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.

Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

“…Reduced expression of miR‐34b*/c 88, hsa‐miR‐200a, hsa‐miR‐34a and hsa‐miR‐449b 89 is frequently identified in advanced‐stage tumours. Hsa‐miR‐378 89 and let‐7i 90 are up‐regulated in patients who are sensitive to platinum; in contrast, miR‐101, 87 miR‐30c, miR‐130a and miR‐335 91 are down‐regulated in several resistant ovarian cancer cell lines, suggesting direct involvement in the development of chemoresistance. MiR‐214 induces cell survival and cisplatin resistance through targeting the 3′‐UTR of the PTEN gene, which leads to reduced expression of PTEN and activation of the Akt pathway 92.…”

The miRNA let-7a1 inhibits the expression of insulin-like growth factor 1 receptor (IGF1R) in prostate cancer PC-3 cells

“…Some miRNAs exert oncogenic function by targeting tumour suppressor genes, and some exert anti-tumour function by targeting oncogenes. Let-7a has been reported to act as a tumour suppressor in some cancer types, such as lung and colon cancer, [26][27][28] and the reduced expression levels of let-7 is correlated with poor clinical prognosis. 29 Each miRNA can potentially interact with several mRNA targets via perfect or imperfect base pairing, primarily in the 39 UTR portion.…”

Measurable evidence of miRNAs as regulators of cancer networks and therapeutic targets

“…The fundamental principles for using miRNAs as anticancer drugs is based on two major findings: that miRNA expression is deregulated in cancer compared with normal tissues; and that the cancer phenotype can be changed by targeting miRNA expression [6,[12][13][14]. One of the most profound effects of miRNAs as therapeutic agents is their ability to target multiple genes, frequently in the context of a network, making them extremely efficient in regulating distinct biological cell processes relevant to normal and malignant cell homeostasis (Figure 1) [6,15].…”