Certain Alphapapillomavirus species classified as high-risk human papillomaviruses (HR-HPVs) have been recognized as the etiologic factors of invasive cervical carcinoma worldwide (1, 2). HR-HPV infections are frequent in young women but they are generally transient, with an estimated mean duration of incident infection of 16 months (3). Only persistent HR-HPV infections are associated with an increased risk of developing high-grade cervical lesions or cancer of the cervix (4-6). Persistent HR-HPV infections may be associated with microscopic abnormalities called low-grade squamous intraepithelial lesions (LSIL). These LSIL present a high rate of regression following HPV clearance but may progress toward high-grade squamous intraepithelial lesions (HSIL) if HR-HPV infection persists. Upon diagnosis, HSIL are treated mostly by excisional procedures to avoid the risk of progression toward invasive cancer (for a review, see reference 7).Among the HR-HPV types, HPV16 exhibits the highest persistence rate (8). Moreover, HPV16 is associated with an increased risk of developing precancerous and cancerous lesions (9) and is considered the most carcinogenic PV in humans (10). This is probably why HPV16 prevalence increases with the severity of cervical lesions (11), reaching 61% in invasive cervical carcinoma worldwide (12).HPV-associated carcinogenesis requires the continuous overexpression of the two main viral oncoproteins E7 and E6, which interact with many cellular proteins leading to the induction and the maintenance of a transformed phenotype in infected cells (for a review, see reference 13). E7 and E6 expression is regulated by the viral E2 protein through the early promoter (named p97 for HPV16) located in the long control region (LCR) of the PV genome. This promoter harbors four specific E2-binding sites (E2BSs) sharing the consensus sequence 5=-ACCG(N) 4 15). The three sites proximal to the TATA box have been shown to be involved in E2-mediated repression of the promoter activity, and E2BS1 and E2BS2 are probably the main sites to achieve this effect (for a review, see reference 16). From a mechanistic point of view, the binding of E2 to E2BS1 and E2BS2 induces a displacement of transcription activators, such as specificity protein 1 (Sp1) and TATA binding protein (TBP), from their binding sites, leading to a repression of E7 and E6 expression from the early promoter (17, 18). HR-HPV DNA integration has been described as a key step in the carcinogenesis process, since it generally results in the disruption of the E2 open reading frame (ORF) (19,20).Epigenetic alterations, and particularly aberrant DNA methylation, are frequently associated with tumor progression. Methylation of DNA mainly occurs on cytosines located in CpG dinucle-
High-risk human papillomaviruses are the etiological agents of cervical cancer and HPV16 is the most oncogenic genotype. Immortalization and transformation of infected cells requires the overexpression of the two viral oncoproteins E6 and E7 following HPV DNA integration into the host cell genome. Integration often leads to the loss of the E2 open reading frame and the corresponding protein can no longer act as a transcriptional repressor on p97 promoter. Recently, it has been proposed that long control region methylation also contributes to the regulation of E6/E7 expression.To determine which epigenetic mechanism is involved in HPV16 early gene regulation, 5-aza-2′-deoxycytidine was used to demethylate Ca Ski and SiHa cell DNA. Decreased expression of E6 mRNA and protein levels was observed in both cell lines in an E2-independent manner. E6 repression was accompanied by neither a modification of the main cellular transcription factor expression involved in long control region regulation, nor by a modification of the E6 mRNA splicing pattern. In contrast, a pronounced upregulation of miR-375, known to destabilize HPV16 early viral mRNA, was observed. Finally, the use of miR-375 inhibitor definitively proved the involvement of miR-375 in E6 repression. These results highlight that cellular DNA methylation modulates HPV16 early gene expression and support a role for epigenetic events in high-risk HPV associated-carcinogenesis.
Preeclampsia (PE) is a hypertensive disease that affects pregnant women after 20 weeks of gestation. This disease is associated with an important risk of maternal and fetal mortality. PE is described as a placental pathology because, after delivery, most women recover normal arterial pressure. Poor invasion of the spiral arteries is a phenomenon well described in PE; this leads to a hypoxic uterine bed and imbalance of antiangiogenic and proangiogenic factors in the uteroplacental region, which in turn triggers the disease phenotype. The causes of the pathology are unclear; nevertheless, numerous approaches, including next-generation sequencing, association, and case control and miRNA studies, have shed light on the genetic/molecular basis of PE. These studies help us better understand the disease to advance new treatment strategies.
Primary ovarian insufficiency (POI) is a frequently occurring disease affecting women under 40 years old. Recently, we have analyzed unrelated POI women via whole exome sequencing (WES) and identified NOTCH2 mutations underlying possible functional effects. The present study involved reanalyzing of WES assays. We used in the KGN granulosa-like cell model, a synthetic gene reporter construct driving luciferase gene expression to assess the functional effects of five NOTCH2 mutations identified in POI patients. We found that NOTCH2-p.Ser1804Leu, p.Ala2316Val, and p.Pro2359Ala mutations had a functional impact on the protein's transcrip-
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