Bromodomain containing protein represses the Ras/Raf/MEK/ERK pathway to attenuate human hepatoma cell proliferation during HCV infection

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Abstract

Hepatitis C virus (HCV) infection facilitates the development of hepatocellular carcinoma (HCC). Activation of Ras/Raf/MEK/ERK pathway is found in more than 30% human cancers. Here, we revealed a novel mechanism underlying the regulation of hepatoma cell proliferation mediated by HCV. On one hand, hepatoma cell proliferation is facilitated by HCV infection through a positive feedback regulatory cycle. HCV promotes hepatoma cell proliferation by activating the Ras/Raf/MEK/ERK pathway, which in turn facilitates HCV replication to further enhance hepatoma cell proliferation. On the other hand, hepatoma cell proliferation is attenuated by the bromodomain containing 7 (BRD7), a tumor suppressor, through a negative feedback regulatory mechanism. After activation, the Ras/Raf/MEK/ERK pathway stimulates BRD7 production, which in turn represses the Ras/Raf/MEK/ERK pathway, leading to the attenuation of hepatoma cell proliferation. However, HCV persistent infection attenuates BRD7 gene expression and facilitates the protein degradation to release the Ras/Raf/MEK/ERK signaling, which results in the facilitation of hepatoma cell proliferation. Therefore, we proposed that the balance between BRD7 function and Ras/Raf/MEK/ERK activity is important for determining the outcomes of HCV infection and HCC development.

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Zhang, Q., Wei, L., Yang, H., Yang, W., Yang, Q., Zhang, Z., … Wu, J. (2016). Bromodomain containing protein represses the Ras/Raf/MEK/ERK pathway to attenuate human hepatoma cell proliferation during HCV infection. Cancer Letters, 371(1), 107–116. https://doi.org/10.1016/j.canlet.2015.11.027

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