Transcriptomic landscape of gene expression profiles and pathways in JORRP tumor tissues and HPV6/11 E6-E7-overexpressing HNSCC cell lines

J Virol. 2021 Oct 20;JVI0134221. doi: 10.1128/JVI.01342-21. Online ahead of print.

Abstract

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 IL-17 signaling pathway 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 IL-17 signaling pathway by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Taken together, our present findings revealed IL-17 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 IL-17 signaling pathway 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 IL-17 signaling pathway. Our results suggested enriched IL-17 signaling pathway resulted from HPV11 infection might contribute to JORRP pathogenesis.