Extracellular miR-224 as a prognostic marker for clear cell renal cell carcinoma

Abstract

Exosome-miRNAs (exo-miR) have recently been identified as modulators of cancer progression and distant metastasis. We previously found that intracellular miR-224 is up-regulated and significantly related to cancer invasion and metastasis in clear cell renal cell carcinoma (ccRCC). We therefore investigated the role of exosome miR-224 in ccRCC and explored the interaction between intra- and extracellular miR-224 in renal cell carcinoma. To validate the method for isolating exosomes from blood samples or cell culture media, we examined exosome morphology using transmission electron microscope (TEM). We investigated the relationship between exo-miR-224 expression and patient prognosis in 108 ccRCC patients. We isolated exosomes from a metastatic renal cancer cell line and tested their effects on a primary renal cancer cell line with several functional analyses. We found that the high expression level exo-miR-224 group has significantly shorter progression-free survival, cancer-specific survival, and overall survival compared with the low expression group. In multivariate analysis, a high level of exo-miR-224 was a significant risk factor related to all prognoses investigated. After adding exosomes from a metastatic RCC cell line to a primary RCC cell line, cell proliferation and invasion were increased while the percentage of apoptotic cells was significantly decreased. Intracellular levels of miR-224 were significantly up-regulated in the primary renal cancer cell line. Extracellular miR-224 in exosomes impacts on patient prognosis and is a potential prognostic biomarker for ccRCC patients.

Circulating Non-coding RNAs in Renal Cell Carcinoma—Pathogenesis and Potential Implications as Clinical Biomarkers

“…Functional experiments revealed an oncogenic role of miR-224 in RCC pathogenesis. Exosomes containing miR-224 from a metastatic RCC cell line that were added to a cell line of primary RCC enhanced proliferation and invasion and, moreover, increased the intracellular miR-224 levels in primary cell lines (Fujii et al, 2017). This indicates the importance of exosomal miRNAs in cancer progression (Fujii et al, 2017;Kulkarni et al, 2019).…”

MicroRNA‑663 inhibits the proliferation and invasion of clear cell renal cell carcinoma cells by directly targeting PAK4

“…An increasing number of previous studies have demonstrated that miRNAs are dysregulated in approximately all types of human malignancy, including ccRCC (13)(14)(15). miRNA (miR)-19a (16), miR-224 (17), miR-1274a (18) and miR-543 (19) were upregulated in ccRCC, whereas, miR-30a (20), miR-200a (21), miR-384 (22) and miR-411 (23) were downregulated. These aberrantly expressed miRNAs are implicated in the oncogenesis and progression of ccRCC, and regulate various crucial biological processes, including cell proliferation, apoptosis, metastasis and angiogenesis (13,24).…”

Roles for Exosome in Various Kidney Diseases and Disorders

“…Similarly, other more recent studies have reported that urinary exosomal miR-30c-5p and miR-204-5p might serve as the diagnostic markers for early-stage ccRCC (in a human study) and Xp11.2 translocation RCC (in a murine model), respectively (Kurahashi et al, 2019;Song et al, 2019). In addition, two consistent studies in humans have revealed that serum exosomal miR-224 and miR-210 could serve as the prognostic and diagnostic biomarkers for ccRCC (Fujii et al, 2017;Wang X. et al, 2019). Furthermore, serum exosomal miR-126-3p, miR-17-5p and miR-21-3p were decreased 1-day after cryoablation of RCC in a murine model and might be used as the biomarker for monitoring therapeutic outcome in RCC .…”