Publications by authors named "Laura Sichero"

50 Publications

Frequency of Human Papillomavirus Detection in Chagasic Megaesophagus Associated or Not with Esophageal Squamous Cell Carcinoma.

Pathobiology 2021 Oct 12:1-9. Epub 2021 Oct 12.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Background: Chagasic megaesophagus (CM) as well as the presence of human papillomavirus (HPV) has been reported as etiological factors for esophageal squamous cell carcinoma (ESCC).

Objective: We assessed the prevalence of HPV DNA in a series of ESCCs associated or not with CM. Data obtained were further correlated to the pathological and clinical data of affected individuals.

Methods: A retrospective study was performed on 92 formalin-fixed and paraffin-embedded tissues collected from patients referred to 3 different hospitals in São Paulo, Brazil: Barretos Cancer Hospital, Barretos, São Paulo; Federal University of Triângulo Mineiro, Uberaba, Minas Gerais; and São Paulo State University, Botucatu, São Paulo. Cases were divided into 3 groups: (i) 24 patients with CM associated with ESCC (CM/ESCC); (ii) 37 patients with ESCC without CM (ESCC); and (iii) 31 patients with CM without ESCC (CM). Detection of HPV DNA was assessed in all samples by a genotyping assay combining multiplex polymerase chain reaction and bead-based Luminex technology.

Results: We identified a high prevalence of high-risk HPV in patients in the CM group (12/31, 38.8%) and CM/ESCC (8/24, 33.3%), compared to individuals in the ESCC group (6/37, 16.3%). The individuals in the groups with cancer (ESCC and CM/ESCC) had a higher frequency of HPV-16 (4/9, 44.5% and 2/8, 25.0%). The other types of high-risk HPVs detected were HPV-31, 45, 51, 53, 56, 66, and 73. We also observed in some samples HPV coinfection by more than one viral type. Despite the high incidence of HPV, it did not show any association with the patient's clinical-pathological and molecular (TP53 mutation status) characteristics.

Conclusion: This is the first report of the presence of HPV DNA in CM associated with ESCC. HPV infection was more presence in megaesophagus lesions. Further studies are needed to confirm and better understand the role of persistent HPV infection in patients with CM.
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http://dx.doi.org/10.1159/000518697DOI Listing
October 2021

Biomarkers of human papillomavirus (HPV)-driven head and neck cancer in Latin America and Europe study: Study design and HPV DNA/p16 status.

Head Neck 2021 Nov 2. Epub 2021 Nov 2.

Center for Translational Research in Oncology, Instituto do Cancer do Estado de Sao Paulo ICESP, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo FMUSP HC, Sao Paulo, Brazil.

Background: Human papillomavirus (HPV)-driven head/neck squamous cell carcinomas (HNSCC) prevalence varies globally. We evaluated HPV DNA and p16 in formalin fixed paraffin embedded (FFPE) HNSCC from Argentina, Brazil, Colombia, and Peru.

Methods: HPV was genotyped by PCR-hybridization. All HPV DNA positive and some HPV DNA negative cases underwent p16 immunohistochemistry.

Results: HPV DNA was detected in 32.8%, 11.1%, and 17.8% of oropharyngeal (OPC), oral cavity (OCC) and laryngeal (LC) cancers, respectively. OPC HPV prevalence was higher in Colombia (94.7%), and Argentina (42.6%) compared to Brazil (10.6%) and Peru (0.0%). HPV-16 was the most detected. Other HPVs were found in LC. Higher rates of p16 positivity were observed among HPV positive OPC/OCC cases compared to LC cases.

Conclusions: Our results support a role for HPV-16 in a subset of HNSCC, corroborate the heterogeneity observed in samples from different countries, and contribute additional etiological and biomarkers information in tumors of significant impact worldwide.
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http://dx.doi.org/10.1002/hed.26912DOI Listing
November 2021

Disruption of miRNA-mRNA Networks Defines Novel Molecular Signatures for Penile Carcinogenesis.

Cancers (Basel) 2021 Sep 23;13(19). Epub 2021 Sep 23.

Departamento de Urologia, ICESP, HCFMUSP, Sao Paulo CEP 01246-000, SP, Brazil.

Penile cancer (PeC) carcinogenesis is not fully understood, and no biomarkers are reported in clinical practice. We aimed to investigate molecular signatures based on miRNA and mRNA and perform an integrative analysis to identify molecular drivers and pathways for PeC development. Affymetrix miRNA microarray was used to identify differentially expressed miRNAs (DEmiRs) comparing 11 tumoral tissues (TT) paired with non-neoplastic tissues (NNT) with further validation in an independent cohort ( = 13). We also investigated the mRNA expression of 83 genes in the total sample. Experimentally validated targets of DEmiRs, miRNA-mRNA networks, and enriched pathways were evaluated in silico. Eight out of 69 DEmiRs identified by microarray analysis were validated by qRT-PCR (miR-145-5p, miR-432-5p, miR-487b-3p, miR-30a-5p, miR-200a-5p, miR-224-5p, miR-31-3p and miR-31-5p). Furthermore, 37 differentially expressed genes (DEGs) were identified when comparing TT and NNT. We identified four downregulated DEmiRs (miR-30a-5p, miR-432-5p, miR-487b-3p, and miR-145-5p) and six upregulated DEGs (, , , , and ) as potential biomarkers in PeC by their capacity of discriminating TT and NNT with accuracy. The integration analysis showed eight dysregulated miRNA-mRNA pairs in penile carcinogenesis. Taken together, our findings contribute to a better understanding of the regulatory roles of miRNAs and altered transcripts levels in penile carcinogenesis.
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http://dx.doi.org/10.3390/cancers13194745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507530PMC
September 2021

E6/E7 Functional Differences among Two Natural Human Papillomavirus 18 Variants in Human Keratinocytes.

Viruses 2021 06 10;13(6). Epub 2021 Jun 10.

Center for Translational Research in Oncology, Instituto do Cancer do Estado de São Paulo (ICESP), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), São Paulo 01246-000, Brazil.

It is suggested that HPV-18 variants from the A lineage have higher oncogenic potential compared to B variants. Some studies show uneven distribution of HPV-18 variants in cervical adenocarcinomas and squamous cell carcinomas. Regarding HPV-18 variants' functions, the few studies reported focus on E6, and none were performed using natural host cells. Here, we immortalized primary human keratinocytes (PHKs) with E6/E7 of HPV-18 A1 and B1 sublineages and functionally characterized these cells. PHK18A1 reached immortalization significantly faster than PHK18B1 and formed a higher number of colonies in monolayer and 3D cultures. Moreover, PHK18A1 showed greater invasion ability and higher resistance to apoptosis induced by actinomycin-D. Nevertheless, no differences were observed regarding morphology, proliferation after immortalization, migration, or epithelial development in raft cultures. Noteworthy, our study highlights qualitative differences among HPV-18 A1 and B1 immortalized PHKs: in contrast to PHK18A1, which formed more compact colonies and spheroids of firmly grouped cells and tended to invade and migrate as clustered cells, morphologically, PHK18B1 colonies and spheroids were looser, and migration and invasion of single cells were observed. Although these observations may be relevant for the association of these variants with cervical cancer of different histological subtypes, further studies are warranted to elucidate the mechanisms behind these findings.
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http://dx.doi.org/10.3390/v13061114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228617PMC
June 2021

Dysregulation of Transcription Factor Networks Unveils Different Pathways in Human Papillomavirus 16-Positive Squamous Cell Carcinoma and Adenocarcinoma of the Uterine Cervix.

Front Oncol 2021 19;11:626187. Epub 2021 May 19.

Instituto Carlos Chagas, FIOCRUZ, Curitiba, Brazil.

Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are the most common histological types of cervical cancer (CC). The worse prognosis of ADC cases highlights the need for better molecular characterization regarding differences between these CC types. RNA-Seq analysis of seven SCC and three ADC human papillomavirus 16-positive samples and the comparison with public data from non-tumoral human papillomavirus-negative cervical tissue samples revealed pathways exclusive to each histological type, such as the epithelial maintenance in SCC and the maturity-onset diabetes of the young (MODY) pathway in ADC. The transcriptional regulatory network analysis of cervical SCC samples unveiled a set of six transcription factor (TF) genes with the potential to positively regulate long non-coding RNA genes , and . Additional analysis revealed a set of MODY TFs regulated in the sequence predicted to be repressed by miR-96-5p or miR-28-3p in ADC. These microRNAs were previously described to target LINC02381, which was predicted to be positively regulated by two MODY TFs upregulated in cervical ADC. Therefore, we hypothesize might act by decreasing the levels of miR-96-5p and miR-28-3p, promoting the MODY activation in cervical ADC. The novel TF networks here described should be explored for the development of more efficient diagnostic tools.
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http://dx.doi.org/10.3389/fonc.2021.626187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170088PMC
May 2021

Genetic variants of HPV-16 and their geographical and anatomical distribution in men: A systematic review with meta-analysis.

Virology 2021 Jun 18;558:134-144. Epub 2021 Mar 18.

The Center for Translational Research in Oncology, Instituto do Cancer do Estado de Sao Paulo ICESP, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo FMUSP HC, Sao Paulo, Brazil.

Background: The prevalence of Human Papillomavirus type 16 (HPV-16) variants in men and the association with tumor development has not been fully investigated. We estimated the prevalence of genital, anal, and oral HPV-16 infections in men through a systematic review and meta-analysis.

Methods: Seven databases were searched and included studies that identified HPV-16 positive males, HPV-16 variants (lineages/sublineages), and indicated the sample's anatomical origin. This protocol is registered in PROSPERO (CRD42020178013).

Results: The database searches yielded 14 studies including 445 HPV-16 positive samples classified as lineage A (n = 390), lineage D (n = 43), lineage B (n = 10), and lineage C (n = 2) variants. Lineage A variants predominated among the anatomical sites and the diverse geographical regions.

Conclusions: HPV-16 lineages vary according to anatomical and geographical region. According to this preliminary evaluation of the current literature, we hypothesize that, similar to women, specific HPV-16 variants may also be associated to increased cancer risk in men.
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http://dx.doi.org/10.1016/j.virol.2021.03.007DOI Listing
June 2021

Valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma patients and associated biomarkers.

Ecancermedicalscience 2020 15;14:1155. Epub 2020 Dec 15.

Department of Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Av Dr Arnaldo, 251 12th floor, CEP 01246-000, Sao Paulo, SP, Brazil.

Background: Cisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, however, relapses are frequent. Our goal was to evaluate if association of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with CCRT improved response rate (RR) and associated biomarkers.

Methods: This phase II trial included patients with unresectable locally advanced (LA) oropharynx (OP) squamous cell carcinoma. CCRT began after 2 weeks of VPA (P1). Primary goal was RR at 8 weeks after chemoradiation (CRT)+VPA (P2). Biomarkers included microRNA (miR) polymerase chain reaction (PCR)-array profiling in plasma compared to healthy controls by two-sample t-test. Distribution of p-values was analysed by beta-uniform mixture. Findings were validated by real-time PCR quantitative polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. p16, HDAC2 and RAD23 Homolog B, Nucleotide Excision Repair Protein (HR23B) tumour immunohistochemistry were evaluated.

Results: Given significant toxicities, accrual was interrupted after inclusion of ten LA p16 negative OP patients. All were male, smokers/ex-smokers, aged 41-65 and with previous moderate/high alcohol intake. Nine evaluable patients yielded a RR of 88%. At false discovery rate of 5%, 169 miRs were differentially expressed between patients and controls, including lower expression of tumour suppressors (TSs) such as miR-31, -222, -let-7a/b/e and -145. miR-let-7a/e expression was validated by qPCR using saliva. A HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease-free survival.

Conclusions: VPA and CRT offered high RR; however, with prohibitive toxicities, which led to early trial termination. Patients and controls had a distinct pattern of miR expression, mainly with low levels of TS miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122).
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http://dx.doi.org/10.3332/ecancer.2020.1155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864693PMC
December 2020

Prevalence of human papillomavirus 6 and 11 variants in recurrent respiratory papillomatosis.

J Med Virol 2021 06 30;93(6):3835-3840. Epub 2020 Sep 30.

Center for Translational Research in Oncology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.

Human papillomavirus (HPV) types 6 and 11 are the etiological agents of recurrent respiratory papillomatosis (RRP). We examined the prevalence and distribution of HPVs 6 and 11 genetic variants in juvenile onset (JORRP) and adult onset (AORRP) laryngeal papillomas. Cases of JORRP and AORRP were collected, retrospectively. HPV detection and genotyping were accessed by polymerase chain reaction-sequencing in 67 RRP samples. Overall, the most prevalent HPV-6 variants were from B1 (55.8%) and B3 (27.9%) sublineages, whereas among HPV-11 positive samples A2 (62.5%) variants were predominant. A higher prevalence of HPV-6 B1 was observed in JORRP (83.3% B1 and 16.7% B3), compared with AORRP cases (58.3% B1 and 41.7% B3). HPV-11 A2 variants were more prevalent both in JORRP (57.2%) and in AORRP cases (70.0%). Nevertheless, with the exception that HPV-6 B1 were significantly less likely to recur, there was a lack of association between any particular HPVs 6 or 11 variant and clinicopathological features. Our data do not support an association between HPVs 6 and 11 variability and RRP.
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http://dx.doi.org/10.1002/jmv.26503DOI Listing
June 2021

Human papillomavirus type 18 E5 oncoprotein cooperates with E6 and E7 in promoting cell viability and invasion and in modulating the cellular redox state.

Mem Inst Oswaldo Cruz 2020 16;115:e190405. Epub 2020 Mar 16.

Universidad de la República, Facultad de Ciencias, Sección Virología, Montevideo, Uruguay.

Background: High-risk human papillomaviruses (HR-HPVs) are the etiological agents of cervical cancer. Among them, types 16 and 18 are the most prevalent worldwide. The HPV genome encodes three oncoproteins (E5, E6, and E7) that possess a high transformation potential in culture cells when transduced simultaneously. In the present study, we analysed how these oncoproteins cooperate to boost key cancer cell features such as uncontrolled cell proliferation, invasion potential, and cellular redox state imbalance. Oxidative stress is known to contribute to the carcinogenic process, as reactive oxygen species (ROS) constitute a potentially harmful by-product of many cellular reactions, and an efficient clearance mechanism is therefore required. Cells infected with HR-HPVs can adapt to oxidative stress conditions by upregulating the formation of endogenous antioxidants such as catalase, glutathione (GSH), and peroxiredoxin (PRX).

Objectives: The primary aim of this work was to study how these oncoproteins cooperate to promote the development of certain cancer cell features such as uncontrolled cell proliferation, invasion potential, and oxidative stress that are known to aid in the carcinogenic process.

Methods: To perform this study, we generated three different HaCaT cell lines using retroviral transduction that stably expressed combinations of HPV-18 oncogenes that included HaCaT E5-18, HaCaT E6/E7-18, and HaCaT E5/E6/E7-18.

Findings: Our results revealed a statistically significant increment in cell viability as measured by MTT assay, cell proliferation, and invasion assays in the cell line containing the three viral oncogenes. Additionally, we observed that cells expressing HPV-18 E5/E6/E7 exhibited a decrease in catalase activity and a significant augmentation of GSH and PRX1 levels relative to those of E5, E6/E7, and HaCaT cells.

Main Conclusions: This study demonstrates for the first time that HPV-18 E5, E6, and E7 oncoproteins can cooperate to enhance malignant transformation.
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http://dx.doi.org/10.1590/0074-02760190405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066992PMC
April 2020

Antiviral activity of curcumin-nanoemulsion associated with photodynamic therapy in vulvar cell lines transducing different variants of HPV-16.

Artif Cells Nanomed Biotechnol 2020 Dec;48(1):515-524

Laboratory of Genomic Studies, Sao Paulo State University - UNESP, São Paulo, Brazil.

Vulvar intraepithelial neoplasia (VIN) is associated with human papillomavirus (HPV) infection. Curcumin is a natural bioactive compound with antineoplastic properties. The use of nanoparticles containing curcumin could allow a better performance of this compound in therapies. So, VIN biopsies were collected and HPV DNA detection was performed by PCR, positive samples were genotyped by Restriction Fragment Length Polymorphism (RFLP) and HPV-16 variants were determined by sequencing. HPV-16 positive vulva carcinoma cells (A431) were transduced with E-P and E-350G HPV-16 E6 variants. The viability of the transduced cells treated with nanoemulsions was determined by MTT assay. Besides, apoptosis was evaluated by enzymatic activity of Caspase-3/7. The cell viability assay showed that both the empty nanoemulsion (NE-V) and the nanoemulsion of curcumin (NE-CUR) had little effect on cell viability as compared to control cells. Additionally, we observed that cells irradiated in the presence of NE-CUR presented 90% of cell death. The apoptosis assay further revealed a significant increase in the activity of caspases 3 and 7 in A431 cells expressing both HPV-16 E6 variants after treatment with NE-CUR. Finally, we submitted the HPV transduced A431 cells to organotypic cultures and observed that the combination of treatments affected tissue architecture with evident signals of tissue damage. We concluded that nanoemulsions attain good biocompatibility, since no cytotoxicity was observed and NE-CUR associated with photoactivation showed promising results, leading to death only in cells subjected to irradiation. This drug delivery system associated with photodynamic therapy may become promising in the treatment of vulva lesions.
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http://dx.doi.org/10.1080/21691401.2020.1725023DOI Listing
December 2020

Role of epstein-barr virus in the severity of recurrent respiratory papillomatosis.

Laryngoscope 2020 11 20;130(11):E611-E618. Epub 2019 Dec 20.

Center for Translational Investigation in Oncology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Objective: The objective was to investigate the prevalence of the Epstein-Barr virus (EBV) and its association with human papilloma virus (HPV) detection, clinicopathological features, and the severity of recurrent respiratory papillomatosis (RRP).

Methods: Cases of juvenile recurrent respiratory papillomatosis (JRRP) (n = 36) and adult recurrent respiratory papillomatosis (ARRP) (n = 44) were collected retrospectively and subdivided into low- and high-risk severity groups based on the Derkay score. We performed HPV detection and genotyping using a reverse hybridization protocol and investigated the presence of EBV by polymerase chain reaction (PCR) and in situ hybridization. CD21 levels were accessed by immunohistochemistry.

Results: All samples were HPV-positive, including 49 cases of HPV 6, 26 cases of HPV 11, four cases of HPV 6 and 11 coinfections, and one case of HPV 16. EBV-DNA was detected in nine samples by PCR, although none of the cases were positive by means of in situ hybridization. CD21 immunoexpression was not statistically associated with any of the variables analyzed. HPV 6 detection was significantly higher in ARRP cases (P = 0.03), whereas HPV 11 was more prevalent in JRRP cases (P = 0.02) and was even more prevalent in JRRP cases of greater severity (Derkay laryngoscopic scale ≥20) (P = 0.04).

Conclusion: The presence of EBV does not seem to play an important role in the progression/severity of RRP.

Level Of Evidence: 4 Laryngoscope, 130:E611-E618, 2020.
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http://dx.doi.org/10.1002/lary.28465DOI Listing
November 2020

Diversity of human papillomavirus typing among women population living in rural and remote areas of Brazilian territory.

Papillomavirus Res 2019 12 17;8:100186. Epub 2019 Sep 17.

Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital, Pio XII Foundation, Brazil; Medical Laboratory of Medical Investigation (LIM) 14. Department of Pathology, Faculty of Medicine, Universidade de São Paulo, Brazil; Research Institute of Life and Health Sciences (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS / 3B's - Associated Laboratory to the Government of Portugal, Braga, Guimarães, Portugal. Electronic address: http://www.icvs.uminho.pt.

Objectives: Genotyping HPV from samples tested positive to careHPV™ assay in rural and remote areas of Brazilian territory.

Methods: A total of 5079 women were enrolled in an opportunistic screening from the Barretos Cancer Hospital, through mobile units or ambulatory unit. All careHPV™ hr-HPV positive samples were tested by a Luminex-based protocol in order to evaluate the HPV infecting types.

Results: Positive hr-HPV results were obtained in 10.6% (536/5068) of women. Among these cases, HPV-56 and HPV-51 were the most common types detected in 32.3% and 31.4%, respectively. HPV-53 (20.5%), HPV-18 (18.5%), HPV-58 (17.6%), HPV-52 (16.0%) and HPV-16.6%) were the other most frequent types detected. These frequencies represent prevalences of 2.35%, 2.12%, 2.02%, 1.84% and 1.80% respectively, within the population studied. Regarding low-risk HPVs, HPV-6 was detected in 12.9% of the samples. The less frequent types (<3%) were: HPV-70, HPV-11 and HPV-26.

Conclusions: The most frequent types detected were: HPV-56, HPV-51, HPV-53, HPV-18, HPV-58, HPV-52 and HPV-16 according to decreasing rates.
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http://dx.doi.org/10.1016/j.pvr.2019.100186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804508PMC
December 2019

Human papillomavirus is not associated to non-small cell lung cancer: data from a prospective cross-sectional study.

Infect Agent Cancer 2019 2;14:18. Epub 2019 Aug 2.

1Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Barretos, Brazil.

Background: The pathogenesis of lung cancer is triggered by a combination of genetic and environmental factors, being the tobacco smoke the most important risk factor. Nevertheless, the incidence of lung cancer in non-smokers is gradually increasing, which demands the search for different other etiological factors such as occupational exposure, previous lung disease, diet among others. In the early 80's a theory linked specific types of human papillomavirus (HPV) to lung cancer due to morphological similarities of a subset of bronchial squamous cell carcinomas with other HPV-induced cancers. Since then, several studies revealed variable rates of HPV DNA detection. The current study aimed to provide accurate information on the prevalence of HPV DNA in lung cancer.

Methods: Biopsies were collected from 77 newly diagnosed non-small cell lung cancer (NSCLC) patients treated at the Thoracic Oncology Department at Barretos Cancer Hospital. The samples were formalin fixed and paraffin embedded (FFPE), histologic analysis was performed by an experienced pathologist. DNA was extracted from FFPE material using a commercial extraction kit and HPV DNA detection was evaluated by multiplex PCR and HPV16 specific real-time PCR.

Results: HPV was not identified in any of the samples analysed (69).

Conclusions: Our data demonstrated a lack of HPV DNA in a series of NSCL cancers.
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http://dx.doi.org/10.1186/s13027-019-0235-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679449PMC
August 2019

Lack of Association between Human Papillomavirus Types 6 and 11 Genetic Variants and Cervical Abnormalities: The Ludwig-McGill Cohort Study.

Cancer Epidemiol Biomarkers Prev 2019 06 13;28(6):1086-1088. Epub 2019 Mar 13.

Division of Cancer Epidemiology, McGill University, Montreal, Canada.

Background: Human papillomavirus (HPV) types 6 and 11 are mainly associated with the development of genital warts and recurrent respiratory papillomatosis. We examined intratypic genetic variability of both viral types with the development of cervical cytologic abnormalities in Brazilian women.

Methods: We used PCR sequencing to characterize variants of HPVs 6 and/or 11 in cervical swabs from women in the Ludwig-McGill Cohort Study. We used a binomial generalized estimating equations (GEE) model with logit link to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations between HPV 6 and 11 variants and cytologic abnormalities.

Results: B1 and B3 HPV6 and A2 HPV11 variants were the most common isolates identified. Compared with HPV6-negative women, the ORs among women harboring HPV6 B1 or B3 variants were 6.3 (95% CI, 2.3-17.0) and 2.3 (95% CI, 0.6-9.7) for atypical cells of undetermined significance (ASCUS)/low squamous intraepithelial lesions (LSIL), respectively, and 1.7 (95% CI, 0.6-5.1) and 1.2 (95% CI, 0.3-4.7) for ASCUS/LSIL/high squamous intraepithelial lesions (HSIL). Respective ORs were 5.0 (95% CI, 1.7-14.6) and 2.8 (95% CI, 1.0-8.1) upon comparing women with HPV11 A2 variants to HPV11-negative women. All associations disappeared when adjusting for coinfections with high-risk HPV types.

Conclusions: Our data do not support an association between low-risk HPVs 6 and 11 genetic variability and cervical abnormalities.

Impact: Risk of cervical cytologic abnormalities is not affected by intratypic polymorphism in HPVs 6 and 11.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548638PMC
June 2019

Human Papillomavirus and Genital Disease in Men: What We Have Learned from the HIM Study.

Acta Cytol 2019 22;63(2):109-117. Epub 2019 Feb 22.

Center for Translational Research in Oncology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, Brazil,

It is currently recognized that in addition to the major impact of human papillomavirus (HPV) infection in females, HPV causes considerable disease in men at the genitals, anal canal, and oropharynx. Specifically, genital HPV infections may progress to genital warts and penile carcinoma. Although studies concerning the natural history of HPV infections and associated neoplasias have mainly focused on women, during the last 2 decades considerable attention has been given in further understanding these infections in men. The HIM (HPV infection in men) Study, the only prospective multicenter study of male HPV natural history, consisted of a large prospective international cohort study in which men from Brazil, the United States, and Mexico were enrolled. The design and protocols of this study allowed unraveling crucial information regarding the relationship between HPV infection and clinical consequences in men, and associated risk factors at each of the anatomic sites where HPV is known to cause cancer in men.
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http://dx.doi.org/10.1159/000493737DOI Listing
May 2019

Beta Human Papillomavirus and Associated Diseases.

Acta Cytol 2019 23;63(2):100-108. Epub 2019 Jan 23.

Infections and Cancer Biology Group, International Agency for Research on Cancer, World Health Organization, Lyon, France.

The cutaneous human papillomavirus (HPV), mostly from β- and γ-HPV genus, is ubiquitously distributed throughout the human body and may be part of the commensal flora. The association of β-HPVs and cutaneous squamous cell carcinoma (cSCC) development was initially reported in patients with the rare genetic disorder Epidermodysplasia verruciformis. Likewise, immunosuppressed organ transplant recipients have an increased susceptibility to β-HPV infections in the skin as well as to cSCC development. Although ultraviolet radiation (UVR) is the main risk factor of cSCC, experimental data points toward β-HPVs as co-carcinogens, which appear to be required solely at early stages of skin carcinogenesis by facilitating the accumulation of UVR-induced DNA mutations. Several epidemiological studies relying on different biomarkers of β-HPV infections have also been conducted in immunocompetent individuals to access their association with cSCC development. Additionally, in vivo and in vitro studies are presenting cumulative evidence that E6 and E7 proteins from specific β-HPVs exhibit transforming activities and may collaborate with different environmental factors in promoting carcinogenesis. Nevertheless, further research is crucial to better understand the pathological implications of the broad distribution of these HPVs.
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http://dx.doi.org/10.1159/000492659DOI Listing
May 2019

Regulation of HPV transcription.

Clinics (Sao Paulo) 2018 10 11;73(suppl 1):e486s. Epub 2018 Oct 11.

Centro de Pesquisa Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.

Human papillomavirus infection is associated with the development of malignant and benign neoplasms. Approximately 40 viral types can infect the anogenital mucosa and are categorized into high- and low-risk oncogenic human papillomavirus, depending on their association with the development of cervical carcinoma. High-risk human papillomavirus 16 and 18 are detected in 55% and 15% of all invasive cervical squamous cell carcinomas worldwide, respectively. Low-risk human papillomavirus 6 and 11 are responsible for 90% of genital warts and are also associated with the development of recurrent respiratory papillomatosis. Human papillomavirus preferentially infects mitotic active cells of the basal layer from both mucosal and cutaneous epithelium through microabrasions. The viral life cycle synchronizes with the epithelial differentiation program, which may be due, in part, to the binding of differentially expressed cellular transcription factors to the long control region throughout the various epithelial layers. This review aimed to summarize the current knowledge regarding the mechanisms by which viral gene expression is regulated and the influence of human papillomavirus heterogeneity upon this phenomenon. A better understanding of the regulatory mechanisms may elucidate the particularities of human papillomavirus-associated pathogenesis and may provide new tools for antiviral therapy.
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http://dx.doi.org/10.6061/clinics/2018/e486sDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157067PMC
October 2018

Epidemiology and biology of cutaneous human papillomavirus.

Clinics (Sao Paulo) 2018 08 20;73(suppl 1):e489s. Epub 2018 Aug 20.

Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.

Cutaneous human papillomaviruses (HPVs) include β- and γ-HPVs, in addition to a small fraction of α-HPVs. β-HPVs were first isolated from patients with the rare genetic disorder Epidermodysplasia verruciformis, and they are associated with the development of nonmelanoma skin cancer at sun-exposed skin sites in these individuals. Organ transplant recipients also have greater susceptibility to β-HPV infection of the skin and an increased risk of developing nonmelanoma skin cancer. In both immunosuppressed and immunocompromised individuals, cutaneous HPVs are ubiquitously disseminated throughout healthy skin and may be an intrinsic part of the commensal flora. Functional analysis of E6 and E7 proteins of specific cutaneous HPVs has provided a mechanistic comprehension of how these viruses may induce carcinogenesis. Nevertheless, additional research is crucial to better understand the pathological implications of the broad distribution of these HPVs.
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http://dx.doi.org/10.6061/clinics/2018/e489sDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097087PMC
August 2018

HPV infection and p53 and p16 expression in esophageal cancer: are they prognostic factors?

Infect Agent Cancer 2017 13;12:54. Epub 2017 Oct 13.

Teaching and Research Institute, Barretos Cancer Hospital - Pius XII Foundation, Rua Antenor Duarte Vilela, 1331, Dr. Paulo Prata, Barretos, São Paulo 14784-400 Brazil.

Background: Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignant tumor. Currently, Human papillomavirus (HPV) is suggested as a potential risk factor for esophageal cancer (EC) in addition to the classic risk factors, alcohol and tobacco, but this hypothesis still remains contradictory. We sought to investigate wether HPV and well-known biomarkers (p16 and p53) and patient-related factors that may have impact on survival of ESCC.

Methods: We conducted a prospective cohort study. By using multiplex PCR, we determined the prevalence of high risk HPV in ESCC, and evaluated the immunohistochemical expression of p16 and p53, molecular markers related to esophageal carcinogenesis in order to verify the potential influence of these variables in patients's survival. Survival rates were estimated using Kaplan-Meier methods. A multivariate confirmatory model was performed using Cox proportional hazards regression.

Results: Twelve (13.8%) of 87 patients were HPV-DNA positive. Positive reactions of p16 and p53 were 10.7% and 68.6%, respectively. Kaplan-Meier analysis indicated that men ( = 0.025) had poor specific-cancer survival and a shorter progression-free survival ( = 0.050) as compared to women; III or IV clinical stage ( < 0.019) had poor specific-cancer survival and a shorter progression-free survival ( < 0.001) compared to I and II clinical stage; not submitted to surgery (<0.001) and not submitted to chemoradiotherapy ( = 0.039) had a poor specific-cancer survival, as well. The multivariate analysis showed that HPV, p16 and p53 status are not predictive parameters of progression-free and specific-cancer survival.

Conclusion: HPV infection and p53 and p16 expression are not prognostic factors in ESCC.
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http://dx.doi.org/10.1186/s13027-017-0163-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640908PMC
October 2017

Prevalence of high risk HPV DNA in esophagus is high in Brazil but not related to esophageal squamous cell carcinoma.

Histol Histopathol 2018 Apr 6;33(4):357-363. Epub 2017 Sep 6.

Teaching and Research Institute, Barretos Cancer Hospital - Pius XII Foundation, Brazil.

Backgrounds: The first publication that associated Human Papillomavirus (HPV) infection and esophageal cancer was published in 1982. However, data are still contradictory and require further investigation. The aim of this study was to identify high risk HPV DNA in esophageal tissue of patients with and without esophageal squamous cell carcinoma (ESCC) and correlate HPV presence with classical risk factors.

Methods: Invited patients signed the informed consent form, and interviews were conducted in order to obtain information about sociodemographic and lifestyle behavior. During endoscopy, esophageal biopsies were collected from case and controls. Multiplex polymerase chain reaction genotyping was conducted on endoscopic biopsies to identify HPV types and HPV-16 was further evaluated by specific PCR real time.

Results: Among 87 cases, 12 (13.8%) had tumors harboring high risk HPV DNA and among 87 controls, 12 (13.8%) had high risk HPV DNA (OR:1.025 [CI:0.405:2.592]). Variables regarding consumption of alcohol and use of tobacco continued to characterize risk factors even after adjustments by presence or absence of high risk HPV.

Conclusion: HPV was demonstrated to be frequently and similarly associated to normal and malignant esophageal tissues, but not as an independent risk factor to esophageal cancer.

Impact: To contribute to the Brazilian population data on this subject, which is still contradictory.
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http://dx.doi.org/10.14670/HH-11-929DOI Listing
April 2018

HPV-11 variability, persistence and progression to genital warts in men: the HIM study.

J Gen Virol 2017 09 15;98(9):2339-2342. Epub 2017 Aug 15.

Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

HPV-11 and HPV-6 are the etiological agents of about 90 % of genital warts (GWs). The intra-typic variability of HPV-11 and its association with infection persistence and GW development remains undetermined. Here, HPV infection in men (HIM) participants who had an HPV-11 genital swab and/or GW, preceded or not by a normal skin genital swab were analysed. Genomic variants were characterized by PCR-sequencing and classified within lineages (A, B) and sublineages (A1, A2, A3, A4). HPV-11 A2 variants were the most frequently detected in the genital swab samples from controls and in both genital swabs and GW samples from cases. The same HPV-11 variant was detected in the GW sample and its preceding genital swab. There was a lack of association between any particular HPV-11 variant and the increased risk for GW development.
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http://dx.doi.org/10.1099/jgv.0.000896DOI Listing
September 2017

Concordance of Beta-papillomavirus across anogenital and oral anatomic sites of men: The HIM Study.

Virology 2017 10 11;510:55-59. Epub 2017 Jul 11.

Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. Electronic address:

We evaluated the concordance between β-HPVs detected in external genital skin, anal canal, and oral cavity specimens collected simultaneously from 717 men that were participating in the multinational HIM Study. Viral genotyping was performed using the Luminex technology. Species- and type-specific concordance was measured using kappa statistics for agreement. Overall, concordance of β-HPVs across sites was low and mainly observed among paired genital/anal canal samples. When grouped by species, solely β-4 HPVs showed moderate concordance in genital/anal pairs (κ = 0.457), which could be attributed to the substantial concordance of HPV-92 in men from Brazil and Mexico (κ > 0.610). β-HPV type concordance was higher in Mexico, where HPV-19 was consistently concordant in all anatomic site combinations. Our analysis indicates that type-specific concordance across sites is limited to few viral types; however, these infections seem to occur more often than would be expected by chance, suggesting that although rare, there is agreement among sites.
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http://dx.doi.org/10.1016/j.virol.2017.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561082PMC
October 2017

The Relation of HPV Infection and Expression of p53 and p16 Proteins in Esophageal Squamous Cells Carcinoma.

J Cancer 2017 9;8(6):1062-1070. Epub 2017 Apr 9.

Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil.

To investigate the HPV prevalence and characterize the expression of potential molecular surrogate markers of HPV infection in esophageal squamous cell carcinoma. The prevalence of HPV in individuals with and without esophageal cancer (EC) was determined by using multiplex PCR; p16 and p53 protein levels were assessed by immunohistochemistry (IHC). High-risk HPV (hr-HPV) was found in the same frequency (13.8%) in esophageal squamous cell carcinoma (ESCC) and in healthy individuals. The p53 expression was positive in 67.5% of tumor tissue, 20.0% of adjacent non-tumoral tissue and 1.8% of normal esophageal tissue. p16 was positive in 11.6% of esophageal cancer cases and 4.7% of adjacent non-tumoral tissue. p16 was undetectable among control group samples. p53 and p16 levels were not significantly associated with the HPV status. These results suggest that hr-HPV types are not associated with the development of ESCC and that p53 and p16 protein expression have no relationship with HPV infection in normal or cancerous esophagus.
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http://dx.doi.org/10.7150/jca.17080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436260PMC
April 2017

HPV-related external genital lesions among men residing in Brazil.

Braz J Infect Dis 2017 Jul - Aug;21(4):376-385. Epub 2017 Apr 8.

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, Centro de Investigação Translacional em Oncologia, São Paulo, SP, Brazil; Universidade de São Paulo, Faculdade de Medicina, Departamento de Radiologia e Oncologia, São Paulo, SP, Brazil. Electronic address:

The aims of this study were to determine the incidence of external genital lesions (EGLs), specifically histologically confirmed condyloma (genital warts) and Penile Intraepithelial Neoplasia (PeIN), and genital HPV infection progression to EGLs among healthy men aged 18-73 residing in Brazil. Subjects included 1118 men enrolled in the HPV Infection in Men (HIM) study between July 2005 and June 2009. At each visit, EGLs were biopsied and subjected to pathological evaluation. HPV status in genital swabs and biopsies was determined by Linear Array and INNO-LiPA, respectively. Age-specific EGLs incidence and the proportion and median time to EGL development were estimated. Kaplan-Meier cumulative incidence rates at 6, 12, and 24 months were determined. During follow-up, 73 men developed an incident EGL. Men could develop multiple EGLs and there were 36 men with condyloma, 27 men with lesions suggestive of condyloma, six men with PeIN, and 20 men with non-HPV lesions. HPV-positive men who developed EGLs were younger (p=0.002) than men that did not develop lesions. Among the 815 men with HPV infection, 4% progressed to EGL with the same HPV detected in the swab. During follow up, 15.7% of genital HPV-6 and HPV-11 infections progressed to condyloma (median progression time of nine months for HPV-6 versus 6.8 months for HPV-11). Approximately 1% of HPV-16 infections progressed to PeIN with a median progression time of 25 months. HPV types covered by the 4-valent HPV vaccine were detected in 82.3% and 83.3% of condyloma and PeIN, respectively. The high burden of HPV and high frequency of progression to disease underscores the need to offer HPV prophylactic vaccination to men to reduce the overall burden of infection and diseases caused by HPV.
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http://dx.doi.org/10.1016/j.bjid.2017.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561086PMC
August 2017

Cervical Infection with Cutaneous Beta and Mucosal Alpha Papillomaviruses.

Cancer Epidemiol Biomarkers Prev 2017 08 4;26(8):1312-1320. Epub 2017 Apr 4.

Center for Translational Investigation in Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Alpha-human papillomavirus (α-HPV) plays a causal role in cervical cancer, but little is known about the epidemiology of genital Beta-human papillomavirus (β-HPV) infection. We used Luminex and PCR hybridization to detect β- and α-HPVs prevalence at enrollment and 12-month follow-up in cervical samples from 505 women enrolled in the Ludwig-McGill cohort study. We compared epidemiologic correlates of both β- and α-HPVs and compared genotypes between these genera with respect to co-occurrence and association with cervical cytologic abnormalities. Infection with β-HPV types was more prevalent than that with α-HPV types at both visits (cumulative prevalences: 27.3% vs. 21.6%, respectively, = 0.034). β-HPVs were mostly transient; however, only 1.98% women retained their original positivity at 12 months, whereas persistence was higher for α-HPVs (5.15%; = 0.007). Age, parity, and sexual activity variables were predictors of α-HPV but not of β-HPV. α- and β-HPV types occurred independently. Increased risk of cervical abnormalities was restricted to women infected with α-9 or α-6 HPV types. We found no epidemiologic correlates for β-HPV infections. Detection of β-HPV types in the cervix tends to occur as random and transient episodes not explained via the sexual-transmission correlates that characterize infections by α-HPVs. Although it is plausible that β-HPVs may play a direct or indirect carcinogenic role, the lack of epidemiologic correlates for detection episodes of these viruses and lack of association with cervical lesions speak against their ancillary role as sexually transmitted agents in cervical carcinogenesis. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540752PMC
August 2017

HPV-6 Molecular Variants Association With the Development of Genital Warts in Men: The HIM Study.

J Infect Dis 2017 02;215(4):559-565

Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil.

Background: Human papillomavirus type 6 (HPV-6) and HPV-11 are the etiological agents of approximately 90% of genital warts (GWs). The impact of HPV-6 genetic heterogeneity on persistence and progression to GWs remains undetermined.

Methods: HPV Infection in Men (HIM) Study participants who had HPV-6 genital swabs and/or GWs preceded by a viable normal genital swab were analyzed. Variants characterization was performed by polymerase chain reaction sequencing and samples classified within lineages (A, B) and sublineages (B1, B2, B3, B4, B5). Country- and age-specific analyses were conducted for individual variants; odds ratios and 95% confidence intervals for the risk of GWs according to HPV-6 variants were calculated.

Results: B3 variants were most prevalent. HPV-6 variants distribution differed between countries and case status. HPV-6 B1 variants prevalence was increased in GWs and genital swabs of cases compared to controls. There was difference in B1 and B3 variants detection in GW and the preceding genital swab. We observed significant association of HPV-6 B1 variants detection with GW development.

Conclusions: HPV-6 B1 variants are more prevalent in genital swabs that precede GW development, and confer an increased risk for GW. Further research is warranted to understand the possible involvement of B1 variants in the progression to clinically relevant lesions.
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http://dx.doi.org/10.1093/infdis/jiw600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388291PMC
February 2017

The differential role of HTRA1 in HPV-positive and HPV-negative cervical cell line proliferation.

BMC Cancer 2016 11 3;16(1):840. Epub 2016 Nov 3.

Department of Biology, Instituto de Biociências, Letras e Ciências Exatas - IBILCE/UNESP, Rua Cristóvão Colombo n° 2265, Jardim Nazareth, CEP 15054-000, São José do Rio Preto, SP, Brazil.

Background: High-risk human papillomaviruses (HPVs) are strongly associated with the development of some malignancies. The E6 and E7 viral oncoproteins are the primary proteins responsible for cell homeostasis alteration and immortalization. Furthermore, the E6 protein from high-risk HPVs can interact with the PDZ (PSD-90/Dlg/ZO-1) domains of cellular proteins, triggering cell transformation. One protein that is associated with pathological conditions and has a PDZ domain is the protease HTRA1 (high temperature requirement 1). This protein is poorly expressed in some cancers, suggesting a tumor suppressor role. The aim of this study was to evaluate the effect of HTRA1 overexpression in HPV16-positive (CasKi) and HPV-negative (C33) cervical cell lines.

Methods: The cells were transfected with a vector containing the HTRA1 ORF or an empty vector. HTRA1 overexpression was confirmed by qRT-PCR. The cells were subjected to cell proliferation, colony formation, apoptosis and cell cycle assays.

Results: C33 cells expressing HTRA1 grew significantly fewer colonies and showed less proliferation than cells without HTRA1 expression. In contrast, in the CasKi cells overexpressing HTRA1, there was an increase in the cell growth rate and in the colonies density compared to cells expressing low levels of HTRA1. An apoptosis assay showed that HTRA1 does not interfere with the apoptosis rate in these cells. A cell cycle immunofluorescence assay revealed more CasKi cells overexpressing HTRA1 in the S phase and more C33 HTRA1-transfected cells in the G0/G1 phase, suggesting that HTRA1 plays different roles in the cell cycle progression of these cells.

Conclusions: HTRA1 overexpression prevents cell proliferation in the HPV-negative cell line and increases cell proliferation in the HPV-positive cell line. Although the E6/HTRA1 interaction has already been described in the literature, more studies are required to confirm whether the present functional findings are a result of this interaction.
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http://dx.doi.org/10.1186/s12885-016-2873-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095955PMC
November 2016

Cutaneous beta human papillomaviruses and the development of male external genital lesions: A case-control study nested within the HIM Study.

Virology 2016 10 10;497:314-322. Epub 2016 Aug 10.

Center for Infection Research in Cancer, Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

Background: Cutaneous human papillomaviruses (HPVs) increase the risk of non-melanoma skin cancer in sun-exposed skin. We examined the role of beta-HPV in the development of male external genital lesions (EGLs), a sun-unexposed site.

Methods: In this nested case-control study (67 men with pathologically-confirmed EGLs and 134 controls), exfoliated cells collected from the surface of lesions and normal genital skin 0, 6, and 12 months preceding EGL development were tested for beta-HPV DNA using a type-specific multiplex genotyping assay. Beta-HPV prevalence was estimated and conditional logistic regression was used to evaluate the association with condyloma, the most common EGL.

Results: While beta-HPV prevalence among controls remained stable, the prevalence among cases was lowest on the surface of lesion. Detecting beta-HPV on the normal genital skin was not associated with the presence or development of condyloma.

Conclusions: Cutaneous beta-HPV does not appear to be contributing to pathogenesis in male genital skin.
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http://dx.doi.org/10.1016/j.virol.2016.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997247PMC
October 2016

HPV16 E6 regulates annexin 1 (ANXA1) protein expression in cervical carcinoma cell lines.

Virology 2016 09 28;496:35-41. Epub 2016 May 28.

Department of Biology, Institute of Bioscience, Language and Exact Science, São Paulo State University, São Jose do Rio Preto, Brazil. Electronic address:

Annexin 1 (ANXA1) is a substrate for E6AP mediated ubiquitylation. It has been hypothesized that HPV 16 E6 protein redirects E6AP away from ANXA1, increasing its stability and possibly contributing to viral pathogenesis. We analyzed ANXA1 expression in HPV-positive and negative cervical carcinoma-derived cells, in cells expressing HPV-16 oncogenes and in cells transduced with shRNA targeting E6AP. We observed that ANXA1 protein expression increased in HPV-16-positive tumor cells, in keratinocytes expressing HPV-16 E6wt (wild-type) or E6/E7 and C33 cells expressing HPV-16 E6wt. ANXA1 protein expression decreased in cells transfected with E6 Dicer-substrate RNAs (DsiRNA) and C33 cells cotransduced with HPV-16 E6wt and E6AP shRNA. Moreover, colony number and proliferation rate decreased in HPV16-positive cells transduced with ANXA1 shRNA. We observed that in cells infected with HPV16, the E6 binds to E6AP to degrade p53 and upregulate ANXA1. We suggest that ANXA1 may play a role in HPV-mediated carcinogenesis.
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http://dx.doi.org/10.1016/j.virol.2016.05.016DOI Listing
September 2016

Diversity of beta-papillomavirus at anogenital and oral anatomic sites of men: The HIM Study.

Virology 2016 08 7;495:33-41. Epub 2016 May 7.

Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. Electronic address:

Our goal was to describe prevalence of β-HPVs at three anatomic sites among 717 men from Brazil, Mexico and US enrolled in the HPV Infection in Men (HIM) Study. β-HPVs were genotyped using Luminex technology. Overall, 77.7%, 54.3% and 29.3% men were positive for any β-HPV at the genitals, anal canal, and oral cavity, respectively. Men from US and Brazil were significantly less likely to have β-HPV at the anal canal than men from Mexico. Older men were more likely to have β-HPV at the anal canal compared to younger men. Prevalence of β-HPV at the oral cavity was significantly associated with country of origin and age. Current smokers were significantly less likely to have β-HPV in the oral cavity than men who never smoked. Lack of associations between β-HPV and sexual behaviors may suggest other routes of contact such as autoinoculation which need to be explored further.
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http://dx.doi.org/10.1016/j.virol.2016.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949595PMC
August 2016
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