Deregulation of cancer-stem-cell-associated miRNAs in tissues and sera of colorectal cancer patients

Abstract

Copyright: Farace et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACTColorectal 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. www.oncotarget.com

Plasma Exosomal miRNA Expression Profile as Oxaliplatin-Based Chemoresistant Biomarkers in Colorectal Adenocarcinoma

“…miR-16 is usually used as an internal control due to its stable expression level in most cases, including in colorectal cancer ( 17 , 28 ). The expression level of miR-16 in CRC tissues was also complicated due to its upregulation ( 29 ) or downregulation ( 30 ). However, none of these studies investigated the expression level of miR-16 in circulating exosomes.…”

“…However, none of these studies investigated the expression level of miR-16 in circulating exosomes. It has been reported that the expression level of miR-16 is negatively related to the CSC phenotype ( 29 ), and higher expression of miR-16 could reverse chemoresistance by inhibiting CSC properties ( 31 ). More studies revealed that the overexpression of miR-16 could sensitize cancer cells to chemotherapy by targeting ATG4B ( 32 ), BCL2 ( 33 ), CCNJ, or FUBP1 ( 34 ).…”

Portrait of Cancer Stem Cells on Colorectal Cancer: Molecular Biomarkers, Signaling Pathways and miRNAome

“…MiRNA expression profile of the isolated colonocytes may be useful for CRC screening [ 188 ]. MiR-18a upregulation in in vitro models and tissues/sera of CRC patients, revealed association to CSC phenotype, metastasis and age, suggesting its role as metastatic biomarkers in CRC [ 189 ]. CSC-related miR-17 expression increases during progression from the primary CRC to liver metastasis [ 190 ].…”

Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development

“…Several miRNAs were identified to be upregulated in CRC CSC subpopulations, suggesting that they promote the stemness of CRC CSCs ( Table 1 ) [ 45 , 46 ]. In both cell lines and patient-derived samples of CRC, miR-210 and miR-221 were generally found to be upregulated in CRC subpopulations that were enriched for CSC surface markers ALDH + and CD44 + [ 47 , 48 ]. MiR-221-5p and miR-221-3p were also found to be upregulated in CRC cells that were sorted for CSC surface markers EpCAM + /CD44 + .…”

“…Within the CRC ALDH + /CD44 + CSC subpopulation, the downregulation of miR-10b was observed. Interestingly, in the same study, although miR-18a was found to be upregulated in CRC cell lines compared to a non-stem and non-cancer colon cell line, miR-18a expression was downregulated after selection for CSC subpopulations, suggesting a possible role for maintaining stemness in CRC [ 47 ]. In CD44v6 + spheroid CRC subpopulations, miR-34a-3p, let-7f-1-3p, miR-101-3p and miR-200c-3p expressions were found to be downregulated.…”