title: Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis.
abstract: 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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Song
authors.forename: Huiwen
authors.initials: H
authors.lastname: Song
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Liang
authors.forename: Dalong
authors.initials: D
authors.lastname: Yin
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.forename: Tongsen
authors.initials: T
authors.lastname: Zheng
authors.forename: Jiabei
authors.initials: J
authors.lastname: Wang
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Lu
authors.forename: Xuan
authors.initials: X
authors.lastname: Song
authors.forename: Tiemin
authors.initials: T
authors.lastname: Pei
authors.forename: Youyou
authors.initials: Y
authors.lastname: Qin
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Li
authors.forename: Changming
authors.initials: C
authors.lastname: Xie
authors.forename: Boshi
authors.initials: B
authors.lastname: Sun
authors.forename: Huawen
authors.initials: H
authors.lastname: Shi
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Meng
authors.forename: Guangchao
authors.initials: G
authors.lastname: Yang
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Zhu
authors.forename: Shuyi
authors.initials: S
authors.lastname: Qi
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002681:China / Q000453:epidemiology; D015331:Cohort Studies; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010750:Phosphoproteins; D011379:Prognosis; D011506:Proteins / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014763:Viral Matrix Proteins; D000097795:ATPase Inhibitory Protein
chemical_list: D016328:NF-kappa B; D010750:Phosphoproteins; D011506:Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D014763:Viral Matrix Proteins; D000097795:ATPase Inhibitory Protein; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; C065418:cytomegalovirus matrix protein 65kDa