Downregulation of exosomal CLEC3B in hepatocellular carcinoma promotes metastasis and angiogenesis via AMPK and VEGF signals

Abstract

Background C-Type Lectin Domain Family 3 Member B (CLEC3B), is down-regulated in serum and tumor tissues in different cancers including hepatocellular carcinoma (HCC). However, the functions of CLEC3B in HCC remains elucidated. The aim of this study is to analyze the roles of CLEC3B in HCC. Methods The expression of genes was evaluated by immunohistochemistry, western blot, real-time PCR, enzyme-linked immunosorbent assays, and analysis on TCGA-LIHC database and gene expression omnibus. Transmission electron microscopy and immunofluorescence were applied to detect CLEC3B in exosomes. The function of exosomal CLEC3B in tumor progression were performed in vivo and in vitro. Results We determined that down-regulated CLEC3B in HCC indicated a poor prognosis. Exosomes derived from HCC with down-regulated CLEC3B promoted migration, invasion, epithelial–mesenchymal transition of both tumor cells and endothelial cells (ECs). Moreover, the downregulation CLEC3B in exosomes suppressed VEGF secretion in both HCC cells and ECs, and eventually inhibited angiogenesis. Mechanistically, CLEC3B-mediated VEGF expression in tumor cells and ECs depends on the activation of AMPK signal pathway. Conclusion This study demonstrates that CLEC3B acts as a novel independent prognostic factor, and CLEC3B in exosomes might be a potential therapeutic target for hepatocellular carcinoma. Graphical abstract Electronic supplementary material The online version of this article (10.1186/s12964-019-0423-6) contains supplementary material, which is available to authorized users.

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

“…C-type lectin domain family 3 member B (CLEC3B) encodes tetranectin, a plasminogen kringle-4-binding protein that is located in cell plasma, extracellular matrix and exosomes [8,9]. Tetranectin plays a role in extracellular proteolysis by inducing plasminogen activation, which is associated with tumor invasion and metastasis [8,[10][11][12][13].…”

“…C-type lectin domain family 3 member B (CLEC3B) encodes tetranectin, a plasminogen kringle-4-binding protein that is located in cell plasma, extracellular matrix and exosomes [8,9]. Tetranectin plays a role in extracellular proteolysis by inducing plasminogen activation, which is associated with tumor invasion and metastasis [8,[10][11][12][13]. Moreover, CLEC3B has been reported in multiple cancers, including hepatocellular carcinoma, ovarian cancer, and oral squamous cell carcinoma, but a large number of in-depth studies are still needed to elucidate the molecular mechanism and specific function of CLEC3B in cancer progression [8,[14][15][16][17][18][19].…”

“…So far, research on CLEC3B has been very limited. Dai W. et al reported that downregulation of exosomal CLEC3B in hepatocellular carcinoma promotes metastasis and angiogenesis via AMP-activated protein kinase and vascular endothelial growth factor signals [8]. Liu J et al reported that CLEC3B has an anti-proliferation function mediated by the mitogen-activated protein kinase pathway in clear cell renal cell carcinoma [15].…”

The landscape of mouse epididymal cells defined by the single-cell RNA-Seq

“…Consisting with GO analysis, all these genes were predominantly localized in the extracellular compartment according to the information from GeneCards (Stelzer G, 2016). In particularly, C-Type Lectin Domain Family 3 Member B (clec3b) was reported to control cell proliferation in clear cell renal cell carcinoma(Liu et al, 2018) as well as low clec3b in exosomes derived from HCC promoted cell migration, invasion and epithelial–mesenchymal transition(Dai et al, 2019), indicating its contribution to the maintenance of epididymal epithelium. Recent study found that Gelsolin (Gsn) was the major secreted protein in the distal region of the bovine epididymis(Belleannee et al, 2011; Dacheux and Dacheux, 2014).…”

Re-clustering and profiling of digestive system tumors according to microenvironment components

“…While the tumors were often founded when the symptoms are obvious, unfortunately, it is often in the malignant advanced stage at this period. On the other hand, the metastasis and recurrent trait of digestive system tumors makes it di cult for conventional treatment programs to exert maximum effectiveness [4][5][6][7][8].…”