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

• Published in: International journal of molecular sciences Vol. 19; no. 10; p. 2958
• Main Authors: Li, Xue, Lei, Yi, Wu, Miao, Li, Nan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 28-09-2018; MDPI AG
• Subjects: Cell Line, Tumor; Cell Polarity; Cell Survival; Cytokines - biosynthesis; Endocytosis; exosomes; Exosomes - metabolism; Exosomes - ultrastructure; Gene Knockdown Techniques; Humans; inflammation; Inflammation Mediators - metabolism; Interleukin-4 - metabolism; Liver Neoplasms - genetics; lncRNA; macrophage; Macrophage Activation - genetics; Phagocytosis; Phenotype; polarization; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Transcriptome - genetics; macrophage; polarization; lncRNA; inflammation; exosomes
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms19102958

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.