STAT3 as a Chemoprevention Target in Carcinogen-Induced Head and Neck Squamous Cell Carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal disease due, in large part, to a high rate of second primary tumor (SPT) formation. The 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis provides a robust system in which to study chemopreventive agents in the context of chemically induced HNSCC tumors. STAT3 is a potent oncogene that is hyperactivated by tyrosine phosphorylation early in HNSCC carcinogenesis and is a rational therapeutic target. We recently reported that loss-of-function of the STAT3 phosphatase PTPRT promotes STAT3 activation in HNSCC tumors and preclinical models and may serve as a predictive biomarker of response to STAT3 inhibitors, including the small-molecule Stattic. We therefore investigated the hypothesis that Ptprt-knockout (KO) mice would be more susceptible to 4-NQO-induced oral carcinogenesis and more sensitive to Stattic-mediated chemoprevention compared with wild-type (WT) mice. Herein, we demonstrate that Ptprt WT and KO mice develop similar spectra of HNSCC disease severity upon 12 weeks of 4-NQO administration, with no apparent effect of Ptprt genotype on carcinogenesis or treatment outcome. Targeting of STAT3 with Stattic resulted in a chemopreventive effect against 4-NQO-induced oral cancer (P = 0.0402). While these results do not support a central role for PTPRT in 4-NQO-induced HNSCC carcinogenesis, further investigation of STAT3 as a chemoprevention target in this cancer is warranted. Cancer Prev Res; 9(8); 657-63. ©2016 AACR.
Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
Noah D
ND
Peyser
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Lin
L
Wang
Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
Yan
Y
Zeng
Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Marie
M
Acquafondata
Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Maria
M
Freilino
Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
Hua
H
Li
Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Malabika
M
Sen
Department of Otolaryngology and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
William E
WE
Gooding
Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
Masanobu
M
Satake
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.
Zhenghe
Z
Wang
Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Daniel E
DE
Johnson
Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California. Jennifer.Grandis@ucsf.edu.
Jennifer R
JR
Grandis
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000517:prevention & control*; D018890:Chemoprevention; D003499:Cyclic S-Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D009062:Mouth Neoplasms / Q000139:chemically induced* / Q000517:prevention & control; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors
D015415:Biomarkers; D002273:Carcinogens; D003499:Cyclic S-Oxides; D050796:STAT3 Transcription Factor; C517409:stattic; D015112:4-Nitroquinoline-1-oxide; C516866:Ptprt protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2