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.

Co-Upregulation of 14-3-3ζ and P-Akt is Associated with Oncogenesis and Recurrence of Hepatocellular Carcinoma

“…Moreover, after the 21-day period, the weight of HCC+14-3-3ζ-derived tumors was significantly greater than that of HCC-or HCC+Vector-derived tumors ( Fig 3B) (P < 0.05). At the molecular level, forced expression of 14-3-3ζ led to increased levels of p-Akt and HIF-1α in the xenograft tumors (Fig 3C), which was in line with our clinical observations and our previous in vitro results [31].…”

“…Moreover, Zhang et al reported that 14-3-3ζ overexpression indicated poor prognosis of intrahepatic cholangiocarcinoma in terms of a shorter patient survival and a higher recurrence [19]. In our previous study, we reported that 14-3-3ζ overexpression was significantly correlated with a shorter survival time and a higher recurrence rate in HCC [20]. In the present study, we found that high expression of 14-3-3ζ was associated with an increased recurrence rate and the risk of PVTT formation in HCC patients.…”

“…Of types of the 14-3-3 proteins, 14-3-3ζ has been found to promote anchorage-independent growth and proliferation, inhibit apoptosis, and enhance chemo-resistance and metastasis of cancer cells [11,12]. In addition, a high level of 14-3-3ζ is correlated with poor prognosis of multiple cancers, including breast cancer [13,14], non-small cell lung cancer [15][16][17], gastric carcinoma [18], intrahepatic cholangiocarcinoma [19], and HCC [20]. A previous study showed that overexpression of 14-3-3ζ could lead to the activation of Akt in human mammary epithelial cells [21].…”

DDIT4 gene expression is switched on by a new HDAC4 function in ataxia telangiectasia

“…The described interaction is able to stabilize HIF-1a transcription activity, 56 but the described gene modulation (SLC22A1) was not evident in AT fibroblasts. Among these, HIF-1a was selected as a potential partner of HDAC4, and this interaction was investigated.…”

“…The expression of SLC22A1 was undetectable (in contrast with Tang et al 56 ) in all the tested samples, while atypical outcomes were obtained testing the expression of vascular endothelial growth factor A (VEGFA), solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), insulin like growth factor-binding protein 1 (IGFBP-1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Supplemental Figure 4S). The expression of SLC22A1 was undetectable (in contrast with Tang et al 56 ) in all the tested samples, while atypical outcomes were obtained testing the expression of vascular endothelial growth factor A (VEGFA), solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), insulin like growth factor-binding protein 1 (IGFBP-1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Supplemental Figure 4S).…”