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 paper highlights three important advances in understanding the biology of HCC metastasis. First, we showed that HCC metastasis relies on a collagen-modifying enzyme, lysyl oxidase-like 2 (LOXL2), which was significantly over-expressed in the 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, TGFβ and microRNAs, converging to control the expression of LOXL2. We found not only that LOXL2 was regulated by hypoxia/ HIF-1α, but also that TGFβ activated LOXL2 transcription via SMAD4, whereas two frequently under-expressed microRNA (miRNA) families, miR-26 and miR-29, cooperatively suppressed LOXL2 transcription through interacting with the 3’ untranslated region (3’UTR) of LOXL2. Third, we demonstrated the imperative roles of LOXL2 in modifying the extracellular matrix (ECM) components in the tumor microenvironment and metastatic niche of HCC. LOXL2 promoted intra-hepatic metastasis by increasing tissue stiffness, thereby enhancing the cytoskeletal reorganization of HCC cells. Furthermore, LOXL2 facilitated extra-hepatic metastasis by enhancing recruitment of bone marrow derived cells (BMDC) to the metastatic site. Overall, our findings have comprehensively revealed the clinical relevance, molecular regulations, and functional implications of LOXL2 in HCC metastasis.