. Conclusion: These results present novel mechanistic insight into a critical role of p28 GANK in HCC progression and metastasis. (HEPATOLOGY 2011;53:181-192)

BAG3 regulates epithelial–mesenchymal transition and angiogenesis in human hepatocellular carcinoma

“…In this study, we observed a role for HIF-1a in BAG3-regulated VEGF and MMP2 expression which was consistent with previous reports that HIF-1a promotes VEGF and MMP2 expression, enhancing angiogenesis and metastasis of HCC. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] Moreover, BAG3 regulated angiogenesis of HCC cells through ERK phosphorylation, in accordance with previous studies. 12 Earlier work showed that autophagy-related genes could downregulate angiogenesis; 18,19 however, in our study, knockdown of BAG3 could downregulate the autophagy process.…”

Epithelial-mesenchymal transition expression profiles as a prognostic factor for disease-free survival in hepatocellular carcinoma: Clinical significance of transforming growth factor-β signaling

“…However, TGF-β signaling was not activated in one-third of patients with an E-cadherin low / vimentin high expression profile. Although the precise mechanism of EMT induction in these patients remains unclear, it is possible that several transcription factors (such as Snail, Twist and ZEB1) as well as other molecules are also involved in the process of EMT and are therefore associated with a poor prognosis in HCC (5,6,(20)(21)(22)(23)(24)(25)(26)(27). Thus, several mechanisms, including TGF-β signaling, may be involved in the process of EMT in HCC patients.…”

Gankyrin Activates IL-8 to Promote Hepatic Metastasis of Colorectal Cancer

“…(v) Gankyrin mediates Ras-induced tumorigenesis by suppressing ROCK activity (16), and (vi) Gankyrin enhances PI3K/AKT/HIFa signaling pathway in hepatocellular carcinoma (HCC; refs. [17][18][19].…”