Abstract
Cervical cancer is a common malignant tumor worldwide ranking fourth in incidence and mortality among females, which was reduced significantly by cytology screening and human papilloma virus (HPV) DNA testing. The specificity of cytology is high; however, the sensitivity is low, in contrast to the HPV DNA testing. Despite the success of these measures, new biomarkers are still considered to aim increasing sensitivity and specificity of screening and diagnosis. Significant alterations in microRNA (miRNA) expression have been detected in several cancers with variable consistency. To investigate the stratification role of miRNAs between normal epithelium and cervical intraepithelial neoplasia (CIN2–3), we screened the expression of 667 miRNAs to identify significant markers (n = 10), out of them 9 miRNAs were applied in the study (miR-20b, −24, −26a, −29b, −99a, −100, −147, −212, −515-3p) along with RNU48 and U6 as the references. To benchmark the miRNAs, 22 paired (tumor-free and tumor tissue pairs) laser microdissection-obtained cervical formalin fixed, paraffin embedded tissue samples were assayed. The expression of miR-20b was 2.4 times higher in CIN2–3 samples as compared to normal tissues (p < 0.0001). In the HPV16-positive subsets of the samples (n = 13), miR-20b showed 2.9-times elevation (p < 0.001), whereas miR-515 was 1.15-times downregulated (p < 0.05) in CIN2–3 as compared to normal tissue. These results suggest the potential value of miR-20b as a statification biomarker in order to differentiate neoplastic and non-tumorous cases.
Highlights
In order to assess the expression of these selected 9 miRNAs in high-grade squamous intraepithelial lesions (HSIL)/CIN2–3 and surrounding morphologically non-altered (“normal”) epithelium, further 22 paired formalin fixed paraffin embedded (FFPE) cervical samples were used from the patient cohort
Statistical analysis of the miRNA expressions in the sample pairs showed a 2.4 fold overexpression of miR-20b in HSIL/CIN2–3 samples compared to normal tissues with high statistical significance (p < 0.0001) (Fig. 1)
Our results demonstrated significantly increased expression of miR-20b in HSIL/CIN2–3 lesions in comparison to the surrounding morphologically non-altered cervical epithelium; while increased miR-212 and decreased miR-515 expression were detected, these expressional differences were not statistically significant regarding the whole study population
Summary
2nd Department of Pathology, Semmelweis University, Budapest Hungary. Nuffield Department of Clinical Neurosciences, Sleep & Circadian Neuroscience Institute, Oxford University, Oxford UK. Discovery of the etiological role of the human papilloma virus (HPV) in cervical carcinogenesis [5] and the introduction of populationbased vaccination programs were further steps towards the prevention of cervical cancer [6]. It became clear, that while being highly specific, the sensitivity of cytology is relatively low regarding the detection of high-grade squamous intraepithelial lesions (HSIL) or cervical intraepithelial neoplasia (CIN) [7]. The demonstration of high-risk HPV (hrHPV) infection does not prove whether the infection is transient or of the transforming type. [6, 8,9,10]
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