Afraa Mamoori

Modulatory roles of microRNAs in the regulation of different signalling pathways in large bowel cancer stem cells.

There are emerging data to suggest that microRNAs (miRNAs) have significant roles in regulating the function of normal cells and cancer stem cells (CSCs). This review aims to analyse the roles of miRNAs in the regulation of colon CSCs through their interaction with various signalling pathways. Studies showed a large number of miRNAs that are reported to be deregulated in colon CSCs. However, few of the studies available were able to outline the function of miRNAs in colon CSCs and uncover their signalling pathways. From those miRNAs, which are better described, miR‐21 followed by miR‐34, miR‐200 and miR‐215 are the most reported miRNAs to have roles in colon CSC regulation. In particular, miRNAs have been reported to regulate the stemness features of colon CSCs mainly via Wnt/B‐catenin and Notch signalling pathways. Additionally, miRNAs have been reported to act on processes involving CSCs through cell cycle regulation genes and epithelial–mesenchymal transition. The relative paucity of data available on the significance of miRNAs in CSCs means that new studies will be of great importance to determine their roles and to identify the signalling pathways through which they operate. Such studies may in future guide further research to target these genes for more effective cancer treatment. miRNAs were shown to regulate the function of cancer stem cells in large bowel cancer by targeting a few key signalling pathways in cells.

Clinical and biological significance of miR-193a-3p targeted KRAS in colorectal cancer pathogenesis

This study was to investigate the expression pattern, mechanisms and clinicopathological implications of miR-193a-3p in colorectal cancer. Fresh-frozen tissues from 70 matched colorectal adenocarciomas and the adjacent non-neoplastic mucosae were prospectively collected. Two colorectal cancer cell lines (SW480 and SW48) and a non-neoplastic colon cell line (FHC) were also used. The expression levels of miR193a-3p in the cells and tissues were measured by quantitative real-time polymerase chain reaction. The expression of KRAS protein as a predicted downstream target for miR-193a was studied by immunohistochemistry. Restoration of the miR-193a level in the cell lines by permanent transfection was achieved and multiple functional and immunological assays were performed to analyze the functions of miR-193a in vitro. Down-regulation of miR-193a-3p was noted in 70% of the colorectal cancer tissues when compared to non-neoplastic colorectal tissues. In addition, down-regulation of miR-193a was significantly correlated with carcinoma of early stages (P<.05). Significant inverse correlation between miR-193a-3p and its target KRAS protein was determined (P<.05). Overexpression of miR-193a in colon cancer cells resulted in reduced cell proliferation, increased apoptosis, induced significant changes in cell cycle events and decreased the expression of epithelial-mesenchymal transition marker TWIST. This study confirms the tumor suppressor roles of miR-193a-3p, its downstream target affinity to KRAS and clinical significance in patients with colorectal adenocarcinoma.

Expression of GAEC1 mRNA and protein and its association with clinical and pathological parameters of patients with colorectal adenocarcinoma

AIM GAEC1 (Gene amplified in esophageal cancer 1) is an oncogene with key regulatory roles in the pathogenesis of oesophageal and colorectal carcinomas. The aim of this study was to investigate expression profiles and clinicopathological significance of GAEC1 mRNA and protein in patients with colorectal carcinomas. METHOD Matched cancer and non-cancer fresh frozen tissues were prospectively collected from 80 patients diagnosed with colorectal adenocarcinoma (39 men and 41 women). The tissues were sectioned for RNA extraction and cDNA conversion and quantified by a real-time polymerase chain reaction. GAEC1 protein expression was analysed by immunohistochemistry using a custom made GAEC1 antibody. RESULT GAEC1 mRNA was upregulated in majority (52%, n=42/80) of the colorectal carcinomas when compared to the matched non-neoplastic tissues. High expression of GAEC1 mRNA as correlated with patients of younger age (p=0.008), with lower grade carcinoma (p=0.028), presence of synchronous adenocarcinomas (p=0.034) and without any associated adenomas (p=0.047). In addition, patients with high GAEC1 mRNA overexpression had a shorter survival time. Furthermore, high GAEC1 protein expression was noted among patients having perforated colorectal carcinoma (p=0.04). CONCLUSION The high expression of GAEC1 mRNA/protein as well as its correlation with multiple clinicopathological characteristics in patients with colorectal carcinoma strongly suggests that GAEC1 is a key regulator in the initiation of colorectal carcinogenesis.

GAEC1 mutations and copy number aberration is associated with biological aggressiveness of colorectal cancer

GAEC1 (gene amplified in oesophageal cancer 1) is a transforming oncogene with tumorigenic potential observed in both oesophageal squamous cell carcinoma and colorectal cancer. Nonetheless, there has been a lack of study done on this gene to understand how this gene exert its oncogenic properties in cancer. This study aims to identify novel mutation sites in GAEC1. To do so, seventy-nine matched colorectal cancers were tested for GAEC1 mutation via Sanger sequencing. The mutations noted were investigated for the correlations with the clinicopathological parameters of the patients with the cancer. Additionally, GAEC1 copy number aberration (CNA), mRNA and protein expression were determined with the use of droplet digital (dd) polymerase chain reaction (PCR), real-time PCR and Western blot (confirmed with immunofluorescence analysis). GAEC1 mutation was noted in 8.8% (n = 7/79) of the cancer tissues including one missense mutation, four loss of heterozygosity (LOH) and two substitutions. These mutations were significantly associated with cancer perforation (p = 0.021). GAEC1 mutation is frequently associated with increased GAEC1 protein expression. Nevertheless, GAEC1 mRNA and protein are only weakly associated. Taken together, GAEC1 mutation affects GAEC1 expression and is associated with poorer clinical outcomes. This further strengthens the role of GAEC1 as an oncogene.

Role of miR-193a in Cancer: Complexity and Factors Control the Pattern of its Expression

BACKGROUND There is emerging data suggesting that the non-coding RNA (microRNA 193a or miR-193a) plays key roles in different types of cancers. OBJECTIVE This review aims to investigate the functional significance of miR-193a in different cancers according to the information of literature. METHOD All the literature concerning miR-193a in cancer in PubMed are analysed. RESULTS Several studies proved the association of miR-193a expression patterns with cancers stages, grades, response to the chemotherapy and even patient survival. Also, miR-193a can be used to differentiate some types of cancer. In cancer, miR-193a can act as a tumour suppressor gene or as an oncogene. Till now, several genetic factors (MAX, RXR α, XB130, P63, P73, AEG-1, HIFs, EGFR, Drosha, DGCR8, Dicer) and epigenetic factors (DNA methylation and long non-coding RNAs) were predicted to control miR-193a expression. They have fundamental effects on its biological behaviour in different types of cancers. CONCLUSION miR-193a has significant roles in cancer and can be targeted in the future for cancer therapy by better understanding of the factors that control its biological behaviour.