Background: Cervical cancer is the third most common disease and the fourth leading cause of death in female's worldwide. Treatment of this disease is successful when detection is at early neoplasic stages. Hence, multiple efforts have been pursued for early detection of cervical neoplasia. The aim of this study was to analyze the differential expression of mitochondrial non-coding RNAs or ncRNA (sense and antisense) in normal and neoplastic cervical biopsies as a potential tool for diagnostic of cervical cancer. Methods: The expression pattern of the sense and the antisense mitochondrial ncRNAs in cervical biopsies was carried out by chromogenic in situ hybridization (ISH). We examined 17 normal cervical tissues, 108 early and late neoplasias and 24 invasive cervical carcinomas. The hybridization results were compared with the diagnostic of each specimen carried out by pathologists. Results: Like normal human keratinocytes, normal cervical epithelium expresses the sense and the antisense mitochondrial ncRNAs at the basal layer of the epithelium. Interestingly, ISH reveals that the antisense transcripts are always localized in the nucleus of basal cells in normal cervical epithelium. Early and late cervical intraepithelial neoplasia as well as invasive cervical carcinoma expresses the sense transcript. In contrast, the antisense transcripts are down-regulated in early and late neoplasia and in invasive cervical carcinoma. Conclusions: This pilot study indicates that down-regulation of the antisense mitochondrial transcripts at early stages of cervical neoplasia can be explored as a diagnostic tool for early cervical neoplasia.
Objective: Cervical cancer is the second most common cancer in women with high rates of mortality worldwide. Cervical cancer is slowly progressive and is preceded by pre-invasive intraepithelial lesions. Therefore, detection of premalignant lesions is key to preventing disease progression to advanced stages. The objective of the present study was examination and quantification of the differentially expressed non-coding mitochondrial RNAs during progression of disease. Material and methods:The differential expression of S-ncmtRNA and AS-ncmtRNA was analyzed by in situ hybridization (ISH) using tissue macroarrays (TMA) from normal, CIN1, CIN2, CIN3 and invasive squamous carcinoma (SCC). PCNA and p16INK-4a were detected in consecutive biopsies by immunohistochemistry. Quantification of ISH signal was carried out with Image ProPlus 6.1 software and the results were expressed as percentage of Integrated Optical Density (IOD). Results:We found a marked down-regulation of AS-ncmtRNA in 95% of tissues analyzed (CIN 1/2, CIN 3, and invasive squamous cancer). Moreover, differential expression of ASncmtRNA v/s S-ncmtRNA showed significant difference. Normal proliferating tissues did not display down-regulation of AS-ncmtRNA. Down regulation of ASncmtRNA correlated with the expression of the tumor suppressor protein p16INK-4a Conclusions:We found down-regulation of AS-ncmtRNA in pre-malignant and tumor samples which could distinguish normal tissues from early lesions and tumor samples. These results suggest that the down-regulation of AS-ncmtRNA is a novel marker of early lesions and cervix neoplasia. Previously, we reported that human cells express a unique family of mitochondrial long ncmtRNAs (ncmtRNAs) [12,13]. One of these transcripts, named sense ncmtRNA (SncmtRNA) is expressed in normal proliferating cells and tumor cells but not in resting cells, suggesting a functional role in cell cycle progression [12]. Normal proliferating cells express, in addition to the S-ncmtRNA, two antisense mitochondrial ncmtRNAs (AS-ncmtRNA-1 and AS-ncmtRNA-2) where both AS-ncmtRNAs are down-regulated in human cancer cells regardless of tissue of origin. In order to analyze the expression pattern of these ncmtRNAs in cervical cancer, we performed a qualitative pilot study in cervical biopsies encompassing the progression of the disease. We found that AS-ncmtRNAs are down-regulated in mild, moderate and severe neoplasia and in invasive cervical carcinoma [14]. In the present study a quantitative analysis of the differential expression of the S-ncmtRNA and the ASncmtRNAs was performed in biopsies of CIN1 to CIN3 and invasive cervical carcinoma, correlating it with the expression of the tumor suppressor p16 Assessment of the Expression of LongINK 4A and proliferating cell nuclear antigen (PCNA). Methods Tissue specimensAll the tissues were purchased from Pantomics Inc. (Richmond, CA, USA), corresponding to Tissue Macroarrays (TMA) containing normal cervix, CIN1, CIN2, CIN3 and invasive squamous carcinoma (SCC). For normal specimens,...
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