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

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.Electronic supplementary materialThe online version of this article (10.1186/s12943-019-0948-8) contains supplementary material, which is available to authorized users.

Angiopoietin-2 induces angiogenesis via exosomes in human hepatocellular carcinoma

“…Accumulating evidence has indicated that HCCderived exosomes may play important roles in tumor angiogenesis by delivering microRNA, proteins and other cargoes to communicate with cells in TME and remold TME [34][35][36]. Here, we also found that HCC cellsecreted exosomes promoted the angiogenesis of HUVECs (Additional file 7: Figure S4).…”

Systemic Sclerosis Dermal Fibroblasts Induce Cutaneous Fibrosis Through Lysyl Oxidase–like 4: New Evidence From Three‐Dimensional Skin‐like Tissues

“…Substantial evidence, including that in this study, implicates LOXL4 as a target that contributes to both vascular and fibrotic processes associated with ECM synthesis and remodeling . Most recently, LOXL4 was found to promote cancer growth and metastasis by regulating cell cycle mediators . Therefore, antibody therapies directed against LOXL4 may not merely target antifibrotic pathways but may also modulate pathways associated with anti‐vasculopathic phenotypes, which regulate the proliferation and migration of endothelial cells.…”

Proteomic Analysis of Blood Exosomes from Healthy Females and Breast Cancer Patients Reveals an Association between Different Exosomal Bioactivity on Non-tumorigenic Epithelial Cell and Breast Cancer Cell Migration in Vitro

“…These vesicular structures are highly stable and are small enough to penetrate into and interact with different tissues. Exosomes are involved in key physiological processes such as cell-to-cell communications [3], proliferation [4], migration [5], invasion [6], angiogenesis [7], and tumor growth [8] through the horizontal transfer of RNA and proteins.…”