Colorectal cancer (CRC) between all types of cancer is ranked as third with regard to prevalence, and second in mortality rates [1, 2], contributing to over 700,000 fatalities per year worldwide [3, 4]. CRC incidence rates are relatively similar in both men and women [5, 6]. The notable difference in the worldwide annually reported frequency of CRC, illustrates the major effect of lifestyle influences on the presence of cancer . For instance, colorectal cancer prevalence rates are approximately 3 times higher in transitioned against developing countries . To achieve a treatment for CRC, early diagnoses, personalized medication, and a clear view on the molecular mechanisms of its incidence and development, are essential . But unfortunately, most CRC cases are found at an advanced phase in patients often at the beginning of metastasis, which contributes to the weak prognosis and the lower patient recovery possibilities [4, 8].
Given the advances achieved in understanding the molecular mechanisms involved in the CRC, several aspects are still vague. Despite that, molecular science developments have contributed to the identification of several prospective biomarkers that are important to colorectal cancer (CRC). Given the fact that in CRCs, a noticeable number of dysregulated miRNAs are identified to have been linked with disease progression and treatment response, microRNAs are considered to be hopeful prognostic biomarkers for this cancer in the latest researches [2, 4, 9, 10]. Compared to normal controls, miRNAs are therefore categorized as oncomiR and miRNA tumor suppressor, and some of them could be utilized as CRC diagnostic, prognostic and predictive biomarkers .
Micro-RNAs (miRNAs) are vast subgroups of small single-strand noncoding RNAs containing 19–22 nucleotides that by binding to the 3'UTR end of the mRNA could inhibit translation or degrade the mRNA before translation. MicroRNA expression irregularities are found to be involved in the dysregulation of cell apoptosis, angiogenesis, metastasis, and tumor development of different malignancies. Moreover, to regulate the expression of their target genes which are associated with CRC proliferation and metastasis, miRNAs can target long non-coding RNA (lncRNA), as well [4, 12–16]. The roles of these dysregulated miRNAs tend to be contextual, showing a double role as oncogenes and the tumor-suppressors regarding their cellular environment. The distinctive expressing characteristics of miRNAs, therefore, contribute to CRC diagnosis, prognosis, and therapeutic results [10, 14, 17]. The biogenesis of miRNAs is done by many enzymes and various cellular compartments and is a complicated multi-phase process with various steps .
The miR-330 gene is found on a fragile genome region of chromosome number 19 . miR-330 as a key regulator for gene expression in some malignancies, such as colorectal cancer , prostate cancer , and melanoma , have been documented to be down-regulated. On the other hand, miR-330 is identified as an oncogenic factor due to overexpression in glioblastoma cells .
In CRC tissues, miR-330 expression was reported to be significantly lower than in adjacent non-tumorous tissues [23, 24]. As the decreased expression of miR-330 in CRC promotes proliferation and metastasis and decreases apoptosis, it can be considered as a therapeutic target and a molecular biomarker for CRC [20, 25]. MiR-330 has been observed in many studies as a regulatory factor, in CRC. For instance, induction of miR-330 inhibits cell proliferation through the suppression of post-transcriptional BACH1 expression . Other results demonstrated that Cdc42 as an oncogene agent was negatively regulated by miR-330 via the specific target motif of Cdc42 3'UTR acting as a CRC tumor suppressor . It has also been found that the downregulation of miR-330 expression may impact the development of CRC by inhibiting the expression of ITGA5 through binding directly to the 3'UTR of ITGA5 mRNA . We have also previously indicated that miR-330 functions as a miRNA tumor suppressor in CRC by suppressing HMGA2 expression and reducing cell viability, proliferation, and migration. Consequently, for patients with CRC, miR-330 could be proposed as a potential candidate for miRNA replacement therapy .
An analysis carried out on CRC cell lines indicated that miR-330 inhibited proliferation of colorectal cells and increased the chemo-sensitivity of CRC cells to 5-fluorouracil (5-FU) via the cell apoptosis pathway . 5-FU is an antimetabolite medication that has a cytotoxic impact on inhibition of thymidylate synthase (TYMS) resulting in dTMP depletion [28, 29]. Hence, TYMS was recognized as a direct target gene of miR-330. Therefore, TYMS can represent a predictive cellular response biomarker for 5-FU and a therapeutic target for 5-FU-based chemotherapy .
Thymidylate synthase (TYMS) gene located on 18p11.32. TYMS catalyzes deoxyuridylate (dUMP) methylation to deoxythymidylate (dTMP) by employing 10-methylenetetrahydrofolate (methylene-THF) as a cofactor. This role protects the dTMP (thymidine-5-prime monophosphate) pool essential to DNA replication and repair. This enzyme has been studied as the target for cancer chemotherapies [19, 30, 31]. In several studies, dysregulation of TYMS in CRC has been recognized. In a study on ERCC1 and TYMS in CRC patients, both were reported to be over-expressed . Although most studies have shown that Tumors expressing high levels of TYMS have a poorer overall survival (OS) contrasted with tumors expressing low levels, others have noted that increased TYMS protein and mRNA expression have been linked with higher relapse-free survival and OS [33–35].
Given these findings, maybe there is a diagnostic and predictive benefit to investigate the miR-330 and TYMS expression and the contribution of these genes in the pathogenesis of CRC, and this research may help to determine their value as a clinical biomarker for disease prediction.