The silent healer: miR-205-5p up-regulation inhibits epithelial to mesenchymal transition in colon cancer cells by indirectly up-regulating E-cadherin expression

Abstract

EMT represents the dominant program within advanced stages of colon cancer, where cells acquire migratory characteristics in order to invade secondary tissues and form metastasis. Where the majority of the therapeutic strategies are concentrated on the reduction of the tumor mass through different apoptotic mechanisms, the present study advocates an important role for miR-205-5p in impairment of colon cancer cells migration and restoration of the epithelial phenotype. Upon identification of a homogenous downregulated profile for miR-205-5p in colon adenocarcinoma patients, functional studies demonstrated that experimental upregulation of this sequence is able to significantly raise the levels of E-cadherin through direct inhibition of ZEB1. Moreover, the elevation in CDH1 expression was translated into functional parameters where cells lost their invasion and migratory characteristics and formed homogenous clusters through adhesion interactions. Survival analysis of colon adenocarcinoma patients revealed that low levels of miR-205-5p are associated with an unfavorable prognostic compared to those with increased expression, demonstrating the possible clinical utility of miR-205-5p replacement. Exogenous administration of miRNA mimics was not associated with significant changes in cell viability or inflammatory pathways. Therefore, the proposed strategy is aiming towards inhibition of metastasis and limitation of the tumor borders in advanced stages patients in order to prolong the survival time and to increase the efficiency of the current therapeutic strategies.

Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes

“…HIFs can activate EMT through various pathways, including TGF-β, Notch, PI3k/Akt, Wnt/β-catenin, and NF-κB. The loss of E-cadherin expression contributes to invasion and metastasis [41,42] and is achieved through hypoxia-mediated transcriptional repression. Another process that is regulated by hypoxia and leads to cancer progression is angiogenesis.…”

“…E-cadherin results from the translation of CDH1 and is a glycoprotein that enhances cell-to-cell adhesion and sustains cytoskeleton organization. Understandably, loss of E-cadherin contributes to cancer progression, invasion and metastasis [41,42]. Transcriptional repressors of E-cadherin in EMT include the zinc-finger E-box binding homeobox (ZEB), SNAIL and bHLH family factors such as TWIST, KLF8, and FOXC2.…”

Plasma and Tissue Specific miRNA Expression Pattern and Functional Analysis Associated to Colorectal Cancer Patients

“…Plasma-released miRNAs may be considered as a promising strategy for increased therapeutic efficacy and particularly for avoiding the activation of drug resistance mechanisms, as we observed in the case of the functional study performed on miR-205 [32]. The network presented in Figure 6A is centered on the key gene TP53, which is involved in the regulation of cell proliferation, but was also proved to interfere with drug resistance related pathways [33].…”

CRISPR-based RNA editing: diagnostic applications and therapeutic options

“…The ability of this RNA-based tool of introducing singlenucleotide changes can be adapted for numerous therapeutic purposes, including modification of primary microRNA sequences with the final purpose of impairing the ability of the 'seed' sequence to bind and inhibit complementary genes. MicroRNAs have evolved as important regulators of carcinogenesis [40][41][42], where numerous therapeutic attempts are made with exogenous mimic or inhibitor sequences for the attenuation of malignant hallmarks [43][44][45][46]. However, the delivery method and its specificity, sometimes the necessity of multiple administrations and potential immunogenicity and toxicity of the exogenous sequence are just several factors that are hampering the clinical implementation of microRNA therapeutics.…”