Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma
| Autor: | Zhengqiu Zhou, Keiko Akagi, Shanying Gui, Weihong Xiao, Jingfeng Li, Tatevik Broutian, Bo Jiang, David E. Symer, Maura L. Gillison |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Cell cycle checkpoint Virus Integration PIM1 Mice Nude Apoptosis medicine.disease_cause Article 03 medical and health sciences Mice 0302 clinical medicine Proto-Oncogene Proteins c-pim-1 medicine Tumor Cells Cultured Animals Humans Epidermal growth factor receptor Cell Proliferation Gene knockdown Human papillomavirus 16 biology Kinase Squamous Cell Carcinoma of Head and Neck Papillomavirus Infections Cancer medicine.disease Prognosis Head and neck squamous-cell carcinoma Xenograft Model Antitumor Assays 030104 developmental biology Oncology Head and Neck Neoplasms 030220 oncology & carcinogenesis Cancer research biology.protein Female Carcinogenesis |
| Zdroj: | Cancer Lett |
| ISSN: | 1872-7980 |
| Popis: | Human papillomavirus (HPV) insertions in cancer genomes have been linked to various forms of focal genomic instability and altered expression of neighboring genes. Here we tested the hypothesis that investigation of HPV insertions in a head and neck cancer squamous cell carcinoma (HNSCC) cell line would identify targetable driver genes contributing to oncogenesis of other HNSCC. In the cell line UPCI:SCC090 HPV16 integration amplified the PIM1 serine/threonine kinase gene ~16-fold, thereby increasing transcript and protein levels. We used genetic and pharmacological approaches to inhibit PIM kinases in this and other HNSCC cell lines. Knockdown of PIM1 transcripts by transfected short hairpin RNAs reduced UPCI:SCC090 viability. CRISPR/Cas9-mediated mutagenesis of PIM1 caused cell cycle arrest and apoptosis. Pharmacological inhibition of PIM family kinases decreased growth of UPCI:SCC090 and additional HNSCC cell lines in vitro and a xenograft UPCI:SCC090 model in vivo. Based on established interactions between intracellular signaling pathways and relatively high levels of gene expression in almost all HNSCC, we also evaluated combinations of PIM kinase and epidermal growth factor receptor (EGFR) inhibitors. Dual inhibition of these pathways resulted in supra-additive cell death. These data support clinical testing of PIM inhibitors alone or in combination in HNSCC. |
| Databáze: | OpenAIRE |
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