Nikhil S Chari1, Cristina Ivan2, Xiandong Le1, Jinzhong Li1,3, Ainiwaer Mijiti1,4, Ameeta A Patel1, Abdullah A Osman1, Christine B Peterson5, Michelle D Williams6, Curtis R Pickering1, Carlos Caulin1,7, Jeffrey N Myers1, George A Calin2, Stephen Y Lai1,8,9. 1. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX. 2. Department of Experimental Therapeutics and The Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX. 3. Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China. 4. Department of Stomatology, Shenzen Luohu People's Hospital, Shenzen, Guandong, China. 5. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX. 6. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX. 7. Department of Otolaryngology-Head and Neck Surgery, The University of Arizona and University of Arizona Cancer Center, Tucson, AZ. 8. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. 9. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Abstract
BACKGROUND: Alterations in the epidermal growth factor receptor and PI3K pathways in head and neck squamous cell carcinomas (HNSCCs) are frequent events that promote tumor progression. Ectopic expression of the epidermal growth factor receptor-targeting microRNA (miR), miR-27a* (miR-27a-5p), inhibits tumor growth. We sought to identify mechanisms mediating repression of miR-27a* in HNSCC, which have not been previously identified. METHODS: We quantified miR-27a* in 47 oral cavity squamous cell carcinoma patient samples along with analysis of miR-27a* in 73 oropharyngeal and 66 human papillomavirus-positive (HPV+) samples from The Cancer Genome Atlas. In vivo and in vitro TP53 models engineered to express mutant TP53, along with promoter analysis using chromatin immunoprecipitation and luciferase assays, were used to identify the role of TP53 and TP63 in miR-27a* transcription. An HNSCC cell line engineered to conditionally express miR-27a* was used in vitro to determine effects of miR-27a* on target genes and tumor cells. RESULTS: miR-27a* expression was repressed in 47 oral cavity tumor samples vs matched normal tissue (mean log2 difference = -0.023, 95% confidence interval = -0.044 to -0.002; two-sided paired t test, P = .03), and low miR-27a* levels were associated with poor survival in HPV+ and oropharyngeal HNSCC samples. Binding of ΔNp63α to the promoter led to an upregulation of miR-27a*. In vitro and in vivo findings showed that mutant TP53 represses the miR-27a* promoter, downregulating miR-27a* levels. ΔNp63α and nucleoporin 62, a protein involved in ΔNP63α transport, were validated as novel targets of miR-27a*. CONCLUSION: Our results characterize a negative feedback loop between TP63 and miR-27a*. Genetic alterations in TP53, a frequent event in HNSCC, disrupt this regulatory loop by repressing miR-27a* expression, promoting tumor survival.
BACKGROUND: Alterations in the epidermal growth factor receptor and PI3K pathways in head and neck squamous cell carcinomas (HNSCCs) are frequent events that promote tumor progression. Ectopic expression of the epidermal growth factor receptor-targeting microRNA (miR), miR-27a* (miR-27a-5p), inhibits tumor growth. We sought to identify mechanisms mediating repression of miR-27a* in HNSCC, which have not been previously identified. METHODS: We quantified miR-27a* in 47 oral cavity squamous cell carcinomapatient samples along with analysis of miR-27a* in 73 oropharyngeal and 66 human papillomavirus-positive (HPV+) samples from The Cancer Genome Atlas. In vivo and in vitro TP53 models engineered to express mutant TP53, along with promoter analysis using chromatin immunoprecipitation and luciferase assays, were used to identify the role of TP53 and TP63 in miR-27a* transcription. An HNSCC cell line engineered to conditionally express miR-27a* was used in vitro to determine effects of miR-27a* on target genes and tumor cells. RESULTS:miR-27a* expression was repressed in 47 oral cavity tumor samples vs matched normal tissue (mean log2 difference = -0.023, 95% confidence interval = -0.044 to -0.002; two-sided paired t test, P = .03), and low miR-27a* levels were associated with poor survival in HPV+ and oropharyngeal HNSCC samples. Binding of ΔNp63α to the promoter led to an upregulation of miR-27a*. In vitro and in vivo findings showed that mutant TP53 represses the miR-27a* promoter, downregulating miR-27a* levels. ΔNp63α and nucleoporin 62, a protein involved in ΔNP63α transport, were validated as novel targets of miR-27a*. CONCLUSION: Our results characterize a negative feedback loop between TP63 and miR-27a*. Genetic alterations in TP53, a frequent event in HNSCC, disrupt this regulatory loop by repressing miR-27a* expression, promoting tumor survival.
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