Abstract
BackgroundLysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). However, the role of LOXL4 in HCC progression remains largely unclear. In this study, we investigated the clinical significance and biological involvement of LOXL4 in the progression of HCC.MethodsLOXL4 expression was measured in HCC tissues and cell lines. Overexpression, shRNA-mediated knockdown, recombinant human LOXL4 (rhLOXL4), and deletion mutants were applied to study the function of LOXL4 in HCC. Exosomes derived from HCC cell lines were assessed for the ability to promote cancer progression in standard assays. The effects of LOXL4 on the FAK/Src pathway were examined by western blotting.ResultsLOXL4 was commonly upregulated in HCC tissues and predicted a poor prognosis. Elevated LOXL4 was associated with tumor differentiation, vascular invasion, and tumor-node-metastasis (TNM) stage. Overexpression of LOXL4 promoted, whereas knockdown of LOXL4 inhibited cell migration and invasion of HCC in vitro, and overexpressed LOXL4 promoted intrahepatic and pulmonary metastases of HCC in vivo. Most interestingly, we found that HCC-derived exosomes transferred LOXL4 between HCC cells, and intracellular but not extracellular LOXL4 promoted cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. In addition, HCC-derived exosomes transferred LOXL4 to human umbilical vein endothelial cells (HUVECs) though a paracrine mechanism to promote angiogenesis.ConclusionsTaken together, our data demonstrate a novel function of LOXL4 in tumor metastasis mediated by exosomes through regulation of the FAK/Src pathway and angiogenesis in HCC.
Highlights
Lysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC)
In conclusion, to our knowledge, we showed for the first time that LOXL4 can be transferred between HCC cells with different expression levels of LOXL4 via exosomes and that intracellular LOXL4 promotes HCC motility and metastasis by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism; in addition, exosomes derived from HCC cells can transfer LOXL4 to human umbilical vein endothelial cells (HUVECs) to promote angiogenesis via maintaining cell survival, promoting cell migration, and inducing tube formation (Fig. 9)
These data provide substantial new evidence that LOXL4 is involved in cancer metastasis and indicate that LOXL4 may serve as a novel prognostic marker and therapeutic target for HCC
Summary
Lysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). We investigated the clinical significance and biological involvement of LOXL4 in the progression of HCC. Hepatocellular carcinoma (HCC), the main type of liver cancer, is one of the most common cancers and is a leading cause of cancer-related death worldwide [1]. Studying the mechanisms underlying HCC metastasis to provide opportunities to improve clinical outcomes and to develop better therapeutic regimens is urgently needed. The lysyl oxidase (LOX) family has five members, consisting of LOX and lysyl oxidase-like 1–4 (LOXL1–4). They were originally considered copper-dependent amine oxidase and catalyze peptidyl-lysine oxidation in
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