MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer.
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.
Yang
Nuo
N
Center for Research on Early Detection and Cure of Ovarian Cancer, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Kaur
Sippy
S
Volinia
Stefano
S
Greshock
Joel
J
Lassus
Heini
H
Hasegawa
Kosei
K
Liang
Shun
S
Leminen
Arto
A
Deng
Shan
S
Smith
Lori
L
Johnstone
Cameron N
CN
Chen
Xian-Ming
XM
Liu
Chang-Gong
CG
Huang
Qihong
Q
Katsaros
Dionyssios
D
Calin
George Adrian
GA
Weber
Barbara L
BL
Bützow
Ralf
R
Croce
Carlo M
CM
Coukos
George
G
Zhang
Lin
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D018628:Gene Dosage; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D035683:MicroRNAs; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human; D002945:Cisplatin