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Abstract
miRNAs are abundant classes of small, endogenous non-coding RNAs, which inhibit the expression of target gene via post-transcriptional regulation. In addition to an important functional role miRNAs play in carcinogenesis, emerging evidence has demonstrated their feasibility as robust cancer biomarkers. In particular, the recent discovery of miRNAs in the body fluids provides an attractive opportunity for the development of non-invasive biomarkers for the diagnosis, prognosis and predictive response to cancer therapy. Colorectal cancer (CRC) is one of the most common cancers worldwide, and accumulating data provides a compelling case for the potential exploitation of miRNAs as CRC-biomarkers. This review summarizes the current state of literature in the field, focusing on the clinical relevance of miRNAs as potential biomarkers for CRC treatment and discussing the forthcoming challenges to further advance this exciting field of ‘academic research’ into ‘bedside clinical care’ of patients suffering from CRC.
Financial & competing interests disclosure
The present work was supported by grants R01 CA72851, CA181572 and CA184792 from the National Cancer Institute, National Institutes of Health, a pilot grant from the Charles A Sammons Cancer Center, and funds from the Baylor Research Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
miRNAs are a class of small, single-stranded, noncoding RNAs, and ever since their initial discovery in 1993, enough evidence has been gathered that implicates their role in cancer pathogenesis due to their ability to post-transcriptionally regulate the expression of various oncogenes and tumor suppressor genes.
Dysregulated expression of many miRNAs regulates the expression of hundreds of growth regulatory genes and pathways that are critical in the multistep model of colorectal carcinogenesis and other human cancers.
Since the recognition that miRNA expression is stable, immune to RNase-mediated degradation, has allowed exploration of these molecular entities in a variety of biological fluids including archival tissues for biomarker studies.
Early diagnosis, including detection of premalignant adenomas, is considered as a key concept for improving patient survival in colorectal cancer (CRC) treatment. Emerging evidence suggests promising potential of miRNAs (miR-21, miR-92a, miR-106a, etc.) as potential noninvasive biomarkers for noninvasive screening in blood (plasma/serum) and fecal specimens.
In stage II CRCs, surgical resection is highly effective; hence treating all patients with stage II CRC with adjuvant chemotherapy is still debatable. However, a significant proportion of stage II CRC patients develop recurrence and the identification of sensitive miRNA biomarkers in such high-risk populations is of key importance.
Early detection of distant metastasis and selective criteria regarding which individuals would benefit most from invasive treatments is essential for improving long-term survival. Several lines of research suggest that miRNAs are intimately involved in the metastatic process in CRC and some of these miRNAs could be used as promising clinical tools for identifying patients with micro-metastasis who will require intensive monitoring after surgery.
Despite the progress of treatment options for advanced CRC during the last decade, major obstacle is intrinsic and acquired resistance to chemotherapy and/or radiotherapy, necessitating the need to develop predictive biomarkers for response to such therapeutic treatments to facilitate personalized treatment of CRC patients. Several studies have identified alterations in miRNA expression (miR-21, miR-145, miR-148, etc.), which could provide crucial additional information on patient’s sensitivity to chemotherapy before starting the therapy, and in supporting development of novel therapeutic strategies for enhancing the sensitivity to chemotherapeutic treatments.
Although miRNA biomarker studies have grown dramatically in numbers in the last few years, future prospective studies are essential in addressing limitations of retrospective trials, as we usher into the next era of miRNA biomarkers that are optimal for clinical practice.