Recent studies demonstrated that CD151 gene delivery activated the PI3K/Akt pathway, induced cell migration, survival, and production of proangiogenic factors such as nitric oxide, and also promoted neovascularization after myocardial infarction in rats.11 On the contrary, mouse lung endothelial cells from CD151null mice displayed a marked reduction LDK378 purchase in pathological angiogenesis-related endothelial events, which apparently were mediated by modulation of the molecular organization of laminin-binding integrins.12 An important downstream molecule of the PI3K/Akt pathway, phosphorylated GSK, mediates the effects of Akt on cell growth, proliferation, protection from proapoptotic

stimuli, and stimulation of neoangiogenesis.32 The expression of Snail, a zinc-finger transcription factor, correlates with cancer invasion

and poor prognosis in HCC patients and is induced by the MMP family.38 In the present study, overexpression of CD151 was correlated positively with up-regulated AktSer473, Snail, and MMP9, and direct evidence has been provided for the involvement of Akt and Snail in MMP9 expression induced by overexpression of CD151. In another study, silencing of CD151 in HCCM3 up-regulated NVP-AUY922 mouse the adhesion molecule E-cadherin, and this suggested that CD151 was involved in the epithelial-to-mesenchymal transitions (unpublished data). Overexpression of CD151 prompted the accumulation of Snail in the nucleus, rather than overexpression of Snail in cytoplasm in HCC cells and HCC patients (Supporting

Information Fig. 9B,C). GSK-3β, an endogenous inhibitor of Snail transcription, can be inactivated by phosphorylated AktSer473 and is involved in the epithelial-to-mesenchymal transitions of cancer cells.39 The present study has shown that inhibition of GSK-3β up-regulates the expression of MMP9, and this indicates that the Akt/GSK-3β/Snail signal affects the expression of MMP9. In summary, overexpression of CD151 promotes the expression of MMP9 in HCCs, apparently primarily through the PI3K/Akt/GSK-3β/Snail signal (Fig. 7). A variety of molecules, such as VEGF, have been implicated in the process of angiogenesis.40 Alectinib cell line Interestingly, in the present study, we found that the expression of VEGF was hardly relevant to CD151-dependent neoangiogenesis, and this was consistent with previous reports.11, 13 Instead, MMP9 had a crucial role in CD151-dependent angiogenesis and remodeling of vessels in vitro. More importantly, the consistency of the expression level of CD151 and its relationship with MMP9 expression and angiogenesis were confirmed in an animal model. Even more significantly, we identified a role for the CD151/MMP9/angiogenesis cascade in the clinical setting of HCCs. HCC patients with CD151high were inclined to harbor higher levels of expression of MMP9 and more neoangiogenesis.