title: Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma.
abstract: Poor prognosis of cancers, including hepatocellular carcinoma (HCC), is mainly associated with metastasis; however, the underlying mechanisms remain poorly understood. This article investigates the role of lysyl oxidase-like 2 (LOXL-2) in the biology of HCC metastasis. First, we showed that HCC metastasis relies on a collagen-modifying enzyme, LOXL2, which was significantly overexpressed in tumorous tissues and sera of HCC patients, indicating that LOXL2 may be a good diagnostic marker for HCC patients. Second, we delineated a complex, interlinked signaling network that involves multiple regulators, including hypoxia, transforming growth factor beta (TGF-β), and microRNAs (miRNAs), converging to control the expression of LOXL2. We found not only that LOXL2 was regulated by hypoxia/hypoxia-inducible factor 1 alpha (HIF-1α), but also that TGF-β activated LOXL2 transcription through mothers against decapentaplegic homolog 4 (Smad4), whereas two frequently underexpressed miRNA families, miR-26 and miR-29, cooperatively suppressed LOXL2 transcription through interacting with the 3' untranslated region of LOXL2. Third, we demonstrated the imperative roles of LOXL2 in modifying the extracellular matrix components in the tumor microenvironment and metastatic niche of HCC. LOXL2 promoted intrahepatic metastasis by increasing tissue stiffness, thereby enhancing the cytoskeletal reorganization of HCC cells. Furthermore, LOXL2 facilitated extrahepatic metastasis by enhancing recruitment of bone-marrow-derived cells to the metastatic site.
  
  
  CONCLUSIONS
  These findings integrate the clinical relevance, molecular regulation, and functional implications of LOXL2 in HCC metastasis.
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
authors.forename: Aki Pui-Wah
authors.initials: AP
authors.lastname: Tse
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Huang
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Zhu
authors.forename: David Kung-Chun
authors.initials: DK
authors.lastname: Chiu
authors.forename: Robin Kit-Ho
authors.initials: RK
authors.lastname: Lai
authors.forename: Sandy Leung-Kuen
authors.initials: SL
authors.lastname: Au
authors.forename: Alan Ka-Lun
authors.initials: AK
authors.lastname: Kai
authors.forename: Joyce Man-Fong
authors.initials: JM
authors.lastname: Lee
authors.forename: Larry Lai
authors.initials: LL
authors.lastname: Wei
authors.forename: Felice Ho-Ching
authors.initials: FH
authors.lastname: Tsang
authors.forename: Regina Cheuk-Lam
authors.initials: RC
authors.lastname: Lo
authors.forename: Jue
authors.initials: J
authors.lastname: Shi
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Zheng
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology*; D016022:Case-Control Studies; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D009362:Neoplasm Metastasis; D051901:Smad4 Protein / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D051901:Smad4 Protein; D003094:Collagen; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; C485601:Loxl2 protein, mouse