Abstract
Colorectal cancer (CRC) is a deadly tumour in Western countries characterized by high cellular/molecular heterogeneity. Cancer stem cells (CSC) act in cancer recurrence, drug-resistance and in metastatic epithelial-to-mesenchymal transition. microRNAs (miRNAs) contribute to cancer is increasing, and miRNA roles in CSC phenotype and fate and their utility as CRC biomarkers have also been reported. Here, we investigated miR-21, miR-221, miR-18a, miR-210, miR-31, miR-34a, miR-10b and miR-16 expression in experimental ALDH+ and CD44+/CD326+ colorectal CSCs obtained from the human CRC cell lines HCT-116, HT-29 and T-84. Then, we moved our analysis in cancer tissue (CT), healthy tissue (HT) and serum (S) of adult CRC patients (n=12), determining relationships with clinical parameters (age, sex, metastasis, biochemical serum markers). Specific miRNA patterns were evident in vitro (normal, monolayers and CSCs) and in patients’ samples stratified by TNM stage (LOW vs HIGH) or metastasis (Met vs no-Met). miR-21, miR-210, miR-34a upregulation ad miR-16 dowregulation associated with the CSCs phenotype. miR-31b robustly overexpressed in monolayers and CSCs, and in CT ad S of HIGH grade and Met patients, suggesting a role as marker of CRC progression and metastasis. miR-18a upregulated in all cancer models and associated to CSC phenotype, and to metastasis and age in patients. miR-10b downregulated in CT and S of LOW/HIGH grade and no-Met patients. Our results identify miRNAs useful as colorectal CSC biomarker and that miR-21, miR-210, miR-10b and miR-31b are promising markers of CRC. A specific role of miR-18a as metastatic CRC serum biomarker in adult patients was also highlighted.
Highlights
Colorectal cancer (CRC) is a major age-related malignant tumour, typical of Western and developing countries
Specific miRNA patterns were evident in vitro and in patients’ samples stratified by TNM stage (LOW vs high TNM grading patients (HIGH)) or metastasis (Met vs no-metastatic patients (Met)). miR-21, miR-210, miR-34a upregulation ad miR-16 dowregulation associated with the Cancer stem cells (CSC) phenotype. miR-31b robustly overexpressed in monolayers and CSCs, and in cancer tissue (CT) ad S of HIGH grade and Met patients, suggesting a role as marker of CRC progression and metastasis. miR-18a upregulated in all cancer models and associated to CSC phenotype, and to metastasis and age in patients. miR-10b downregulated in CT and S of low TNM grading www.oncotarget.com patients (LOW)/HIGH grade and non metastatic patients (no-Met) patients
Cancer stem cell enrichment was achieved in the HCT-116, healthy tissue (HT)-29 and T-84 CRC cell lines after secondary colonosphere formation
Summary
Colorectal cancer (CRC) is a major age-related malignant tumour, typical of Western and developing countries. Western countries have the record for the number of CRC cases and mortality, the trend is changing. Management and diagnosis must be improved because the age of onset has recently decreased [1]. This trend is highly contentious [2,3,4,5], it is quite clear that symptoms appear earlier in younger patients, who are at greater risk of second primary cancers [6]. Diagnostic/prognostic procedures that take advantage of this valuable temporal window, as well as during cancer initiation, progression ad metastasis are strongly recommended
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