Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis
Charbel Darido, Smitha R Georgy, Tomasz Wilanowski, Sebastian Dworkin, Alana Auden, Quan Zhao, Gerhard Rank, Seema Srivastava, Moira J Finlay, Anthony T Papenfuss, Pier Paolo Pandolfi, Richard B Pearson, Stephen M Jane
CANCER CELL | CELL PRESS | Published : 2011
Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which ..View full abstract
Awarded by Worldwide Cancer Research
We thank Andreas Strasser, George Thomas, and Paul Mischel for critical appraisal of the manuscript; the staff from the Bio21 Institute for animal care; the Victorian Cancer Biobank for human SCC samples; Dr. Hong-Jian Zhu for constructs; Dr. Tak Mak for Pten<SUP>+/-</SUP> mice; Dr. Garry Anderson for assistance with biostatistical analysis; Dr. Michael Buchert for assistance with IHC quantification; and the Australian Cancer Research Foundation for the LCM. S.M.J. is a Principal Research Fellow of the Australian National Health and Medical Research Council (NHMRC). The work was partially supported by Project Grants from the NHMRC, and Grants from the Association for International Cancer Research and the March of Dimes Foundation.