Abstract
An increasing number of studies suggest the implication of microRNAs (miRNAs) in colorectal (CRC) carcinogenesis and disease progression. Nevertheless, the basic mechanism is not yet clear. We determined plasma miRNA expression levels using Agilent microarray technology followed by overlapping with The Cancer Genome Atlas (TCGA) tissue data and a qRT-PCR validation step and analysis of the altered miRNA signatures to emphasize new mechanistic insights. For TGCA dataset, we identified 156 altered miRNAs (79 downregulated and 77 upregulated) in colorectal tissue samples versus normal tissue. The microarray experiment is based on 16 control samples, 38 CRC plasma samples from colorectal cancer patients who have not undergone chemotherapy, and 17 chemo-treated samples. In the case of the analysis of CRC cancer versus healthy control we identified 359 altered miRNAs (214 downregulated and 60 upregulated), considering as the cutoff value a fold-change of ±1.5 and p < 0.01. An additional microarray analysis was performed on plasma from untreated colorectal cancer (n = 38) and chemotherapy-treated colorectal cancer patients (n = 17), which revealed 15 downregulated miRNAs and 53 upregulated miRNAs, demonstrating that the plasma miRNA pattern is affected by chemotherapy and emphasizing important regulators of drug resistance mechanisms. For the validation of the microarray data, we selected a panel of 4 miRNAs from the common miRNA signatures for colon and rectal cancer (miR-642b-3p, miR-195-5p and miR-4741). At the tissue level, the expression levels were in agreement with those observed in colorectal plasma. miR-1228-3p, the top upregulated miRNA in CRC, was chosen to be validated on tissue and plasma samples, as it was demonstrated to be downregulated at tissue level in our patient cohort. This was confirmed by TCGA data and was one example of ta ranscript that has a different expression level between tumor tissue and plasma. Developing more efficient investigation methods will help explain the mechanisms responsible for miRNAs released in biofluids, which is the most upregulated transcript in colorectal plasma samples and which can function as a prediction tool within the oncological field.
Highlights
Colorectal carcinoma is the most common tumor affecting the entire digestive tract [1]
The microarray experiment is based on 38 plasma samples from colorectal cancer patients who have not undergone chemotherapy, and 16 control samples
The top 15 most upregulated and downregulated microRNAs for each comparison are presented in Table 4, and the complete list in Tables S4–S6; we show the heatmaps (Figure 1A–C) and the Venn diagrams for the downregulated miRNAs (Figure 1D) and classification of biological processes (Figure 1E)
Summary
Colorectal carcinoma is the most common tumor affecting the entire digestive tract [1]. Colorectal cancer is a highly prevalent disease which, according to Globocan 2018, ranks fourth in terms of both incidence (9.7%) and mortality (8.4%) worldwide, for both genders combined [2,3,4], with more than half of patients identified in regions which present a higher degree of development. This malignancy is the second most common type of cancer to affect women (with both incidence and mortality values around 9%), right after breast and cervical cancer, and the third in men, after lung and prostate cancers (with an incidence of 10.1% and a mortality of 8%). It has been shown that miRNAs have an important role in tumorigenesis, and the involvement of these transcripts in the etiology of cancer is a subject of study for researchers across the world [12,13,14,15]
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