The tumor microenvironment facilitates tumor occurrence and progression [
1]. An increasing number of studies have confirmed that extracellular vesicles carry functional cargoes, such as RNA, proteins, and lipids, which play pivotal roles in cell-to-cell communication [
2‐
6]. It is clear that a large number of extracellular vesicles are released during the occurrence and development of hepatocellular carcinoma (HCC) to participate in tumor progression and metastasis [
7‐
9], but the mechanism of extracellular vesicle secretion much remains unclear. Researchers have studied the generation and secretion of extracellular vesicles, trying to explain the specific mechanism of exosome secretion [
6,
10]. Our published review confirmed that the process of exosome secretion mainly involves the multivesicular body (MVB) biogenesis, intraluminal vesicle (ILV) formation, sorting of different cargoes, and the regulation of cargo fate [
5]. Specifically, cell membrane endocytosis generates early endosomes, which then internalize and form ILVs via endosomal sorting complex required for transport (ESCRT), which includes HRS, STAM1, TSG101 ALIX, VPS4, and VPS33B to form mature MVBs [
11]. It is important that MVBs can target lysosomes for content degradation or target the plasma membrane for exosome release [
5]. Current research reveals that MVB-targeted transport involves small GTPases and their complexes in combination with different molecular motor proteins and the microtubule cytoskeleton. Centrifugal and centripetal transport through the traction of the cytoskeleton is a key step in the regulation of MVB fate [
5,
12]. Importantly, 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‐
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]. The goal is to extensively study the SNARE proteins involved in exosome docking and fusion, including Syntaxin-4, VAMP3, VAMP7, VAMP8, YKT6, SYX5, SNAP23 and SNAP25 [
5,
17]. Among them, VAMP3, YKT6, and SNAP23 play key roles in tumorigenesis and in regulating exosome release [
16,
18]. For example, a study showed that pyruvate kinase type M2 promotes exosome release from tumor cells by phosphorylating SNAP23 [
18]. Our previous work showed that HOTAIR promotes the colocalization of VAMP3 with SNAP23, which influences SNARE complex formation, leading to MVB fusion with the plasma membrane [
16]. Mounting evidences have confirmed that the docking and fusion of MVBs is a complex process in which the RAB protein and SM protein are also involved.
Note that the metastasis of tumor cells is an important sign of tumor deterioration. Tumor cells can not only release exosomes to reorganize the extracellular matrix but also secrete MMP (membrane matrix metalloproteinase) and other metalloenzymes to facilitate migration and invasion [
19‐
21]. Invadopodia, which are specialized F-actin-based structures, play a key role in the process of tumor metastasis [
20‐
22]. Several studies have shown that invadopodia are critical docking and secretion sites for MVBs and significantly induce the secretion of exosomes and MMPs to induce tumor invasion and metastasis [
5,
21]. Interestingly, previous studies have revealed that the SNARE complex is involved in invadopodia formation, which indirectly affects the exosome secretion, indicating that there may be a positive feedback mechanism involving the SNARE complex and invadopodia [
5,
23]. MiR-612 can regulate tumor metastasis and progression, probably resulting in abnormities in invadopodia structure and function in HCC [
24]. The abundance of SNX27 plays an important role in the assembly of recycled MT1-MMP to invadopodia and further promotes breast cancer metastasis [
22].
However, few studies have revealed the mechanism by which the abnormal expression of lncRNAs affects exosome secretion in tumor cells. LINC00511 has been widely confirmed to be an oncogene, is abnormally expressed in many tumors and induces the malignant biological behaviour of cancer cells [
25‐
27]. However, the relationship between LINC00511, and exosome secretion and the invadopodia formation in HCC has not yet been studied. Our study first confirmed that the abnormal expression of LINC00511 promotes exosome secretion. Furthermore, we confirmed that LINC00511 induces the generation and distribution of MVBs. Interestingly, we found that LINC00511 dramatically regulates the expression of RAB27B and the colocalization of VAMP7 and SNAP23, which are involved in MVB trafficking and fusion with the plasma membrane, respectively. Importantly, LINC00511 induces the formation of invadopodia by inducing MVB docking and exosome secretion and accelerates the effect of LINC00511 on the invasion and progression of HCC. In conclusion, our study showed that LINC00511 induces the release of exosomes and the formation of aggressive invadopodia in HCC cells, which may provide a new perspective for the study of tumor progression.