Penile cancer (PeCa) is a rare tumor, generally associated with socioeconomic conditions in low-income countries. Hence, a delay in diagnosis and treatment leads in more advanced tumors, to higher comorbidity, and mortality. Human papillomavirus (HPV) infection has been identified as one of the major risk factors for PeCa. In addition, viral integration sites have been related to copy number alterations, impacting miRNAs/mRNA interactions and, consequently, the molecular pathways related to them. Nonetheless, studies on differentially expressed miRNAs (miRDEs) in PeCa are still scarce, especially in PeCa associated with high-risk HPV (hrHPV). To investigate the role of these gene regulators in PeCa progression, 827 miRNAs (Nanostring Technologies™, Seattle, WA, USA) were evaluated in 22 hrHPV-associated penile squamous cell carcinomas and five non-tumor penile tissues. For functions of miRNAs/target genes and relationship with HPV we conducted an integrated analysis by Diana Tools, KEGG, HPVbase, and InterSPPI-HVPPI platforms. We found that 25 miRNAs of the most differentially expressed impact 43 top molecular pathways, of which the fatty acid biosynthesis pathway, prions, miRNAs in cancer and hippo signaling (P<1.0-325, for each) were the most statistically significant. Notably, 23 out of 25 are located at HPV integration sites (HPVis). MiR-1206, miR-376b-3p and miR-495-3p were downregulated and associated with perineural invasion. In addition, a comparison between advanced and early diseases revealed 143 miRDEs. ROC analysis of a single (miR-376a-2-5p), paired (miR-376a-2-5p, miR-551b-3p) or combination of five miRDEs (miR-99a-5p, miR-150-5p, miR-155-5p, let-7c-5p, miR-342-3p) showed robust discriminatory power (AUC = 0.9; P = 0.0114, for each). Strikingly, miR-376a-2-5p exhibited the highest values of sensitivity and specificity, with 100% and 83.3%, respectively, indicating this miRNA as a potential prognostic marker in hrHPV-penile carcinogenesis.
American journal of cancer research. 2023 Nov 15*** epublish ***
Jenilson M Silva, Amanda J Deus, André A M Vale, Ana Paula S Azevedo-Santos, Leudivan Nogueira, Ana C Laus, Luciane Sussuchi, Rui M Reis, Alexander Birbrair, André S Khayat, Silma Regina Pereira
Postgraduate Program in Health Science, Federal University of Maranhão São Luís 65080-805, MA, Brazil., Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão São Luís 65080-805, MA, Brazil., Laboratory of Applied Cancer Immunology, Department of Physiological Sciences, Federal University of Maranhão São Luís 65080-805, MA, Brazil., Aldenora Bello Cancer Hospital São Luís 65031-630, MA, Brazil., Molecular Oncology Research Center, Barretos Cancer Hospital Barretos 14784-400, SP, Brazil., Department of Pathology, Federal University of Minas Gerais Belo Horizonte 31270-901, MG, Brazil., Oncology Research Center, Federal University of Pará Belém 66073-005, PA, Brazil.