Journal Article

Exosome-mediated secretion of LOXL4 promotes hepatocellular carcinoma cell invasion and metastasis

Li, Jun, Wang, Yahui, Fang, Fang, Zhang, Zhigang, Feng, Mingxuan, Jiang, Shuheng, Zhang, Xiaoxin, Xia, Qiang, Li, Rongkun, Ma, Jun, Yang, Xiaomei, Shang, Mingyi

2019

Overview

Background Lysyl 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. Methods LOXL4 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. Results LOXL4 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. Conclusions Taken 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Aged / Amines / Amino Acid Oxidoreductases - antagonists & inhibitors / Amino Acid Oxidoreductases - genetics / Amino Acid Oxidoreductases - metabolism / Angiogenesis / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer metastasis / Cancer Research / Carcinoma / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - mortality / Carcinoma, Hepatocellular - pathology / Cell adhesion & migration / Cell Line, Tumor / Cell migration / Cell Movement / Cell Proliferation / Clonal deletion / Collagen / Deletion mutant / Development and progression / Disease Progression / Endothelial cells / Endothelium / Epidermal growth factor / Exosomes / Exosomes - metabolism / Exosomes - pathology / Extracellular matrix / Female / Focal Adhesion Kinase 1 - genetics / Focal Adhesion Kinase 1 - metabolism / Gene Expression Regulation, Neoplastic / Hepatocellular carcinoma / Hepatocytes - metabolism / Hepatocytes - pathology / Human Umbilical Vein Endothelial Cells - cytology / Human Umbilical Vein Endothelial Cells - metabolism / Humans / Hydrogen peroxide / Hydrogen Peroxide - metabolism / Kinases / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - mortality / Liver Neoplasms - pathology / LOXL4 / Lymphatic Metastasis / Lysyl oxidase / Male / Medical prognosis / Medical schools / Metastases / Metastasis / Middle Aged / Milk / Neoplasm Staging / Neovascularization, Pathologic - genetics / Neovascularization, Pathologic - metabolism / Neovascularization, Pathologic - mortality / Neovascularization, Pathologic - pathology / Novels / Oncology / Oxidases / Paracrine Communication / Paracrine signalling / Peroxides / Phosphorylation / Proteins / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Roles / Secretion / Signal Transduction / src-Family Kinases - genetics / src-Family Kinases - metabolism / Studies / Survival Analysis / Tumors / Umbilical vein / Western blotting