Human papillomavirus type 16 E6 and E7 oncoproteins act synergistically to cause head and neck cancer in mice

Abstract

High-risk human papillomaviruses (HPVs) contribute to cervical and other anogenital cancers, and they are also linked etiologically to a subset of head and neck squamous cell carcinomas (HNSCC). We previously established a model for HPV-associated HNSCC in which we treated transgenic mice expressing the papillomaviral oncoproteins with the chemical carcinogen 4-nitroquinoline-1-oxide (4-NQO). We found that the HPV-16 E7 oncoprotein was highly potent in causing HNSCC, and its dominance masked any potential oncogenic contribution of E6, a second papillomaviral oncoprotein commonly expressed in human cancers. In the current study, we shortened the duration of treatment with 4-NQO to reduce the incidence of cancers and discovered a striking synergy between E6 and E7 in causing HNSCC. Comparing the oncogenic properties of wild-type versus mutant E6 genes in this model for HNSCC uncovered a role for some but not other cellular targets of E6 previously shown to contribute to cervical cancer.

Fig. 1

Response of head and neck epithelia to ionizing radiation. Shown in panels A and B are the percentage BrdU-positive cells present in tongue and esophagus epithelia, respectively, from mice that were (black bars) or were not (white bars) exposed to 12 Gy ionizing radiation (see methods for complete description of protocol used). For each condition and genotype, three mice were evaluated. In both tissues, significant reductions (p<0.05 based upon 2-sided Wilcoxon rank sum test) in Brdu-positive cells were observed only in the nontransgenic and the K14E6^I128T transgenic mice (see *). In contrast there was the complete abrogation of growth arrest in the K14E6 and K14E6^Δ146-151 mice, consistent with inactivation of p53.

Fig. 2

Total size per mouse of head and neck tumors in mice treated with 4-NQO. Each dot represents the cumulative measured size of tumors in one mouse. The average total size of tumors per mouse is listed in parentheses under the genotypes. ^*p < 10⁻⁴ versus non-transgenic mice and ^†p < 0.03 versus K14E7 mice, two-sided Wilcoxon rank-sum tests. There were no significant differences between K14E6^mutant/K14E7 and K14E6/K14E7 mice (p > 0.20, two-sided Wilcoxon rank-sum tests).