Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma

Carmen Chak Lui Wong, Aki Pui Wah Tse, Yan Ping Huang, Yan Ting Zhu, David Kung Chun Chiu, Robin Kit Ho Lai, Sandy Leung Kuen Au, Alan Ka Lun Kai, Joyce Man Fong Lee, Larry Lai Wei, Felice Ho Ching Tsang, Regina Cheuk Lam Lo, Jue Shi, Yongping Zheng, Chun Ming Wong, Irene Oi Lin Ng

Research output: Journal article publicationJournal articleAcademic researchpeer-review

124 Citations (Scopus)

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. Conclusion: These findings integrate the clinical relevance, molecular regulation, and functional implications of LOXL2 in HCC metastasis. (Hepatology 2014;60:1645-1658).
Original languageEnglish
Pages (from-to)1645-1658
Number of pages14
JournalHepatology
Volume60
Issue number5
DOIs
Publication statusPublished - 1 Nov 2014

ASJC Scopus subject areas

  • Hepatology

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