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Hypoxic TAM-derived exosomal miR-155-5p promotes RCC progression through HuR-dependent IGF1R/AKT/PI3K pathway

Wenyu Gu1, Linjing Gong2, Xu Wu3

  • 1Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

Cell Death Discovery
|June 16, 2021
PubMed

Insights

Hypoxic tumor-associated macrophages release exosomes containing miR-155-5p, which promote clear cell renal cell carcinoma (ccRCC) progression by enhancing IGF1R mRNA stability. This highlights a novel mechanism of cancer cell communication and potential therapeutic target.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Medicine

Background:

  • Hypoxic tumor-associated macrophages (TAMs) correlate with poor prognosis in clear cell renal cell carcinoma (ccRCC).
  • Exosomes mediate intercellular communication, influencing tumor progression and metastasis.
  • The role of hypoxic TAM-derived exosomes in ccRCC progression within the tumor microenvironment remains unclear.

Purpose of the Study:

  • To investigate the effect of hypoxic TAM-derived exosomes on ccRCC progression.
  • To elucidate the mechanism by which miR-155-5p within these exosomes promotes ccRCC.
  • To explore the therapeutic potential of targeting this exosome-mediated communication pathway.

Main Methods:

  • Gene Set Enrichment Analysis (GSE) and RT-qPCR to identify and quantify miR-155-5p in RCC.
  • Immunohistochemical staining to correlate miR-155-5p levels with TAM infiltration (CD163+) and HIF-1α expression.
  • In vitro and in vivo studies using exosomes purified from normoxic/hypoxic TAMs, with miR-155-5p inhibition, co-culture experiments, and xenograft models.
  • RNA immunoprecipitation (RIP) assays to determine the interaction between miR-155-5p and HuR.

Main Results:

  • miR-155-5p was upregulated in RCC and correlated with increased CD163+ TAM infiltration and HIF-1α expression.
  • Hypoxic TAM-derived exosomes transferred miR-155-5p, promoting ccRCC cell proliferation and migration.
  • miR-155-5p directly binds to HuR, stabilizing IGF1R mRNA and activating the IGF1R/PI3K/AKT signaling pathway.

Conclusions:

  • Exosomal transfer of miR-155-5p from hypoxic TAMs to ccRCC cells drives tumor progression.
  • This mechanism involves HuR-mediated stabilization of IGF1R mRNA, activating oncogenic signaling pathways.
  • Targeting exosomal miR-155-5p represents a potential therapeutic strategy for ccRCC.

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