Regulation of Macrophage Activation and Polarization by HCC-Derived Exosomal lncRNA TUC339

Abstract

Exosomes released by cells can serve as vehicles for delivery of biological materials and signals. Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nt, which roles are increasingly appreciated in various biological content. Tumor-derived exosomal lncRNAs have been implicated as signaling mediators to orchestrate cell function among neighbor tumor cells. However, the role of tumor-derived lncRNAs in cross-talk with environmental macrophages has yet to be explored. In this paper, we demonstrated that hepatocellular carcinoma (HCC) cells–derived exosomes contain elevated levels of lncRNA TUC339 and that HCC-derived exosomes could be taken up by THP-1 cells. In seeking to dissect the biological function of tumor secreting TUC339 in macrophages, we applied loss-of-function and gain-of-function strategies. We observed increased pro-inflammatory cytokine production, increased co-stimulatory molecule expression, and enhanced phagocytosis upon suppression of TUC339 by siRNA in THP-1 cells, and the opposite effect upon over-expression of this lncRNA, which indicates that TUC339 was involved in the regulation of macrophage activation. Moreover, we detected an elevated level of TUC339 in M(IL-4) macrophages as compared to M(IFN-γ + LPS) macrophages and a down-regulation of TUC339 expression during M(IL-4)-to-M(IFN-γ + LPS) repolarization and vice versa. Furthermore, suppression of TUC339 in macrophages diminished the expression of M(IL-4) markers upon IL-4 treatment while overexpression of TUC339 in macrophages enhanced M(IL-4) markers upon IFN-γ + LPS treatment, which suggests a critical function of TUC339 in the regulation of macrophage M1/M2 polarization. Lastly, using microarray analysis, we identified cytokine-cytokine receptor interaction, CXCR chemokine receptor binding, Toll-like receptor signaling, FcγR-mediated phagocytosis, regulation of the actin cytoskeleton, and cell proliferation are related with TUC339 function in macrophages. Our results provide evidence for a novel regulatory function of tumor-derived exosomal lncRNA TUC339 in environmental macrophages and shed light on the complicated interactions between tumor and immune cells through exosomal lncRNAs.

Long Non-coding RNAs: Emerging Roles in the Immunosuppressive Tumor Microenvironment

“…Exosomes are small membrane-bound vesicles that deliver a specific cargo of proteins and nucleic acids from the parent cells to the recipient cells. Several studies indicate that exosome-transmitted lncRNAs secreted from tumor cells can promote the immunosuppressive function of stromal cells, such as cancer associated fibroblasts and macrophages (37)(38)(39). Additionally, the phenomena that exosomes being delivered from immune cells to tumor cells or other kinds of immune cells are observed.…”

“…Tumor-derived exosomal lncRNAs have been indicated as signaling mediators that orchestrate the communications between tumor cells and macrophages in TME. Li et al demonstrated that hepatocellular carcinoma (HCC) cell-derived exosomes contained overexpressed TUC339 lncRNA, which may be taken up by the non-polarized THP-1 macrophages (37). Additionally, in vitro experiments suggested that TUC339 is majorly involved in macrophage polarization (37).…”

“…Li et al demonstrated that hepatocellular carcinoma (HCC) cell-derived exosomes contained overexpressed TUC339 lncRNA, which may be taken up by the non-polarized THP-1 macrophages (37). Additionally, in vitro experiments suggested that TUC339 is majorly involved in macrophage polarization (37). In addition to macrophages, the functions of Tregs and fibroblasts can also be regulated by lncRNAs from tumor cells in TME.…”

LncGBP9/miR-34a axis drives macrophages toward a phenotype conducive for spinal cord injury repair via STAT1/STAT6 and SOCS3

“…As we have mentioned, the deregulation and dysfunction of lncRNAs in the process of a proinflammatory (M1) to an anti-inflammatory phenotype (M2) have been observed [38,53]. In the present study, we attempted to identify lncRNAs related to the inappropriate activation of macrophage phenotypes (macrophage polarization) after SCI.…”

Exosomal long noncoding RNAs in aging and age‐related diseases

“…LncRNA TUC339 is enriched in HCC‐derived exosomes, regulating the M2 polarization of macrophages and reducing the phagocytic function of macrophages after their uptake by THP‐1 cells. Therefore, intercellular delivery of TUC339 by exosomes is one of the signaling mechanisms that promote the HCC growth . LncRNA H19 is enriched in CD90 + HCC cells and can be transferred by exosomes to ECs to stimulate endothelial angiogenesis by regulating the expression of vascular endothelial growth factor (VEGF) receptor 1 and VEGF.…”