Role Of miRNAs In Colorectal Cancer Research Articles

Identifying metastasis-initiating miRNA-target regulations of colorectal cancer from expressional changes in primary tumors

Colorectal cancer (CRC) is prevalent with high mortality, with liver metastasis contributing as a major factor that worsens the survival of patients. The roles of miRNAs in CRC have been elucidated, subsequent to recent studies that suggest the involvement of miRNAs in cancer biology. In this study, we compare the miRNA and gene expression profiles of primary tumors between two groups of patients (with and without liver metastasis) to identify the metastasis-initiating microRNA-target gene regulations. Analysis from 33 patients with metastasis and 14 patients without metastasis revealed that 17 miRNAs and their 198 predicted target genes are differentially expressed, where the target genes showed association with cancer progression and metastasis with statistical significance. In order to evaluate the clinical implications of the findings, we classified CRC patients of independent data into two groups based on the identified miRNA-target regulations, where one group was closer to primary tumors with metastasis than the other group. The comparison of survival showed statistically significant difference, thereby implying the roles of the identified miRNA-target regulations in cancer progression and metastasis. The identification of metastasis-initiating miRNA-target regulations in this study will lead to better understanding of the roles of miRNAs in CRC progression.

Post-Transcriptional Dysregulation of microRNA and Alternative Polyadenylation in Colorectal Cancer.

BackgroundColorectal cancer (CRC) is one of the leading causes of cancer death worldwide. microRNAs (miRNAs) repress gene expression by binding to complementary sequences in the 3' untranslated region (3'UTR) of target mRNAs. Alternative polyadenylation (APA) are relevant to the variability of the 3'UTR of mRNA. However, the posttranscriptional dysregulation of miRNAs and APA in CRC are poorly understood.MethodIn this study, we conducted small RNA sequencing to identify differentially expressed miRNAs (DERs) and their target genes. Function analysis on DER-target genes can explain the regulation roles of miRNAs in CRC. The mutual regulation of miRNAs and APA was analyzed by combining miRNA data to 3'UTR alteration using 3' termini of polyadenylated RNAs sequencing (3T-seq) technique, and this was validated using TCGA gene expression data.ResultsOur results showed 64 significant differentially expressed miRNAs (DERs) in CRC patients. Their target genes were related to cell adhesion and transcription regulation and were prevailingly involved in the CRC-related pathway. Integrative analysis of the miRNA and APA profile revealed 16 DERs were correlated with 12 polyadenylation factors, and six of them were significantly differently expressed in CRC. We also found four DERs that lost binding sites due to APA and showed a positive correlation between the miRNA and gene expression.ConclusionOur study found that miRNAs regulated APA by modulating key polyadenylation factors, and several miRNAs lost their suppression on mRNA due to APA. Associating this with gene expression may provide some important clues for a deeper study of posttranscriptional cellular regulation and biomarker research in CRC. Our data provided the first evidence that the interaction between miRNAs and APA associated with gene expression could serve as biomarkers for CRC, suggesting that hsa-miR-133a-3p and MLEC, hsa-miR-145-5p and SET, hsa-miR-1-3p and PPIA, and hsa-miR-378d and YY1 might be novel and potential biomarkers in improving the diagnosis of CRC.

The Role and Therapeutic Potential of miRNAs in Colorectal Liver Metastasis

Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Liver metastasis is the major cause of CRC patient mortality, occurring in 60% patients with no effective therapies. Although studies have indicated the role of miRNAs in CRC, an in-depth miRNA expression analysis is essential to identify clinically relevant miRNAs and understand their potential in targeting liver metastasis. Here we analyzed miRNA expressions in 405 patient tumors from publicly available colorectal cancer genome sequencing project database. Our analyses showed miR-132, miR-378f, miR-605 and miR-1976 to be the most significantly downregulated miRNAs in primary and CRC liver metastatic tissues, and CRC cell lines. Observations in CRC cell lines indicated that ectopic expressions of miR-378f, -605 and -1976 suppress CRC cell proliferation, anchorage independent growth, metastatic potential, and enhance apoptosis. Consistently, CRC patients with higher miR-378f and miR-1976 levels exhibited better survival. Together, our data suggests an anti-tumorigenic role of these miRNAs in CRC and warrant future in vivo evaluation of the molecules for developing biomarkers or novel therapeutic strategies.

MicroRNA-769 is downregulated in colorectal cancer and inhibits cancer progression by directly targeting cyclin-dependent kinase 1.

BackgroundIn recent years, microRNAs (miRNAs) have been reported to be aberrantly expressed in colorectal cancer (CRC). The deregulation of miRNAs is implicated in the formation and progression of CRC, and participates in the regulation of a wide range of biological behaviors. Considering the crucial role of miRNAs in CRC, miRNAs are thought to have significant promise in the diagnosis and therapy of patients with this malignancy.Material and methodsReverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect miR-769 expression in CRC tissues and cell lines. MTT assay and flow cytometry analysis were used to determine the effects of miR-769 upregulation in CRC cell proliferation and apoptosis, respectively. The influence of miR-769 overexpression in CRC cell migration and invasion was evaluated through migration and invasion assays. Notably, the possible mechanisms underlying the action of miR-769 in CRC cells were explored.ResultsIn the present study, miR-769 was frequently found to be poorly expressed in CRC tissues and cell lines. Functional assays showed that recovery of miR-769 expression suppressed CRC cell proliferation, migration, and invasion, increased cell apoptosis in vitro, and inhibited tumor growth in vivo. Cyclin-dependent kinase 1 (CDK1) was the direct target of miR-769 in CRC cells. CDK1 was overexpressed in CRC tissue samples and negatively correlated with miR-769 expression. In addition, CDK1 inhibition imitated the tumor suppressor activity of miR-769 in CRC cells, and restoration of CDK1 expression partially abolished the tumor-suppressing roles of miR-769 in malignant CRC cells.ConclusionThe results of this study demonstrated that miR-769 was downregulated in CRC and directly targeted CDK1 to be implicated in the regulation of CRC cell proliferation, apoptosis, migration and invasion. Thus, the miR-769/CDK1 axis might be an effective therapeutic target for treating patients with CRC.

Evaluation of microRNAs-29a, 92a and 145 in colorectal carcinoma as candidate diagnostic markers: An Egyptian pilot study

Colorectal cancer (CRC) is one of the most common malignant neoplasms in Egypt, and interestingly in young age. Adenomatous polyps and inflammatory bowel diseases (IBD) are considered the commonest pre-malignant lesions for CRC. A possible diagnostic role for different microRNAs on CRC has been suggested by numerous studies. To assess the serum expression of 3 microRNA markers (miR-29a, miR-92a and miR-145) in pre-malignant and malignant colorectal lesions. The 60 patients studied were divided into 4 groups: CRC group (25 patients), IBD group (11 patients), adenomatous polyps group (14 patients) and control group (10 patients). The serum expression of the 3 markers (miR-29a, miR-92a and miR-145) has been assessed by RT-PCR. All CRCs were sporadic cases. Significant downregulation of miR-145 in CRC group was reported at all levels, i.e. when compared to normal, among the 3 studied groups, and when compared between CRC and non-CRC groups. Significant upregulation of miR-29a in CRC was reported when compared to normal, but no significant difference existed either among the 3 studied groups or between CRC and the other 2 groups. All 3 miRNAs studied were positively inter-correlated. miR-145 may be considered a promising non-invasive reliable diagnostic marker in CRC. Extended studies are needed to ascertain the diagnostic role of miRNAs in CRC.

MicroRNA-223 functions as an oncogene in human colorectal cancer cells.

Aberrant microRNA (miRNA) expression has been frequently observed in colorectal cancer (CRC), the third most common human cancer in the world. However, the roles of miRNAs in CRC remain poorly understood. The present study explored, identified and characterized the miRNAs that correlate with CRC progression. Deregulated level of microRNA-223 (miR-223) was screened out by miRNA microarray in colorectal tumor tissues and further confirmed by quantitative real-time PCR in a large cohort of CRC samples (n=90). After silencing miR-223 by artificial anti‑miR-223 (miR-223-inhibitor), WST-1 and colony formation assays were employed to assess cell proliferation, and cell migration and invasion were evaluated by wound healing test and Transwell assays, respectively. Compared with adjacent non-tumor tissues, 22 miRNAs were screened out in CRC tissues with significance (>2-fold), of which 13 were upregulated and 9 were downregulated. miR-223 is one of the noticeably upregulated miRNAs. Large cohort CRC sample analyses showed that a higher level of miR-223 correlated with a higher clinical stage. Reducing miR-223 expression resulted in a decreased cell proliferation, migration and invasion in CRC cells. miR-223 functions as an oncomiR in CRC, therefore serving as a potential diagnostic and therapeutic target for the treatment of CRC.