Exosomal MicroRNAs Are Diagnostic Biomarkers and Can Mediate Cell–Cell Communication in Renal Cell Carcinoma

Butz, Henriett; Nofech‐Mozes, Roy; Ding, Qiang; Khella, Heba; Szabó, Péter M.; Jewett, Michael A.S.; Finelli, Antonio; Lee, Jason; Ordon, Michael; Stewart, Robert; Krylov, Sergey N.; Yousef, George M.

doi:10.1016/j.euf.2015.11.006

Cited by 117 publications

(110 citation statements)

References 28 publications

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“…To date, several miRNA species have been proposed as having diagnostic and prognostic value in renal cell carcinoma, where either as solitary biomarkers or as part of a diagnostic panel, they appear able to distinguish clear cell renal cell carcinoma (ccRCC) patients from healthy controls and benign renal tumors from malignant ones (6). Most of these panels have been developed from serum samples (7)(8)(9)(10)(11), but two recent studies have focused on urine specimens as a source of diagnostic information (12,13). Urinary miRNAs are particularly attractive as RCC biomarkers since urine can be sampled frequently by non-invasive means.…”

Section: Introductionmentioning

confidence: 99%

Comparison of exosomal microRNAs secreted by 786‑O clear cell renal carcinoma cells and HK‑2 proximal tubule‑derived cells in culture identifies microRNA‑205 as a potential biomarker of clear cell renal carcinoma

2018

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Previous reports have indicated that the abundance of specific microRNAs (miRNA) contained within the exosome/microvesicle compartment of patient biofluids may be useful in diagnosing specific types of cancer. In the present study, the 786-O cell line, which is derived from a clear cell renal cell carcinoma (ccRCC), was used as an ccRCC tumor model and the human renal proximal tubule cell line HK-2 was used as its normal renal tissue control to investigate the similarities of exosomal content of selected ccRCC miRNA biomarkers in the supernatant with the content of those markers in the cells themselves. A PCR array identified miRNA biomarkers of solid RCC tumors (miR-210, MiR-34a, miR-155-5p and miR-150-5p) that were increased by 2-8 fold in 786-O exosomes compared with the control. These were subsequently chosen for further investigation using TaqMan RT-qPCR in addition to miR-15a and miR-205, which were selected based on prior interest as RCC biomarkers. MiR-15a, -34a, -210 and -155 levels were significantly lower in exosomes when compared with that in whole cells but did not differ between the HK-2 and 786-O cells in either the cytoplasmic, exosome or exosome-free supernatant fractions. By contrast, cytoplasmic miR-150 and miR-205 exhibited significant differences in concentration between the two cell lines. In addition, the cytoplasmic content of miR-150 and miR-205 was mirrored in the exosomal content of these miRNAs. Furthermore, the difference in exosomal miR-205 content was statistically significant. The present study indicated that measurements of the exosomal content of miR-205 and possibly miR-150, but not those of the other examined miRNAs, are proportional to their respective contents in the cells that secreted them. These findings suggest that RCC systems may be useful in identifying miRNAs with sufficiently high levels of exportation into exosomes; and with sufficiently different expression levels between tumor and normal cells to serve as ccRCC biomarkers .

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Section: Introductionmentioning

confidence: 99%

Comparison of exosomal microRNAs secreted by 786‑O clear cell renal carcinoma cells and HK‑2 proximal tubule‑derived cells in culture identifies microRNA‑205 as a potential biomarker of clear cell renal carcinoma

2018

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“…However, the majority of exosomal biomarker studies in RCC had focused on miRNAs. A study on urinary exosomes had shown that exosomal miR-126-3p combined with miR-449a or miR-34b-5p could discriminate ccRCC from healthy individuals (Butz et al, 2016). Moreover, urinary exosomal miR-126-3p combined with miR-486-5p could discriminate ccRCC from benign lesions (Butz et al, 2016).…”

Section: Renal Cell Carcinomamentioning

confidence: 99%

“…A study on urinary exosomes had shown that exosomal miR-126-3p combined with miR-449a or miR-34b-5p could discriminate ccRCC from healthy individuals (Butz et al, 2016). Moreover, urinary exosomal miR-126-3p combined with miR-486-5p could discriminate ccRCC from benign lesions (Butz et al, 2016). 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).…”

Section: Renal Cell Carcinomamentioning

confidence: 99%

Roles for Exosome in Various Kidney Diseases and Disorders

Thongboonkerd

2020

Front. Pharmacol.

104

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“…Recently, several additional studies were published, which also analysed miRNA of RCC in the urine, with no known direct correlation to endothelin. Butz et al [2016] (Table 2) analysed a preoperative sample, and subsequently a larger cohort (81 ccRCC patients, 24 patients with benign lesions, and 33 healthy participants) for both cell-free and exosomal miRNAs. They needed a combination of two miRNAs (miRNA-126-3p plus miRNA-449a or plus miRNA-34b-5p) for a significant differentiation.…”

Section: Renal Tumours Express Endothelin-mediated Mirnas Detectable mentioning

confidence: 99%

MicroRNAs as markers to monitor endothelin‐1 signalling and potential treatment in renal disease: Carcinoma − proteinuric damage − toxicity

Fries¹

2019

Biology of the Cell

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This review highlights new developments in miRNA as diagnostic and surveillance tools in diseases damaging the renal proximal tubule mediated by endothelin in the field of renal carcinoma, proteinuric kidney disease and tubulotoxicity. A new mechanism in the miRNA regulation of proteins leads to the binding of the miRNA directly to the DNA with premature transcriptional termination and hence the formation of truncated protein isoforms (Mxi2, Vim3). These isoforms are mediated through miRNA15a or miRNA 498, respectively. ET‐1 can activate a cytoplasmic complex consisting of NF‐κB p65, MAPK p38α, and PKCα. Consequently, PKCα does not transmigrate into the nucleus, which leads to the loss of suppression of a primiRNA15a, maturation of this miRNA in the cytoplasm, tubular secretion and detectability in the urine. This mechanism has been shown in renal cell carcinoma and in proteinuric disease as a biomarker for the activation of the signalling pathway. Similarly, ET‐1 induced miRNA 498 transmigrates into the nucleus to form the truncated protein Vim3, which is a biomarker for the benign renal cell tumour, oncocytoma. In tubulotoxicity, ET‐1 induced miRNa133a down‐regulating multiple‐drug‐resistant related protein‐2, relevant for proteinuric and cisplatin/cyclosporine A toxicity. Current advantages and limitations of miRNAs as urinary biomarkers are discussed.

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Exosomal MicroRNAs Are Diagnostic Biomarkers and Can Mediate Cell–Cell Communication in Renal Cell Carcinoma

Cited by 117 publications

References 28 publications

Comparison of exosomal microRNAs secreted by 786‑O clear cell renal carcinoma cells and HK‑2 proximal tubule‑derived cells in culture identifies microRNA‑205 as a potential biomarker of clear cell renal carcinoma

Comparison of exosomal microRNAs secreted by 786‑O clear cell renal carcinoma cells and HK‑2 proximal tubule‑derived cells in culture identifies microRNA‑205 as a potential biomarker of clear cell renal carcinoma

Roles for Exosome in Various Kidney Diseases and Disorders

MicroRNAs as markers to monitor endothelin‐1 signalling and potential treatment in renal disease: Carcinoma − proteinuric damage − toxicity

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