Abstract
BackgroundThe epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer progression and may promote resistance to therapy. An analysis of patients (n = 71) profiled with both gene expression and a global microRNA assessment (∼415 miRs) identified miR-147 as highly anti-correlated with an EMT gene expression signature score and postulated to reverse EMT (MET).Methods and FindingsmiR-147 was transfected into colon cancer cells (HCT116, SW480) as well as lung cancer cells (A-549). The cells were assessed for morphological changes, and evaluated for effects on invasion, motility, and the expression of key EMT markers. Resistance to chemotherapy was evaluated by treating cells with gefitinib, an EGFR inhibitor. The downstream genes regulated by miR-147 were assayed using the Affymetrix GeneChip U133 Plus2.0 platform. miR-147 was identified to: 1. cause MET primarily by increasing the expression of CDH1 and decreasing that of ZEB1; 2. inhibit the invasion and motility of cells; 3. cause G1 arrest by up-regulating p27 and down-regulating cyclin D1. miR-147 also dramatically reversed the native drug resistance of the colon cancer cell line HCT116 to gefitinib. miR-147 significantly repressed Akt phosphorylation, and knockdown of Akt with siRNA induced MET. The morphologic effects of miR-147 on cells appear to be attenuated by TGF-B1, promoting a plastic and reversible transition between MET and EMT.ConclusionmiR-147 induced cancer cells to undergo MET and induced cell cycle arrest, suggesting a potential tumor suppressor role. miR-147 strikingly increased the sensitivity to EGFR inhibitor, gefitinib in cell with native resistance. We conclude that miR-147 might have therapeutic potential given its ability to inhibit proliferation, induce MET, as well as reverse drug sensitivity.
Highlights
The epithelial-mesenchymal transition (EMT) has been described as a cell-biological program that is required for the remodeling of cells and tissues during embryogenesis, during certain types of wound healing, and during the acquisition of malignant traits by carcinoma cells [1], [2].The epithelialmesenchymal transition is a key developmental program that is often activated during cancer invasion, metastasis, and may promote resistance to chemotherapy.MicroRNAs are noncoding mRNA sequences containing around 22-nucleotides that act as important regulators of gene expression. miRNAs can silence their cognate target genes by binding and cleaving mRNAs or inhibiting their translation [3]
Conclusion: miR-147 induced cancer cells to undergo Mesenchymal-To-Epithelial Transition (MET) and induced cell cycle arrest, suggesting a potential tumor suppressor role. miR-147 strikingly increased the sensitivity to epidermal growth factor receptor (EGFR) inhibitor, gefitinib in cell with native resistance
We recently reported an unsupervised, global gene expression analysis (Affymetrix GeneChip) of 250 frozen human colorectal cancer specimens (CRC) identified two intrinsic subpopulations of patients that were characterized by a signature strongly linked to the process of the epithelial-mesenchymal transition (EMT) [13]
Summary
The epithelial-mesenchymal transition (EMT) has been described as a cell-biological program that is required for the remodeling of cells and tissues during embryogenesis, during certain types of wound healing, and during the acquisition of malignant traits by carcinoma cells [1], [2].The epithelialmesenchymal transition is a key developmental program that is often activated during cancer invasion, metastasis, and may promote resistance to chemotherapy.MicroRNAs (miRNAs, or miRs) are noncoding mRNA sequences containing around 22-nucleotides that act as important regulators of gene expression. miRNAs can silence their cognate target genes by binding and cleaving mRNAs or inhibiting their translation [3]. MicroRNAs (miRNAs, or miRs) are noncoding mRNA sequences containing around 22-nucleotides that act as important regulators of gene expression. The miR-200 family, which suppresses the EMT drivers ZEB1 and ZEB2, is selectively expressed in the sarcomatous component of metaplastic breast cancers [6]. Loss of the expression of any members of the miR-200 family may play a critical role in the repression of CDH1 by ZEB1 and ZEB2 during the EMT, thereby enhancing migration and invasion during cancer progression. The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer progression and may promote resistance to therapy.
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