Exosomal AP000439.2 from clear cell renal cell carcinoma induces M2 macrophage polarization to promote tumor progression through activation of STAT3

Cell Commun Signal. 2022 Sep 24;20(1):152. doi: 10.1186/s12964-022-00957-6.


Background: Tumorigenic phenotype of M2 tumor-associated macrophages promote tumor progression in response to exosomes cues imposed by tumor cells. However, the effect and underlying mechanisms of clear cell renal cell carcinoma (ccRCC)-derived exosomes (ccRCC-exo) on instructing macrophages phenotype remains unclear.

Methods: Macrophages were cocultured with ccRCC-exo and then evaluate the polarization of macrophages and migration of ccRCC cells. The effect and mechanism of lncRNA AP000439.2 overexpressed or deleted exosomes on macrophages M2 polarization were examined. Xenograft tumor mice model was used for in vivo validation.

Results: The ccRCC-exo significantly activated macrophages to M2 phenotype presented by increased expression of transforming growth factor-beta (TGF-β) and interleukin 10 (IL-10) at mRNA and protein levels, and these M2 macrophages in turn facilitating the migration of ccRCC cells. LncRNA AP000439.2 was highly enriched in the ccRCC-exo. Overexpression of exosomal AP000439.2 promoted M2 macrophage polarization whereas AP000439.2-deficient exosome had the opposite effects. Nuclear-localized AP000439.2 directly interacted with signal transducer and activator of transcription 3 (STAT3) proteins and phosphorylated STAT3 in macrophages. RNA-Seq results showed overexpression of AP000439.2 activated NF-κB signaling pathway. Silencing of STAT3 suppressed overexpression of AP000439.2-induced up-regulation of TGF-β and IL-10 expression, and p65 phosphorylation. AP000439.2-deleted exosome inhibited tumor growth in vivo.

Conclusion: Exosomes from ccRCC deliver AP000439.2 to promote M2 macrophage polarization via STAT3, thus enhancing ccRCC progression, indicating exosomal AP000439.2 might be a novel therapeutic target in ccRCC. Video Abstract.

Keywords: Clear cell renal cell carcinoma; Exosomes; Macrophage; NF-κB signaling pathway; STAT3; lncRNA AP000439.2.

Publication types

  • Video-Audio Media
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Renal Cell* / pathology
  • Cell Line, Tumor
  • Exosomes* / metabolism
  • Humans
  • Interleukin-10 / metabolism
  • Kidney Neoplasms* / metabolism
  • Macrophage Activation / genetics
  • Macrophages / metabolism
  • Mice
  • MicroRNAs* / genetics
  • NF-kappa B / metabolism
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • RNA, Messenger / metabolism
  • STAT3 Transcription Factor / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factors / metabolism


  • MicroRNAs
  • NF-kappa B
  • RNA, Long Noncoding
  • RNA, Messenger
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transforming Growth Factor beta
  • Interleukin-10
  • Transforming Growth Factors