title: Mechanisms through Which Hypoxia-Induced Caveolin-1 Drives Tumorigenesis and Metastasis in Hepatocellular Carcinoma.
abstract: In solid tumors, hypoxia triggers an aberrant vasculogenesis, enhances malignant character, and elevates metastatic risk. The plasma membrane organizing protein caveolin-1 (Cav1) is increased in a variety of cancers, including hepatocellular carcinoma (HCC), where it contributes to metastatic capability. However, the reason for elevation of Cav1 in tumor cells and the mechanistic basis for its contributions to metastatic risk are not fully understood. Here, we show that in HCC cells, hypoxia elevates expression of Cav1, which then acts through the calcium-binding protein S100P to promote metastasis. Hypoxic regions of HCC xenografts displayed elevated expression of Cav1. Hypoxia promoted HCC cell migration and invasion and distant pulmonary metastases, whereas Cav1 silencing abolished these effects. Gene expression profiling revealed that hypoxia-induced Cav1 functioned as a positive regulator of S100P via activation of the NF-κB pathway. S100P elevation under hypoxic conditions was abrogated by silencing of Cav1 or NF-κB function. Conversely, restoring S100P in Cav1-silenced cells rescued the migratory potential of HCC cells along with tumor formation and lung metastasis. In clinical specimens of HCC, we observed S100P overexpression to correlate with venous invasion, microsatellites, direct liver invasion, and absence of tumor encapsulation. Collectively, our findings demonstrated how hypoxia-induced expression of Cav1 in HCC cells enhances their invasive and metastatic potential. Cancer Res; 76(24); 7242-53. ©2016 AACR.
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors: Xiaowen
authors: X
authors: Mao
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors: Sivia Yuen Sze
authors: SY
authors: Wong
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors: Edith Yuk Ting
authors: EY
authors: Tse
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors: Frankie Chi Fat
authors: FC
authors: Ko
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors: Sze Keong
authors: SK
authors: Tey
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors: Yin Shan
authors: YS
authors: Yeung
authors: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors: Kwan
authors: K
authors: Man
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.|Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors: Regina Cheuk-Lam
authors: RC
authors: Lo
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.|Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors: Irene Oi-Lin
authors: IO
authors: Ng
authors: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. judyyam@pathology.hku.hk.|Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors: Judy Wai Ping
authors: JW
authors: Yam
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D051242:Caveolin 1 / Q000378:metabolism*; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D020411:Oligonucleotide Array Sequence Analysis; D059467:Transcriptome
chemical_list: C495540:CAV1 protein, human; D002135:Calcium-Binding Proteins; D051242:Caveolin 1; D009363:Neoplasm Proteins; C103003:S100P protein, human