Abstract
An early cancer diagnosis is essential to treat and manage patients, but it is difficult to achieve this goal due to the still too low specificity and sensitivity of classical methods (imaging, actual biomarkers), together with the high invasiveness of tissue biopsies. The discovery of novel, reliable, and easily collectable cancer markers is a topic of interest, with human biofluids, especially blood, as important sources of minimal invasive biomarkers such as circulating microRNAs (miRNAs), the most promising. MiRNAs are small non-coding RNAs and known epigenetic modulators of gene expression, with specific roles in cancer development/progression, which are next to be implemented in the clinical routine as biomarkers for early diagnosis and the efficient monitoring of tumor progression and treatment response. Unfortunately, several issues regarding their validation process are still to be resolved. In this review, updated findings specifically focused on the clinical relevance of circulating miRNAs as prognostic and diagnostic biomarkers for the most prevalent cancer types (breast, lung, and prostate cancers in adults, and osteosarcoma in children) are described. In addition, deep analysis of pre-analytical, analytical, and post-analytical issues still affecting the circulation of miRNAs’ validation process and routine implementation is included.
Highlights
Cancer represents a significant global cause of death, so early diagnosis with a constant checkup of disease progression and patient response to chemotherapy and surgery are essential to efficiently manage subjects with cancer
MiR-122 is elevated in 70% of hepatocellular carcinoma (HCC) cases, but it is increased in case of hepatitis B infection or liver injury [291] and it fluctuates in response to therapy in chronic hepatitis C [292]
Given the biological variability of circulating miRNA and the plethora of variables affecting their levels, the current evidence suggests that miRNAs may not yet be usable as universal markers for response to chemotherapy [293]
Summary
Cancer represents a significant global cause of death, so early diagnosis with a constant checkup of disease progression and patient response to chemotherapy and surgery are essential to efficiently manage subjects with cancer. Tissue biopsies have been considered one of the most valuable methods for cancer diagnosis, but they are an invasive procedure To overcome these limits, great efforts have been made in the past few years to find novel, minimally invasive, fast, reproducible, and low-cost techniques for cancer management, such as circulating biomarkers in human biofluids (i.e., blood and derived plasma or serum). In the nucleus, miRNAs are transcribed and processed into a hairpin precursor (pre-miRNA), by the DROSHA–DGCR8 complex, which is translocated into the cytoplasm and cleaved by DICER obtaining, a double-stranded miRNA Both strands are, or only one strand is, selected for incorporation into the RNA-induced silencing complex (RISC) to act as mature miRNAs and, to bind the “seed” region of the target mRNA. MiRNA biogenesis and functions can be affected by: (i) epigenetic modifications, (ii) alteration in protein activity involved in this process [13,14,15,16], (iii) single nucleotide polymorphisms (SNPs) in miRNA genes [17,18], (iv) hereditary mutations in the miRNA seed region [19,20,21]; (v) somatic mutation in miRNA genes [22,23], and (vi) somatic copy-number variation of miRNA genes [24]
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