title: 14-3-3ζ promotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1α.
abstract: 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.
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.|Department of Hepatobiliary Surgery, General Hospital of Shenyang Military Area Command, Liaoning 110016, China.
authors.forename: Yufu
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Shupeng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Weixing
authors.initials: W
authors.lastname: Guo
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Yu
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Wang
authors.affiliation: Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Shangrong
authors.initials: S
authors.lastname: Liu
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Cheng
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011169:Portal Vein / Q000473:pathology; D011379:Prognosis
chemical_list: D048948:14-3-3 Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C572235:YWHAZ protein, human
keywords: hepatocellular carcinoma; hypoxia; metastasis; portal vein tumor thrombus