Abstract
BackgroundThe aberrant expression of miR-23b is involved in the development and progression of cancer. The aim of this study was to evaluate the potential role of methylation in the silencing of miR-23b in cervical cancer cell lines and to determine its expression in stages of malignant progression and in cervical cancer tissues HPV16-positive.MethodsThe methylation of the miR-23b promoter was determined in HeLa, SiHa, CaSki and C33A cells using a Human Cancer miRNA EpiTectMethyl II Signature PCR Array®. The cells were treated with 5-Aza-2′-deoxycytidine, and the expression of miR-23b, uPa, c-Met and Zeb1 was determined by qRT-PCR. miR-92a and GAPDH were used as controls. The expression of miR-23b was determined in cervical scrapes and biopsies of women without squamous intraepithelial lesions, with precursor lesions and with cervical cancer, all were HPV16-positive. The Fisher exact and Mann–Whitney tests were used to compare the differences of the expression of miR-23b, uPa, c-Met and Zeb1 among cell groups, and the difference among patients, respectively. The association between the expression of miR-23b and cervical cancer was determined by logistic regression with a confidence level of 95 %. A value of p < 0.05 was considered statistically significant.ResultsIn C33A, HeLa and CaSki cells, methylation was associated with decreased expression of miR-23b. After treatment with 5-Aza-CdR, the expression of miR-23b increased in all cell lines and the expression of c-Met decreased in HeLa cells, while uPa and Zeb1 decreased in C33A and CaSki cells. In SiHa cells the expression of uPa, c-Met and Zeb1 increased. The expression of miR-23b decreased in relation to the increase in the severity of the lesion and was significantly lower in cervical cancer. In women with premalignant lesions HPV16-positive, decreased levels of miR-23b increased the risk of cervical cancer (OR = 36, 95 % CI = 6.7-192.6, p < 0.05).ConclusionsThe results suggest that the expression of miR-23b is regulated by the methylation of its promoter and is possible that this microRNA influence the expression of uPa, c-Met and Zeb1 in cervical cancer cells lines. In women with premalignant lesions and cervical cancer infected with HPV16, the expression level of miR-23b agree with a tumor suppressor gene.
Highlights
The aberrant expression of miR-23b is involved in the development and progression of cancer
The most significant findings of this study were as follows: 1) the miR-23b promoter is methylated in cervical cancer cell lines; 2) the expression of miR-23b is low in cervical cancer cell lines; 3) the expression of miR-23b increases significantly in HeLa, SiHa, CaSki and C33A cells after treatment with 5′-Aza-CdR; 4) the expression of miR-23b is higher in Low-grade squamous intraepithelial (LSIL) than in highgrade squamous intraepithelial lesions (HSIL) and cervical cancer, that is, it decreases as the grade of the lesion increases; 5) in biopsies positive for HPV16 cervical cancer, the expression level of miR-23b is similar to that found in HeLa, SiHa, CaSki and C33A cell lines, and 6) the expression of uPa, c-Met and Zeb1, which are likely targets for miR-23b, is different among cervical cancer cell lines
We found that the expression of miR-23b is higher in LSILs than in HSILs and cervical cancer, that is, the expression of this miRNA decreased as the grade of the lesion increased
Summary
The aberrant expression of miR-23b is involved in the development and progression of cancer. The aim of this study was to evaluate the potential role of methylation in the silencing of miR-23b in cervical cancer cell lines and to determine its expression in stages of malignant progression and in cervical cancer tissues HPV16-positive. The high-risk human papillomavirus (HR-HPV) causes cervical cancer [1], and this infection is associated with precancerous lesions of the cervix [2, 3]. The aberrant expression of miRNAs has been associated with the maintenance of the undifferentiated state of cancer cells [8]. The miR-23b gene is encoded in the human chromosome 9q22.32 in a cluster that includes miR-24-1 and miR-27b, the mature sequences of each miRNA are differentially expressed [11, 12]
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