Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes

Abstract

High-risk human papillomavirus (HR HPV) causes nearly all cervical cancers, half of which are due to HPV type 16 (HPV16). HPV16 oncoprotein E6 (16E6) binds to NFX1-123, and dysregulates gene expression, but their clinical implications are unknown. Additionally, HPV16 E7’s role has not been studied in concert with NFX1-123 and 16E6. HR HPVs express both oncogenes, and transformation requires their expression, so we sought to investigate the effect of E7 on gene expression. This study’s goal was to define gene expression profiles across cervical precancer and cancer stages, identify genes correlating with disease progression, assess patient survival, and validate findings in cell models. We analyzed NCBI GEO datasets containing transcriptomic data linked with cervical cancer stage and utilized LASSO analysis to identify cancer-driving genes. Keratinocytes expressing 16E6 and 16E7 (16E6E7) and exogenous NFX1-123 were tested for LASSO-identified gene expression. Ten out of nineteen genes correlated with disease progression, including CEBPD, NOTCH1, and KRT16, and affected survival. 16E6E7 in keratinocytes increased CEBPD, KRT16, and SLPI, and decreased NOTCH1. Exogenous NFX1-123 in 16E6E7 keratinocytes resulted in significantly increased CEBPD and NOTCH1, and reduced SLPI. This work demonstrates the clinical relevance of CEBPD, NOTCH1, KRT16, and SLPI, and shows the regulatory effects of 16E6E7 and NFX1-123.

Fatty acid metabolism: A new therapeutic target for cervical cancer

“…Inhibition of CPT1A significantly inhibits tumor growth, improves survival, and increases the sensitivity of nasopharyngeal carcinoma to radiotherapy ( 125 ). Almost all CCs are associated with high-risk HPV infections, and HPV16 is responsible for nearly 50% of infections ( 12 , 13 ). The level of CPT1A in HPV16-positive CC tissues was reported to be markedly higher than that in normal tissues, suggesting that CPT1A could promote cervical cancer progression through lipid metabolism modifications ( 51 ).…”

“…Of note, nearly a quarter of CC patients do not have elevated SCC Ag levels ( 11 ). Furthermore, almost all CCs are related to high-risk human papillomavirus (HPV) infections, of which nearly 50% are HPV16 infections ( 12 , 13 ). However, HPV infection is not a requirement.…”

Post-Transcriptional Gene Regulation by HPV 16E6 and Its Host Protein Partners

“…Not only did 16E6 bind NFX1 gene products, but we have determined that NFX1-123 expression is increased in cervical dysplasia samples and is highly expressed in cervical cancers and cervical cancer cell lines [ 31 ]. Additionally, in The Cancer Genome Atlas cervical cancer data set, 13.2% of genes correlated with NFX1 expression; among those correlative genes, there was significant enrichment for those associated with protein binding and RNA binding [ 32 ]. These data emphasize the value of understanding how 16E6 may increase the expression and co-opt the typical function of NFX1-123 and, based on the protein motifs found in NFX1-123, how 16E6 may utilize this host protein to drive oncogenesis in keratinocytes.…”