Transcriptomic Landscape of Gene Expression Profiles and Pathways in JORRP Tumor Tissues and HPV6/11 E6-E7-overexpressing HNSCC Cell Lines

Juvenile-onset recurrent respiratory papillomatosis (JORRP) is the most common benign laryngeal neoplasm in children and is considered to be primarily caused by human papillomavirus (HPV) types 6 and 11. In the present study, we performed RNA sequencing (RNA-seq) of 8 tumors and 4 adjacent nontumor tissues to explore the transcriptional profiles of JORRP tumors. A total of 1151 upregulated genes involved in the signaling and 1620 downregulated genes involved in dysregulated inflammatory responses were reported. Immunohistochemistry (IHC) assays confirmed the upregulation of IL-17C in JORRP tumors compared with paired adjacent nontumor tissues. Real-time PCR (RT-PCR) assays showed positive correlations between CXCL1 and CXCL8 and the Derkay Clinic Score of JORRP patients. We further overexpressed the HPV6 or HPV11 E6 and E7 oncogenes in SNU-1076 head and neck squamous cell carcinoma (HNSCC) cell lines and carried out RNA-seq. We found that HPV6-E6-E7 gene overexpression resulted in only 16 upregulated genes and 1 downregulated gene; however, HPV11-E6-E7 gene overexpression resulted in 1776 upregulated genes and 461 downregulated genes compared with the control cell lines. The DEGs of HPV11-E6-E7 gene overexpression were positively enriched in the DNA replication-related terms by Gene Ontology (GO) analysis and the signaling by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Taken together, our present findings revealed signaling pathway-related gene profiles that might contribute to disease pathogenesis and that the HPV11 E6 and E7 oncogenes promote disease progression by enhancing tumor growth and activating the signaling in JORRP patients. Importance JORRP is primarily caused by HPV 6 and HPV11 infection, however, the gene signatures of tumor are less understood currently. In the present study, we performed RNA-sequencing and found up-regulated genes associated with IL-17 signaling pathway and down-regulated genes associated with inflammatory-related pathways. Further RNA-sequencing was performed in HPV6-E6-E7 or HPV11-E6-E7 over-expressing SNU-1076 HNSCC cells lines to explore the potential pathogenic molecular mechanisms of HPV virus. We found HPV11-E6-E7 over-expression resulted in gene expressions related to DNA replication and signaling pathway. Our results suggested enriched signaling resulted from HPV11 infection might contribute to JORRP pathogenesis.