An integrative approach toward identification and analysis of therapeutic targets involved in HPV pathogenesis with a focus on carcinomas

Article type: Research Article

Authors: Gupta, Amit Kumar^a | Kumar, Manoj^{a; b; *}

Affiliations: [a] Virology Unit and Bioinformatics Centre, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Chandigarh, India | [b] Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India

Correspondence: [*] Corresponding author: Manoj Kumar, Virology Unit and Bioinformatics Centre, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39-A, Chandigarh 160036, India. Tel.: +91 172 2880158; E-mail: [email protected].

Abstract: BACKGROUND: Persistent infection of high-risk HPVs is known to cause diverse carcinomas, mainly cervical, oropharyngeal, penile, etc. However, efficient treatment is still lacking. OBJECTIVE: Identify and analyze potential therapeutic targets involved in HPV oncogenesis and repurposing drug candidates. METHODS: Integrative analyses were performed on the compendium of 1887 HPV infection-associated or integration-driven disrupted genes cataloged from the Open Targets Platform and HPVbase resource. Potential target genes are prioritized using STRING, Cytoscape, cytoHubba, and MCODE. Gene ontology and KEGG pathway enrichment analysis are performed. Further, TCGA cancer genomic data of CESC and HNSCC is analyzed. Moreover, regulatory networks are also deduced by employing NetworkAnalyst. RESULTS: We have implemented a unique approach for identifying and prioritizing druggable targets and repurposing drug candidates against HPV oncogenesis. Overall, hundred key genes with 44 core targets were prioritized with transcription factors (TFs) and microRNAs (miRNAs) regulators pertinent to HPV pathogenesis. Genomic alteration profiling further substantiated our findings. Among identified druggable targets, TP53, NOTCH1, PIK3CA, EP300, CREBBP, EGFR, ERBB2, PTEN, and FN1 are frequently mutated in CESC and HNSCC. Furthermore, PIK3CA, CCND1, RFC4, KAT5, MYC, PTK2, EGFR, and ERBB2 show significant copy number gain, and FN1, CHEK1, CUL1, EZH2, NRAS, and H2AFX was marked for the substantial copy number loss in both carcinomas. Likewise, under-explored relevant regulators, i.e., TFs (HINFP, ARID3A, NFATC2, NKX3-2, EN1) and miRNAs (has-mir-98-5p, has-mir-24-3p, has-mir-192-5p, has-mir-519d-3p) is also identified. CONCLUSIONS: We have identified potential therapeutic targets, transcriptional and post-transcriptional regulators to explicate HPV pathogenesis as well as potential repurposing drug candidates. This study would aid in biomarker and drug discovery against HPV-mediated carcinoma.

Keywords: HPVs, oncogenesis, therapeutic targets, cervical cancer, HNSCC, TCGA, repurposed drugs

DOI: 10.3233/CBM-210413

Journal: Cancer Biomarkers, vol. 36, no. 1, pp. 31-52, 2023