Disruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer.

TitleDisruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer.
Publication TypeJournal Article
Year of Publication2020
AuthorsChari NS, Ivan C, Le X, Li J, Mijiti A, Patel AA, Osman AA, Peterson CB, Williams MD, Pickering CR, Caulin C, Myers JN, Calin GA, Lai SY
JournalJ Natl Cancer Inst
Date Published2020 Mar 01
KeywordsCase-Control Studies, Chromatin Immunoprecipitation, Feedback, Physiological, Head and Neck Neoplasms, Humans, MicroRNAs, Mouth Neoplasms, Mutation, Neoplasm Staging, Promoter Regions, Genetic, Squamous Cell Carcinoma of Head and Neck, Survival Rate, Transcription Factors, Transcription, Genetic, Tumor Suppressor Protein p53, Tumor Suppressor Proteins

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.

Alternate JournalJ Natl Cancer Inst
PubMed ID31124563
PubMed Central IDPMC7073912
Grant ListK12 CA088084 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
Faculty Reference: 
Carlos Caulin, PhD