Potential pharmacologic targets for cervical cancer prevention in small RNA world

A139 MicroRNAs (miRNAs) are a class of small non-coding RNAs in small RNA world of genome which are newly found to be able to regulate the function of target genes. miRNAs shown to be up- or down-regulated in tumors may be used as molecular diagnostic/prognostic tumor markers and therapeutic targets, while correlation between the expression of miRNAs and pre-cancer status may also implicate potential pharmacologic targets for human cancer chemoprevention. Cervical cancer is the most common gynaecologic malignancy in Hong Kong and about 80-90 % of this cancer are cervical squamous cell origin. Cervical squamous cell carcinoma is commonly preceded by a well-defined pre-malignant stage called cervical intraepithelial neoplasia (CIN). Our preliminary study was to investigate miRNAs in the tumorigenesis of cervical cancer. We examined the expression of 198 mature miRNAs using real-time RT-PCR in 24 microdissected CIN (including 11 cases of CIN grade II cases and 13 cases of CIN grade III) and compared that to 9 microdissected normal cervical epithelium specimens. When this data set of global miRNA expression profiling was analyzed using unsupervised hierarchical clustering, the normal samples were located in a single node, while the other tumors were clustered in a separate node. Supervised clustering analysis identified a group of 10 and 2 miRNA up-regulated and down-regulated, respectively, in CIN specimens. Their stringent (lower bound) fold-change of expression observed in CIN in relation to normal controls varied between 2.07 and 3.52-fold up-regulation, and between -2.67 and -2.81-fold down-regulation. In addition, when the miRNA expression profiles in CIN III were compared to those in CIN II, 2 miRNAs, miRNA-323 and miRNA-523 were significantly over-expressed in CIN III. The results obtained from this study suggest miRNA deregulation as an important event in cervical epithelial cell transformation. Unique miRNA candidate-pharmacologic targets for cervical cancer prevention might be further identified in expanded study of expression profiles and functional role of miRNAs in the cervical pre-malignancy and malignancy.