Extracellular MicroRNAs as Intercellular Mediators and Noninvasive Biomarkers of Cancer

Abstract

MicroRNAs (miRNAs) are released by different types of cells through highly regulated mechanisms under normal and pathological conditions. These extracellular miRNAs can be delivered into recipient cells for functional purposes, acting as cell-to-cell signaling mediators. It has been discovered that cancer cells release miRNAs into their surroundings, targeting normal cells or other cancer cells, presumably to promote tumor development and progression. These extracellular miRNAs are associated with oncogenic mechanisms and, because they can be quantified in blood and other bodily fluids, may be suitable noninvasive biomarkers for cancer detection. This review summarizes recent evidence of the role of extracellular miRNAs as intercellular mediators, with an emphasis on their role in the mechanisms of tumor development and progression and their potential value as biomarkers in solid tumors. It also highlights the biological characteristics of extracellular miRNAs that enable them to function as regulators of gene expression, such as biogenesis, gene silencing mechanisms, subcellular compartmentalization, and the functions and mechanisms of release.

MicroRNA‑1301‑3p promotes the progression of non‑small cell lung cancer by targeting Thy‑1 and predicts poor prognosis of patients

“…The clinical outcome of NSCLC remains unsatisfactory due to the high metastasis and recurrence rates ( 4 ). It is well-known that miRNAs play important roles in the progression and development of several diseases, including cancers ( 21 – 23 ). For example, miR4766-5p, miR-1915-3p and miR-615-3p are associated with tumor development in gastric cancer ( 24 – 26 ).…”

Circulating MicroRNAs in Blood and Other Body Fluids as Biomarkers for Diagnosis, Prognosis, and Therapy Response in Lung Cancer

“…In 2007, miRNAs were reported to be released by cells into the extracellular space, and these cell-free miRNAs are transferable and functional in recipient cells [ 38 , 39 ]. Cell-free miRNAs can be released and uptaken by cells through vesicle trafficking and protein carrier mechanisms, and they are able to function as gene expression regulators in cell-to-cell communication mechanisms under normal and pathological conditions, such as cancer [ 10 , 14 , 38 , 39 , 40 ].…”

“…Since these initial studies, levels of circulating miRNAs in the plasma and serum of healthy individuals were found to be constant [ 8 , 59 ], whereas the levels in cancer patients (including lung cancer) are altered. These altered miRNAs could be used to distinguish cancer patients from healthy individuals, prompting the search for miRNAs that may be used as non-invasive biomarkers for diagnosis and prognosis [ 8 , 9 , 10 , 14 ].…”

“…The processing and quantification of circulating miRNAs face specific challenges related to their pre-analytical variables, which include the use of an efficient RNA extraction method, an efficient method for cDNA synthesis, verification of the sample quality (presence of hemolysis), verification of the RNA extraction quality using spike-in methods, and the use of proper normalizers [ 14 , 73 , 74 ]. Because miRNAs are present at very low levels in body fluids, small variations in these pre-analytical variables may significantly alter the analysis of circulating miRNA levels [ 14 ].…”

“…Furthermore, it was discovered that cell-free miRNAs are released by tumor cells into the extracellular space and delivered into recipient cells in the tumor microenvironment, where they function as regulators of gene expression. As is the case with their counterpart, endogenous miRNAs, cell-free miRNAs have been associated with cancer-related processes such as metastasis, epithelial–mesenchymal transition (EMT), angiogenesis, and evasion of immune response, as part of a cell-to-cell communication mechanism in cancer [ 14 ].…”