MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer.

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.

• Authors: Nuo Yang, Sippy Kaur, Stefano Volinia, Joel Greshock, Heini Lassus, Kosei Hasegawa, Shun Liang, Arto Leminen, Shan Deng, Lori Smith, Cameron N Johnstone, Xian-Ming Chen, Chang-Gong Liu, Qihong Huang, Dionyssios Katsaros, George Adrian Calin, Barbara L Weber, Ralf Bützow, Carlo M Croce, George Coukos, Lin Zhang
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 24 Pg. 10307-14 (Dec 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 19074899 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• DNA, Neoplasm
• MicroRNAs
• RNA, Messenger
• mirnlet7 microRNA, human
• Cisplatin

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (biosynthesis, genetics)
• Cisplatin (pharmacology)
• DNA, Neoplasm (genetics)
• Drug Resistance, Neoplasm
• Female
• Gene Dosage
• Humans
• MicroRNAs (biosynthesis, genetics)
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Ovarian Neoplasms (drug therapy, genetics, metabolism)
• RNA, Messenger (genetics)
• Young Adult