14-3-3ζ promotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1α
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Yufu Tang1,3,*, Shupeng Liu2,*, Nan Li1,*, Weixing Guo1,*, Jie Shi1, Hongming Yu1, Long Zhang1, Kang Wang1, Shangrong Liu2, Shuqun Cheng1
1Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
2Changhai Hospital, Second Military Medical University, Shanghai 200433, China
3Department of Hepatobiliary Surgery, General Hospital of Shenyang Military Area Command, Liaoning 110016, China
*These authors have contributed equally to this work
Shuqun Cheng, e-mail: firstname.lastname@example.org
Shanrong Liu, e-mail: email@example.com
Keywords: hypoxia, portal vein tumor thrombus, hepatocellular carcinoma, metastasis
Received: July 09, 2015 Accepted: January 05, 2016 Published: February 19, 2016
Portal vein tumor thrombus (PVTT) is a type of intrahepatic metastasis arising from hepatocellular carcinoma (HCC) and is highly correlated with a poor prognosis. Hypoxia is common in solider tumors, including HCC, where it alters the behavior of HCC cells. We asked whether and how hypoxia contributes to PVTT formation. We demonstrated that increased intratumoral hypoxia is strongly associated with PVTT formation in HCC. We also showed that 14-3-3ζ is induced by hypoxia in HCC cells and correlates with PVTT formation in clinical HCC samples. In addition, 14-3-3ζ up-regulates HIF-1α expression by recruiting HDAC4, which prevents HIF-1α acetylation, thereby stabilizing the protein. Under hypoxic conditions in vitro, 14-3-3ζ knockdown inhibits hypoxia-induced HCC invasion by the HIF-1α/EMT pathway. Blockade of 14-3-3ζ in HCC cells reduces PVTT formation and distant lung metastasis in vivo. Moreover, a combination of 14-3-3ζ and HIF-1α expression is more prognostic for HCC patients than either protein alone. These results suggest that the hypoxia/14-3-3ζ/HIF-1α pathway plays an important role in PVTT formation and HCC metastasis.
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