ROCK Is Involved in Vasculogenic Mimicry Formation in Hepatocellular Carcinoma Cell LineReportar como inadecuado




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Ras homolog family member A RhoA and Rho-associated coiled coil-containing protein kinases 1 and 2 ROCK1 and 2 are key regulators of focal adhesion, actomyosin contraction and cell motility. RhoA-ROCK signaling has emerged as an attractive target for the development of new cancer therapeutics. Whether RhoA-ROCK is involved in regulating the formation of tumor cell vasculogenic mimicry VM is largely unknown. To confirm this hypothesis, we performed in vitro experiments using hepatocellular carcinoma HCC cell lines. Firstly, we demonstrated that HCC cells with higher active RhoA-ROCK expression were prone to form VM channels, as compared with RhoA-ROCK low-expressing cells. Furthermore, Y27632 a specific inhibitor of ROCK rather than exoenzyme C3 a specific inhibitor of RhoA effectively inhibited the formation of tubular network structures in a dose-dependent manner. To elucidate the possible mechanism of ROCK on VM formation, real-time qPCR, western blot and immunofluorescence were used to detect changes of the key VM-related factors, including VE-cadherin, erythropoietin-producing hepatocellular carcinoma-A2 EphA2, phosphoinositide 3-kinase PI3K, matrix metalloproteinase MMP14, MMP2, MMP9 and laminin 5γ2-chain LAMC2, and epithelial-mesenchymal-transition EMT markers: E-cadherin and Vimentin. The results showed that all the expression profiles were attenuated by blockage of ROCK. In addition, in vitro cell migration and invasion assays showed that Y27632 inhibited the migration and invasion capacity of HCC cell lines in a dose-dependent manner markedly. These data indicate that ROCK is an important mediator in the formation of tumor cell VM, and suggest that ROCK inhibition may prove useful in the treatment of VM in HCC.



Autor: Ji-Gang Zhang , Xiao-Yu Li , Yu-Zhu Wang , Qi-Di Zhang, Sheng-Ying Gu, Xin Wu, Guan-Hua Zhu, Qin Li , Gao-Lin Liu

Fuente: http://plos.srce.hr/



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