LINC00511 drives invasive behavior in hepatocellular carcinoma by regulating exosome secretion and invadopodia formation

Xueqiang Peng,Bo Wu,Xinyu Li,Jingang Liu,Hangyu Li,Shuo Yang,Shibo Wei,Qing Fan,Yan Li,Hongyuan Jin,Yingbo Ma,Mingyao Huang,Liang Yang,Shilei Tang,Bowen Li

doi:10.1186/s13046-021-01990-y

Abstract

BackgroundTumor cells are known to release large numbers of exosomes containing active substances that participate in cancer progression. Abnormally expressed long noncoding RNAs (lncRNAs) have been confirmed to regulate multiple processes associated with tumor progression. However, the mechanism by which lncRNAs affect exosome secretion remains unclear.MethodsThe underlying mechanisms of long noncoding RNA LINC00511 (LINC00511) regulation of multivesicular body (MVB) trafficking, exosome secretion, invadopodia formation, and tumor invasion were determined through gene set enrichment analysis (GSEA), immunoblotting, nanoparticle tracking analysis, confocal colocalization analysis, electron microscopy, and invasion experiments.ResultsWe revealed that the tumorigenesis process is associated with a significant increase in vesicle secretion in hepatocellular carcinoma (HCC). Additionally, LINC00511 was significantly more highly expressed in HCC tissues and is related to vesicle trafficking and MVB distribution. We also found that in addition to the formation of invadopodia in HCC progression, abnormal LINC00511 induces invadopodia formation in HCC cells by regulating the colocalization of vesicle associated membrane protein 7 (VAMP7) and synaptosome associated protein 23 (SNAP23) to induce the invadopodia formation, which are key secretion sites for MVBs and control exosome secretion. Finally, we revealed that LINC0051-induced invadopodia and exosome secretion were involved in tumor progression.ConclusionsOur experiments revealed novel findings on the relationship between LINC00511 dysregulation in HCC and invadopodia production and exosome secretion. This is a novel mechanism by which LINC00511 regulates invadopodia biogenesis and exosome secretion to further promote cancer progression.

Highlights

Tumor cells are known to release large numbers of exosomes containing active substances that participate in cancer progression
To clarify the link between LINC00511 and the secretion of exosomes in hepatocellular carcinoma (HCC), we first examined LINC00511 expression in HCC tissue samples through the The Cancer Genome Atlas (TCGA) database, and the results showed that LINC00511 was significantly expressed in HCC tissues (Fig. 1a)
The results we obtained through the GEPIA database on the LINC00511 expression in HCC, HCC stage and prognosis were consistent with those obtained through the TCGA database (Supplementary Fig. 1a-c)

Summary

Introduction

Tumor cells are known to release large numbers of exosomes containing active substances that participate in cancer progression. Small GTPases (RAB27A, RAB27B, RAB35, RAB11, RAB7, and RAL-1) play well-established roles in MVB trafficking for exosome release [5, 6, 12, 13] These key proteins may undergo mutations and abnormal expression during tumorigenesis and development, which may regulate abnormal exosome secretion and play a role in tumorigenesis and metastasis [5, 12,13,14,15]. The final key step in achieving exosome secretion involves the formation of SNARE complex intermediates (SNAREpins) to complete MVB docking and plasma membrane fusion [5, 16, 17]. Mounting evidences have confirmed that the docking and fusion of MVBs is a complex process in which the RAB protein and SM protein are involved

Methods

Results

Conclusion