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

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.

HuR drives lung fibroblast differentiation but not metabolic reprogramming in response to TGF-β and hypoxia

“…Alterations in translation control occur in the context of IPF [ 36 ] and one cellular pathway implicated in cellular protein synthesis is the PI3K/Akt/mTORC1 signal transduction pathway [ 37 ]; this pathway is also involved in metabolism [ 38 ]. Recent evidence points to an indirect role for HuR in regulating components of this pathway in hypoxic cells [ 39 ]. Although not evaluated in this study, it could be that HuR fine-tunes translation control via the PI3K/Akt/mTORC1, and thus account for the discrepancy between mRNA and protein expression caused by combined exposure to hypoxia and TGF-β.…”

Hypoxia Induced Changes of Exosome Cargo and Subsequent Biological Effects

“…MiR-155-5p was found to be upregulated in RCC specimens and hypoxia promoted its selective enrichment in exosomes secreted by hypoxic tumor-associated macrophages (TAM). The exosomes transferred miR-155-5p to RCC and promoted the tumor progression partially through activating IGF1R/PI3K/AKT cascades ( 71 ). lncHILAR was also reported to be secreted by hypoxic cancer cells and transferred to normoxic cancer cells through exosomes to activate the miR-613/206/1-1-3p/Jagged-1/Notch/CXCR4 axis, thereby promoting cell invasion and metastasis ( 69 ).…”

Extracellular Vesicles in Redox Signaling and Metabolic Regulation in Chronic Kidney Disease

“…For example, miRNA-155-5p expression is increased in NRK-52E cell cultures, kidneys from experimental models of DN, and even plasma from patients with CKD [ 54 , 55 ]. MiRNA-155-5 in pathological conditions is found inside of exosomes [ 179 ], and its inhibition showed beneficial effects by reducing fibrosis and promoting autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway [ 54 ].…”