These authors contributed equally to this work.
Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis
Article first published online: 2 OCT 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 5, pages 1659–1673, November 2014
How to Cite
Song, R., Song, H., Liang, Y., Yin, D., Zhang, H., Zheng, T., Wang, J., Lu, Z., Song, X., Pei, T., Qin, Y., Li, Y., Xie, C., Sun, B., Shi, H., Li, S., Meng, X., Yang, G., Pan, S., Zhu, J., Qi, S., Jiang, H., Zhang, Z. and Liu, L. (2014), Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis. Hepatology, 60: 1659–1673. doi: 10.1002/hep.27312
Potential conflict of interest: Nothing to report.
Supported by the China National Natural Science Foundation (No. 81272705), Program for Innovative Research Team by Chinese Ministry of Education (IRT1122), Program for Innovative Research Team (in Science and Technology) in Higher Educational Institutions of Heilongjiang Province (2009td06), Heilongjiang Province Science Fund for Outstanding Youths (JC200616), Foundation of Harbin Science and Technology Bureau for Creative Young Talents (2010RFQXS069), and Foundation of Health Department of Heilongjiang Province (Grant No. 2009-043). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.
- Issue published online: 23 OCT 2014
- Article first published online: 2 OCT 2014
- Accepted manuscript online: 14 JUL 2014 04:57AM EST
- Manuscript Accepted: 9 JUL 2014
- Manuscript Received: 28 FEB 2014
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. (Hepatology 2014;60:1659–1673)