ReviewMicroRNAs as novel biomarkers for colorectal cancer: New outlooks
Introduction
Colorectal Cancer (CRC) is the third most prevalent malignancy after lung and breast cancer all over the world, especially in developed countries [1]. In many areas of the world, incidence rates of CRC are rapidly increasing. Prevalence and mortality rates of CRC have been estimated as high as 1,200,000 and 600,000 cases/year respectively [2]. In spite of diagnosing and treatment of this cancer, patients’ survival is vastly correlated with tumor stage at the time of diagnosis and 40–50% of patients die due to distant metastasis [3], [4]. Genetic and epigenetic alterations can dysregulate tumor suppressor genes and oncogenes in CRC [5].
MicroRNAs are a class of 21–25 nucleotide non-coding RNAs known to post-transcriptionally regulate gene expression and control different biological mechanisms such as activation of immune system and inflammatory responses, regulation of cholesterol homeostasis, osteogenesis regulation, etc. [6], [7], [8], [9]. Affecting oncogenes and/or tumor suppressor genes, Dysregulated miRNAs are implicated in the pathogenesis of CRC [10]. Since, the expression patterns of miRNAs are different in tumor tissues and body fluids such as plasma, serum, urine, saliva, etc. [6]. in comparison with normal controls; thus miRNAs are classified as oncomiR and tumor suppressor miRNA and numerous of them can be used as diagnostic, prognostic and predictive biomarkers of CRC [11], [12]. Furthermore, different studies have demonstrated that miRNAs are highly potential molecules to be utilized as therapeutic agents in CRC therapy [10]. Given these, interventions such as inhibition of oncomiRs and restoration of tumor suppressor microRNAs, might be beneficial for CRC treatment [12].
In this review, we summarize new outlooks of miRNAs on the issue of their functioning as oncomiRs or tumor suppressors in CRC through upregulation and downregulation of target genes with accentuating their targets, different molecular mechanisms, and significance of their application as a novel target in CRC diagnosis, prognosis and potential treatment.
Section snippets
Biogenesis of miRNA
Involving several enzymes and diverse cellular compartments, biogenesis of miRNAs is a complex multipart process with different phases [13]. Primarily, the process starts in the nucleus where miRNA genes are transcripted by RNA Polymerase II and primary miRNAs with variable length (1–3 kb) in the stem-loop form are resulted [14], [15]. Through next step in the nucleus, DROSHA and its cofactor DGCR8 cleave the stem-loop structures into short 70 nucleotide precursor-miRNAs (pre-miRNA), which will
General features of miRNA
MicroRNAs (miRNAs) are a family of small, evolutionarily conserved, noncoding RNA molecules (21–25 nucleotides in length) in vertebrates, plants, and protozoa [23] that play an important role in post-transcriptional gene regulation [24]. These molecules exert regulating effects on gene expression by inhibiting translation and causing degradation of target messenger RNA (mRNA) [25].
In 1993, Lee et al. were the first ones to indicate the role of lin-4 in regulation of some biological processes in
Role of miRNAs in colorectal cancer signaling pathways
According to the literature, there are many miRNAs playing different roles in CRC indisputable upregulation, downregulation or switching off of which can be important in the carcinogenesis of CRC [10], [35], [36].
MiRNAs are generally classified as tumor suppressor miRNAs and oncomiRs according to their function and status in cancers. OncomiRs are known to downregulate tumor suppressor genes, by contrast, tumor suppressor miRNAs are responsible for downregulation of oncogenes, and are mostly
Tissue miRNAs as CRC biomarkers
Abnormal expression of miRNAs has different effects on carcinogenesis of the large bowel and leads to formation of adenomas and carcinomas. There is a wide range of up-regulated and/or down-regulated miRNAs in CRC found in cell lines, tumors and healthy tissues which may associated with patient’s diagnosis, prognosis and response to therapeutic agents (Fig. 3).
MiR-143 and miR-145 has been reported to be down-regulated in different stages of colorectal tissue for the first time [39]. Decreased
Circulating miRNAs as CRC biomarkers
After discovery of miRNAs and the correlation between particular miRNAs with CRC, circulating miRNAs have been considered as diagnostic and prognostic biomarkers.
Different cells can express hundreds of copies of certain miRNA alone, and cancer cells are not separated from this. Divers efforts have been made to identify CRC-specific miRNA transcripts as prospective diagnostic biomarkers which can be used to develop precancerous stage detection [4], [114].
For using miRNA as a diagnostic
Involvement of miRNAs in drug resistance
Chemotherapy is the imperative method of therapeutic strategy for patients with CRC. Five-fluorouracil (5-Fu), oxaliplatin, doxorubicin, paclitaxel and monoclonal antibodies have been applied in CRC therapy [153].
Nevertheless, many patients resist to anticancer drugs during the treatment and it is major obstacle for efficient response to chemotherapeutic agents [154]. Several studies have focused on miRNAs regulatory roles in the induction of chemo-resistance and their involvement in the
Targeting miRNAs for treatment of CRC
As mentioned previously, dysregulation of miRNAs expression levels in cancers might influence cancer phenotype. Manipulation of miRNAs pathways might be applied as a therapeutic strategy and intervention tool for inhibition of growth, invasion, metastasis, angiogenesis, induction of apoptosis and sensitivity to therapeutic mediators [193], [194].
In recent years, evidences have shown that gene therapy may be effective for CRC and may inhibit progression of tumor cells by manipulating of the
Conclusion
After the discovery of miRNAs as post-transcriptional regulators, numerous studies have focused on the role of miRNAs in tumorigenesis and development of tumor cells including cell growth, angiogenesis, invasion, metastasis, apoptosis, and drug-resistance.
Regarding CRC, there are several mechanisms involved in its progression including over-growth, loss of apoptotic regulation, invasion, angiogenesis and maintenance of cancer stem cells (CSCs).
One of the reasons for these alterations is miRNAs
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