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Reciprocal activation between ATPase inhibitory factor 1 and NF‐κB drives hepatocellular carcinoma angiogenesis and metastasis
Author(s) -
Song Ruipeng,
Song Huiwen,
Liang Yingjian,
Yin Dalong,
Zhang Heng,
Zheng Tongsen,
Wang Jiabei,
Lu Zhaoyang,
Song Xuan,
Pei Tiemin,
Qin Youyou,
Li Yuejin,
Xie Changming,
Sun Boshi,
Shi Huawen,
Li Shuai,
Meng Xianzhi,
Yang Guangchao,
Pan Shangha,
Zhu Jiyuan,
Qi Shuyi,
Jiang Hongchi,
Zhang Zhiyong,
Liu Lianxin
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27312
Subject(s) - angiogenesis , cancer research , metastasis , chromatin immunoprecipitation , biology , snai1 , hepatocellular carcinoma , transcription factor , vascular endothelial growth factor , tumor necrosis factor alpha , medicine , epithelial–mesenchymal transition , cancer , immunology , gene expression , promoter , biochemistry , gene , vegf receptors
Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent extrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effects of ATPase inhibitory factor 1 (IF1), an inhibitor of the mitochondrial H(+)‐adenosine triphosphate (ATP) synthase, on HCC angiogenesis and metastasis. We found that increased expression of IF1 in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and metastasis, expressed high levels of IF1. Invasive tumors overexpressing IF1 were featured by active epithelial‐mesenchymal transition (EMT) and increased angiogenesis, whereas silencing IF1 expression attenuated EMT and invasion of HCC cells. Mechanistically, IF1 promoted Snai1 and vascular endothelial growth factor (VEGF) expression by way of activating nuclear factor kappa B (NF‐κB) signaling, which depended on the binding of tumor necrosis factor (TNF) receptor‐associated factor 1 (TRAF1) to NF‐κB‐inducing kinase (NIK) and the disruption of NIK association with the TRAF2‐cIAP2 complex. Suppression of the NF‐κB pathway interfered with IF1‐mediated EMT and invasion. Chromatin immunoprecipitation assay showed that NF‐κB can bind to the Snai1 promoter and trigger its transcription. IF1 was directly transcribed by NF‐κB, thus forming a positive feedback signaling loop. There was a significant correlation between IF1 expression and pp65 levels in a cohort of HCC biopsies, and the combination of these two parameters was a more powerful predictor of poor prognosis. Conclusion : IF1 promotes HCC angiogenesis and metastasis by up‐regulation of Snai1 and VEGF transcription, thereby providing new insight into HCC progression and IF1 function. (H epatology 2014;60:1659–1673)