Overexpression of ANXA1 in Penile Carcinomas Positive for High-Risk HPVs

Marilia Freitas Calmon,Ana Paula Girol,José Germano Ferraz De Arruda,Bruno Miziara Rosa,Luisa Lina Villa,Rodrigo Vellasco Duarte Silvestre,Fernando Augusto Soares,Érica Babeto,Jane Lopes Bonilha,Gustavo Hernandez Américo Medeiros,Carlos Fabian Mendiburu,Paula Rahal,Natália Maria Candido,Sonia Maria Oliani,Jorge Alberto Thomé,José Vassallo,Mânlio Tasso De Oliveira Mota,Gustavo Cardoso Guimarães,Amanda Ewart Toland

doi:10.1371/journal.pone.0053260

Abstract

The incidence of penile cancer varies between populations but is rare in developed nations. Penile cancer is associated with a number of established risk factors and associated diseases including phimosis with chronic inflammation, human papillomavirus (HPV) infection, poor hygiene and smoking. The objective of this study was to identify genes related to this type of cancer. The detection of HPV was analyzed in 47 penile squamous cell carcinoma samples. HPV DNA was detected in 48.9% of penile squamous cell carcinoma cases. High-risk HPV were present in 42.5% of cases and low-risk HPV were detected in 10.6% of penile squamous cell carcinomas. The RaSH approach identified differential expression of Annexin A1 (ANXA1), p16, RPL6, PBEF1 and KIAA1033 in high-risk HPV positive penile carcinoma; ANXA1 and p16 were overexpressed in penile squamous cells positive for high-risk HPVs compared to normal penile samples by qPCR. ANXA1 and p16 proteins were significantly more expressed in the cells from high-risk HPV-positive penile carcinoma as compared to HPV-negative tumors (p<0.0001) independently of the subtype of the carcinoma. Overexpression of ANXA1 might be mediated by HPV E6 in penile squamous cell carcinoma of patients with high-risk HPVs, suggesting that this gene plays an important role in penile cancer.

Highlights

Penile cancer affects predominantly men aged between 50 and 70 years [1,2,3]
Pathological Findings and human papillomavirus (HPV) Detection The presence of penile squamous cell carcinoma was confirmed in all samples analyzed using a histopathological revision examination; these samples were subjected to DNA extraction for molecular analysis
High-risk HPVs were present in 42.5% (20/47) of the cases and low-risk HPVs were identified in 10.6% (5/47) of penile squamous cell carcinoma samples

Summary

Introduction

Penile cancer affects predominantly men aged between 50 and 70 years [1,2,3]. Penile cancer is associated with several established risk factors and associated diseases including phimosis with chronic inflammation, human papillomavirus (HPV) infection, poor hygiene and smoking [4]. Studies reported an overall HPV prevalence of, approximately, 48% in penile cancer worldwide [5,6]. HPV 16 is most prevalent in North America, Europe, South America and India [5,7]. HPV contributes to tumorigenesis predominantly through the action of viral oncoproteins (E6 and E7) [8]. E6 inhibits apoptotic signaling in response to growth-suppressive cytokines by interacting with tumor necrosis factor (TNF)-a receptor TNFR1, FASassociated protein with death domain (FADD) and caspase 8, and via degradation of pro-apoptotic BAX and BAK. E6 can interfere with the regulation of expression of genes by interacting with and binding to the proteins mentioned above, prompting the interest of some researchers in identifying new genes whose expression can be disturbed by E6 protein

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