Abstract
Hypoxic tumor-associated macrophages (TAMs) are related to poor prognosis of patients with clear cell renal cell carcinoma (ccRCC). Exosomes are small lipid-bilayer vesicles that implicated in tumor progression and metastasis. However, whether hypoxic TAM-derived exosomes affect RCC progression within the hypoxic tumor microenvironment has not been elucidated. GSE analysis identified miR-155-5p was upregulated in RCC. Moreover, we quantified levels of miR-155-5p using RT-qPCR, performed immunohistochemical staining in 79 pairs of primary RCC specimens and related them to clinicopathological parameters. Higher miR-155-5p levels were related to more CD163 + TAM infiltration and elevated HIF-1a expression in our cohort. In the in vitro studies, we initially purified and characterized the exosomes from the supernatant of TAMs subjected to normoxia or hypoxia, and then transfected antagomiR-155-5p or control into these TAMs to produce corresponding exosomes. Gain and loss-of-function studies further investigated the effect of transferred hypoxic exosomal miR-155-5p on the cross-talk between TAMs and RCC cells in xenograft model and in vitro co-culture experiments. The results of RNA immunoprecipitation analyses elucidated that miR-155-5p could directly interact with human antigen R (HuR), thus increasing IGF1R mRNA stability. Mechanistically, hypoxic TAM-Exo transferred miR-155-5p promoted RCC progression partially through activating IGF1R/PI3K/AKT cascades. Taken together, transfer of miR-155-5p from hypoxic TAMs by exosomes to renal cancer cells explains the oncogenic manner, in which M2 macrophages confer the malignant phenotype to RCC cells by enhancing HuR-mediated mRNA stability of IGF1R.
Highlights
As the most prevalent and aggressive renal cell carcinoma (RCC) subtype, clear cell RCC is characterized by extreme chemo- and radio-resistance
We the presence of 100 ng/ml phorbol 12-myristate 13-acetate (PMA) performed qRT–qPCR to quantify the levels of miR-155-5p from 79 for 48 h incubation
Exosomal miR-155-5p facilitates the malignant phenotype of RCC cells by binding to human antigen R (HuR) To elucidate the putative mechanism by which tumor-associated macrophages (TAMs)-Exos and their transferred miR-155-5p regulated RCC cells functions, we found that miR-155-5p contains a binding site for HuR’s mRNA through bioinformatic analysis
Summary
As the most prevalent and aggressive renal cell carcinoma (RCC) subtype, clear cell RCC (ccRCC) is characterized by extreme chemo- and radio-resistance. Oxygen within the necrotic tumor-core becomes depleted, resulting in hypoxia and a higher intracellular level of hypoxia inducible factor (HIF-1α and HIF2α) through degradation of VHL [2]. Accumulating studies show that HIF-1α induction could facilitate the oncogenic effect of hypoxic condition on RCC angiogenesis and tumor growth by activation of AKT and VEGFR kinases [3]. The expression levels of HIF2α show positive correlation with increasing signs of cellular atypia, as well as conversion to RCC [5, 6], pointing to an important role for hypoxic microenvironment in RCC
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