Comprehensive bioinformatic analysis reveals oncogenic role of H2A.Z isoforms in cervical cancer progression.

Objectives: Cervical cancer ranks as the fourth most common neoplasia in women worldwide in which epigenetic alterations play an important role. Several studies have reported pro-oncogenic role of the histone variant H2A.Z in different types of cancer; however, the role of H2A.Z in cervical cancer remains poorly studied. This study aimed to determine the potential role of H2A.Z in cervical cancer through a bioinformatic approach. Materials and Methods: H2A.Z expression was analyzed in The Human Protein Atlas, The Cancer Genome Atlas, and Gene Expression Omnibus datasets. The promoter regions of H2AZ1 and H2AZ2 genes were downloaded from Expasy, and the prediction of transcription factor binding motifs was performed using CONSITE, Alibaba, and ALGGEN. ChIP-seq and RNA-seq data from HeLa-S3 cells were downloaded from ENCODE. The discovery motif was investigated using MEME-ChIP. The functional annotation was examined in Enrich. Results: The expression of H2A.Z is elevated in cervical cancer. Interestingly, DNA methylation, copy number, and transcription factors AP2α and ELK1 are involved in H2A.Z overexpression. Additionally, H2A.Z is enriched on promoter and enhancer regions of genes involved in pathways associated with cancer development. In these regions, H2A.Z enables the recruitment of transcription factors such as NRF1, NFYA, and RNA Pol II. Finally, H2A.Z allows the expression of genes associated with proliferation in patients with cervical cancer. Conclusion: Our findings suggest that H2A.Z overexpression and its presence in promoters and enhancers could be regulating the transcription of genes involved in cervical carcinogenesis.

Presence of Papillomavirus DNA sequences in the canine transmissible venereal tumor (CTVT).

BACKGROUND: The canine transmissible venereal tumor (CTVT) or Sticker's sarcoma is a neoplastic disease affecting dogs. This disease is presented as a tumoral mass in the genital organs of both, male and female individuals. Up to date, there is no clear evidence indicating a viral agent as the causative mediator for CTVT development. PURPOSE: The present work aims to analyze 21 samples from canines with CTVT for molecular identification of Papillomavirus DNA sequences. In addition, microbiological analysis, cytologic and histopathologic evaluations were also performed. RESULTS: All patients showed no biochemical and microbiological alterations. Molecular analysis demonstrated the viral DNA presence in the samples using different primer sets. The MY primers amplified a 450 bp band in seven out of 21 samples (33%). The PVF and Fap64 primer set, targeting the L1 sequence of Canine Papillomavirus (CPV), showed positivity in 16 out of 21 samples (76%). CONCLUSION: These results support the possible causative association between CPV and CTVT; nevertheless, additional studies are required to uphold such statement. This work presents evidence indicating that a viral agent might be involved in the pathogenesis of CTVT and set the bases for a better understanding of the CTVT pathobiology.

The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA.

Persistent infection with high-risk Human Papillomavirus (HR-HPV) is the main requisite for cervical cancer development. Normally, HPV is limited to the site of infection and regulates a plethora of cellular elements to avoid the immune surveillance by inducing an anti-inflammatory state, allowing the progress through the viral cycle and the carcinogenic process. Recent findings suggest that the AT-hook transcriptional factor AKNA could play a role in the development of cervical cancer. AKNA is strongly related to the expression of co-stimulatory molecules such CD40/CD40L to achieve an anti-tumoral immune response. To date, there is no evidence demonstrating the effect of the HPV E6 oncoprotein on the AT-hook factor AKNA. In this work, minimal expression of AKNA in cervical carcinoma compared to normal tissue was found. We show the ability of E6 from high-risk HPVs 16 and 18 to interact with and down-regulate AKNA as well as its co-stimulatory molecule CD40 in a proteasome dependent manner. We also found that p53 interacts with AKNA and promotes AKNA expression. Our results indicate that the de-regulation of CD40 and AKNA is induced by the HPV E6 oncoprotein, and this event involves the action of p53 suggesting that the axis E6/p53A/AKNA might play an important role in the de-regulation of the immune system during the carcinogenic process induced by HR-HPV.