Abstract
Breast cancer is the second leading cause of cancer death in women. Despite improvement in treatment over the past few decades, there is an urgent need for development of targeted therapies. miR-155 (microRNA-155) is frequently up-regulated in breast cancer. In this study, we demonstrate the critical role of miR-155 in regulation of cell survival and chemosensitivity through down-regulation of FOXO3a in breast cancer. Ectopic expression of miR-155 induces cell survival and chemoresistance to multiple agents, whereas knockdown of miR-155 renders cells to apoptosis and enhances chemosensitivity. Further, we identified FOXO3a as a direct target of miR-155. Sustained overexpression of miR-155 resulted in repression of FOXO3a protein without changing mRNA levels, and knockdown of miR-155 increases FOXO3a. Introduction of FOXO3a cDNA lacking the 3'-untranslated region abrogates miR-155-induced cell survival and chemoresistance. Finally, inverse correlation between miR-155 and FOXO3a levels were observed in a panel of breast cancer cell lines and tumors. In conclusion, our study reveals a molecular link between miR-155 and FOXO3a and presents evidence that miR-155 is a critical therapeutic target in breast cancer.
Highlights
Introduction ofFOXO3a cDNA Lacking 3Ј-UTR Largely Abrogates miR-155 Cellular Function—Because miR-155 directly targets FOXO3a through interaction between FOXO3a 3Ј-UTR and miR-155, we reasoned that ectopic expression of FOXO3a by transfection of the cDNA that only contains the open reading frame of FOXO3a (FOXO3a-ORF) should escape the regulation by miR-155 and attenuate or decrease miR-155 function
BIC/ miR-155 knock-out mice resulted in impaired immune response and cytokine production [23], further supporting the vital role of miR-155 in immunology
Down syndrome or trisomy 21 was recently linked with high levels of miR-155 and provides further insights into the resulting cognitive impairment and congenital heart defects seen in patients [47]
Summary
Statistical Analysis—Statistical significance was analyzed by unpaired Student’s t test, and p Յ 0.05 was considered to be statistically significant
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