Circulating biomarkers in renal cell carcinoma: the link between microRNAs and extracellular vesicles, where are we now?

Abstract

Renal cell carcinoma (RCC) is a lethal urological cancer, with incidence and mortality rates increasing by 2-3% per decade. The lack of standard screening tests contributes to the fact that one-third of patients are diagnosed with locally invasive or metastatic disease. Moreover, 20-40% of RCC patients submitted to surgical nephrectomy will develop metastasis. MicroRNAs (miRNAs) are small non-coding RNAs responsible for gene regulation at a post-transcriptional level. It is accepted that they are deregulated in cancer and can influence tumor development. Thus, miRNAs are promising RCC biomarkers, since they can be detected using non-invasive methods. They are highly stable and easier to quantify in circulating biofluids. The elevated miRNA stability in circulating samples may be the consequence of their capacity to circulate inside of extracellular microvesicles (EMVs), for example, the exosomes. The EMVs are bilayered membrane vesicles secreted by all cell types. They can be released in the interstitial space or into circulating biofluids, which allows the travelling, binding and entrance of these vesicles in receptor cells. This type of cell communication can shuttle bioactive molecules between cells, allowing the horizontal transference of genetic material. In this review, we focus on circulating miRNAs (miR-210, miR-1233, miR-221, miR-15a, miR-451, miR-508, miR-378) in the biofluids of RCC patients and attempt to establish the diagnostic and prognostic accuracy, their synergic effects, and the pathways involved in RCC biology.

Tumor suppressor microRNA‑136‑5p regulates the cellular function of renal cell carcinoma

“…Transwell chamber inserts (BD Biosciences, Franklin Lakes, NJ, USA) with or without Matrigel (for invasion assays) were used. Serum-free medium (200 µl DMEM) containing ~1x10 4 transfected cells was seeded into upper chamber of the insert. Medium mixed with 10% FBS was added to the lower chamber of the inserts.…”

“…However, during early stage RCC there are typically no clear symptoms, making diagnosis difficult, and ~25-30% of patients with RCC are metastatic at diagnosis (3). At present, no standardized approaches to biomarker sampling or analysis have been adopted for RCC since the majority of the putative tumor markers themselves remain under active investigation for further validation (4). Reliable biomarkers have not yet been established for screening (2).…”

Plasmatic miR-210, miR-221 and miR-1233 profile: potential liquid biopsies candidates for renal cell carcinoma

“…These features allow their use in screening programs and the close monitoring of disease progression and treatment response, allowing earlier intervention and a dynamic treatment management [ 5 ]. Among the possible non-invasive biomarkers that have been studied in RCC, the ones that seem more promising are the microRNAs (miRNAs), since they can be detected using non-invasive procedures and are easier to quantify when compared to other molecules [ 6 ]. MiRNAs are small (18–24 nucleotides) non-coding RNAs that are responsible for the regulation of gene expression at a post-transcriptional level and have been widely studied in oncology since they are potent modulators of cellular behaviour and tumoral microenvironment [ 7 , 8 ].…”

“…Regarding circulating miRNAs in RCC, only a few have been suggested as potential biomarkers for diagnosis and/or prognosis [ 6 , 25 ]. Despite promising, the miRNAs were studied in small cohorts and few were replicated by other groups, which empathizes the need for more studies in order to replicate, validate and establish circulating miRNAs as RCC biomarkers [ 6 ]. Our aim in this study is the evaluation of the impact of plasma levels of miR-210, miR-218, miR-221 and miR-1233 in clinical endpoints and their association with clinicopathological characteristics of RCC patients.…”

microRNA‑181a‑5p functions as an oncogene in renal cell carcinoma

“…Renal cell carcinoma (RCC) is the 9th most common cancer diagnosis and cause of cancer-associated mortality, and accounts for 3% of all malignancies worldwide (1,2). Considering that, at present, there are no available biomarkers for RCC screening, ~30% of patients develop metastasis at the time of diagnosis, and 20-40% patients develop recurrence or metastases following initial surgical resection (3)(4)(5). Furthermore, RCC is insensitive to conventional chemotherapy and radiotherapy (6).…”