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Lysyl oxidase‐like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma
Author(s) -
Wong Carmen ChakLui,
Tse Aki PuiWah,
Huang YanPing,
Zhu YanTing,
Chiu David KungChun,
Lai Robin KitHo,
Au Sandy LeungKuen,
Kai Alan KaLun,
Lee Joyce ManFong,
Wei Larry Lai,
Tsang Felice HoChing,
Lo Regina CheukLam,
Shi Jue,
Zheng YongPing,
Wong ChunMing,
Ng Irene OiLin
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.27320
Subject(s) - lysyl oxidase , metastasis , hepatocellular carcinoma , cancer research , biology , transcription factor , microrna , tumor microenvironment , transforming growth factor beta , extracellular matrix , transforming growth factor , pathology , medicine , cancer , microbiology and biotechnology , gene , genetics , tumor cells
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. Conclusion : These findings integrate the clinical relevance, molecular regulation, and functional implications of LOXL2 in HCC metastasis. (H epatology 2014;60:1645–1658)