Abstract
ObjectiveMiR-21 is an oncomir expressed by malignant cells and/or tumor microenvironment components. In this study we focused on understanding the effects of stromal miR-21 on esophageal malignant cells.DesignMiR-21 expression was evaluated in formalin-fixed paraffin-embedded samples from patients with esophageal squamous-cell carcinoma (SCC) by quantitative RT-PCR. MiR-21 tissue distribution was visualized with in situ hybridization. A co-culture system of normal fibroblasts and esophageal cancer cells was used to determine the effects of fibroblasts on miR-21 expression levels, and on SCC cell migration and invasion.ResultsMiR-21 was overexpressed in SCCs, when compared to the adjacent non-tumor tissues (P = 0.0007), and was mainly localized in the cytoplasm of stromal cells adjacent to malignant cells. Accordingly, miR-21 expression was increased in tumors with high versus low stromal content (P = 0.04). When co-cultured with normal fibroblasts, miR-21 expression was elevated in SCC cells (KYSE-30), while its expression was restricted to fibroblasts when co-cultured with adenocarcinoma cells (OE-33 and FLO-1). MiR-21 was detected in conditioned media of cancer cell lines, illustrating the release of this miRNA into the environment. Co-culturing with normal fibroblasts or addition of fibroblast conditioned media caused a significant increase in cell migration and invasion potency of KYSE-30 cells (P<0.0001). In addition, co-culturing cancer cells with fibroblasts and expression of miR-21 induced the expression of the cancer associated fibroblast (CAF) marker S100A4.ConclusionsMiR-21 expression is mostly confined to the SCC stroma and its release from fibroblasts influences the migration and invasion capacity of SCC cells. Moreover, miR-21 may be an important factor in “activating” fibroblasts to CAFs. These findings provide new insights into the role of CAFs and the extracellular matrix in tumor microenvironment formation and in tumor cell maintenance, and suggest miR-21 may contribute to cellular crosstalk in the tumor microenvironment.
Highlights
MicroRNAs are short (,22 nucleotides), endogenous non-coding RNAs, which act as post-transcriptional modulators of a variety of cellular processes including development, proliferation, differentiation and apoptosis [1,2,3]
When co-cultured with normal fibroblasts, miR-21 expression was elevated in squamous-cell carcinoma (SCC) cells (KYSE-30), while its expression was restricted to fibroblasts when co-cultured with adenocarcinoma cells (OE-33 and FLO-1)
MiR-21 expression is mostly confined to the SCC stroma and its release from fibroblasts influences the migration and invasion capacity of SCC cells
Summary
MicroRNAs (miRNAs) are short (,22 nucleotides), endogenous non-coding RNAs, which act as post-transcriptional modulators of a variety of cellular processes including development, proliferation, differentiation and apoptosis [1,2,3]. MicroRNAs were initially found to inhibit translation or degrade their mRNA targets by imperfect or perfect complementary binding, new publications have assigned other regulatory roles for miRNAs, including promoter companionship [4]. Alterations in the expression of miRNAs are associated with a variety of diseases including cancer, where they show tumor-specific expression signatures. MiR-21 is involved in cellular proliferation, evasion of apoptosis, epithelial to mesenchymal transition (EMT), and invasion [8,14,15,16]
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