MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer
- 15 December 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (24), 10307-10314
- https://doi.org/10.1158/0008-5472.can-08-1954
Abstract
MicroRNAs (miRNA) are approximately 22-nucleotide noncoding RNAs that negatively regulate protein-coding gene expression in a sequence-specific manner via translational inhibition or mRNA degradation. Our recent studies showed that miRNAs exhibit genomic alterations at a high frequency and their expression is remarkably deregulated in ovarian cancer, strongly suggesting that miRNAs are involved in the initiation and progression of this disease. In the present study, we performed miRNA microarray to identify the miRNAs associated with chemotherapy response in ovarian cancer and found that let-7i expression was significantly reduced in chemotherapy-resistant patients (n = 69, P = 0.003). This result was further validated by stem-loop real-time reverse transcription-PCR (n = 62, P = 0.015). Both loss-of-function (by synthetic let-7i inhibitor) and gain-of-function (by retroviral overexpression of let-7i) studies showed that reduced let-7i expression significantly increased the resistance of ovarian and breast cancer cells to the chemotherapy drug, cis-platinum. Finally, using miRNA microarray, we found that decreased let-7i expression was significantly associated with the shorter progression-free survival of patients with late-stage ovarian cancer (n = 72, P = 0.042). This finding was further validated in the same sample set by stem-loop real-time reverse transcription-PCR (n = 62, P = 0.001) and in an independent sample set by in situ hybridization (n = 53, P = 0.049). Taken together, our results strongly suggest that let-7i might be used as a therapeutic target to modulate platinum-based chemotherapy and as a biomarker to predict chemotherapy response and survival in patients with ovarian cancer. [Cancer Res 2008;68(24):10307–14]Keywords
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This publication has 50 references indexed in Scilit:
- Unique microRNA molecular profiles in lung cancer diagnosis and prognosisCancer Cell, 2006
- MicroRNA expression profiles classify human cancersNature, 2005
- Combinatorial microRNA target predictionsNature Genetics, 2005
- RAS Is Regulated by the let-7 MicroRNA FamilyCell, 2005
- Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAsNature Reviews Genetics, 2004
- MicroRNAs: Genomics, Biogenesis, Mechanism, and FunctionCell, 2004
- Ovarian cancer: strategies for overcoming resistance to chemotherapyNature Reviews Cancer, 2003
- The C. elegans hunchback Homolog, hbl-1, Controls Temporal Patterning and Is a Probable MicroRNA TargetDevelopmental Cell, 2003
- Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNANature, 2000
- The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegansNature, 2000