Upregulated miRNAs on the TP53 and RB1 Binding Seedless Regions in High-Risk HPV-Associated Penile Cancer

Abstract

Cancer development by the human papillomavirus (HPV) infection can occur through the canonical HPV/p53/RB1 pathway mediated by the E2/E6/E7 viral oncoproteins. During the transformation process, HPV inserts its genetic material into host Integration Sites (IS), affecting coding genes and miRNAs. In penile cancer (PeCa) there is limited data on the miRNAs that regulate mRNA targets associated with HPV, such as the TP53 and RB1 genes. Considering the high frequency of HPV infection in PeCa patients in Northeast Brazil, global miRNA expression profiling was performed in high-risk HPV-associated PeCa that presented with TP53 and RB1 mRNA downregulated expression. The miRNA expression profile of 22 PeCa tissue samples and five non-tumor penile tissues showed 507 differentially expressed miRNAs: 494 downregulated and 13 upregulated (let-7a-5p, miR-130a-3p, miR-142-3p, miR-15b-5p miR-16-5p, miR-200c-3p, miR-205-5p, miR-21-5p, miR-223-3p, miR-22-3p, miR-25-3p, miR-31-5p and miR-93-5p), of which 11 were identified to be in HPV16-IS and targeting TP53 and RB1 genes. One hundred and thirty-one and 490 miRNA binding sites were observed for TP53 and RB1, respectively, most of which were in seedless regions. These findings suggest that up-regulation of miRNA expression can directly repress TP53 and RB1 expression by their binding sites in the non-canonical seedless regions.

Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients

“…Our previous studies corroborate the role of HPV in PeCa, showing a high frequency of cytobands with copy number alterations (CNAs) harboring HPVis, as well as the impact of miRNA/mRNA changes on HPV-related molecular pathways [ 10 , 11 , 12 ]. However, the molecular characterization of these tumors, especially upon HPV infection, is still limited.…”

“…Altogether, these results point out that SNV/Indels in these genes may be related to penile carcinogenesis regardless of HPV infection. On the other hand, we have previously suggested that downregulation of TP53 and RB1 mRNAs in PSCC [ 10 ] occurs through the upregulation of 13 miRNAs mapped at HPVis [ 12 ]. We also reported the impact of HPVis-localized CNAs on miRNA/mRNA interactions, which may alter critical pathways, such as P53 signaling, hippo and TGF-β signaling, proteoglycans in cancer, and viral carcinogenesis [ 11 ].…”

The role of microRNA-142a in Toxoplasma gondii infection-induced downregulation of Foxp3: implications for adverse pregnancy outcomes

“…P53 (also known as TP53 in humans and TrP53 in mice), a canonical tumor suppressor, acts as an oncogenic modulator and mediates intracellular repair in different cell types [ 44 , 45 ]. P53 functionally tunes transcriptional regulation including miRNA genes [ 46 ]. P53 induces up-regulation of miR-194 expression in THBS1 retrovirus-induced HCT116 cells, consequently, with the decreased thrombospondin-1 (TSP-1) [ 47 ].…”

Microbiome reveals inflammatory‐related bacteria and putative functional pathways involved in human papillomavirus‐associated penile squamous cell carcinoma

“…Adjacent tissues were collected 2 cm away from the primary tumor, within the surgical safety margin, and classified through histopathological and immunohistochemical analysis 20 . In addition, gene expression, miRNA expression, copy number alteration, and exome sequencing data support that penile tumor‐adjacent tissues are a suitable normal control in relation to the tumors 21–23 . The cancer staging was determined using the 2016 World Health Organization tumor–node–metastasis (TNM) classification 24,25 …”

“…20 In addition, gene expression, miRNA expression, copy number alteration, and exome sequencing data support that penile tumor-adjacent tissues are a suitable normal control in relation to the tumors. [21][22][23] The cancer staging was determined using the 2016 World Health Organization tumor-node-metastasis (TNM) classification. 24,25 The mean age of patients at the time of diagnosis was 62.6 ± 16.5 years, with a range of 32-85 years.…”