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PMID: 10760290 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 8 ·2000-04-11 ·Pages 4227-32

Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y, Kim JD

Abstract

Field cancerization predisposes the upper aerodigestive tract mucosa to the formation of multiple primary tumors, when exposed to environmental carcinogens. Up-regulation of epidermal growth factor receptor occurs early in squamous cell carcinogenesis and is critical for the loss of growth control in a variety of human cancers, including head and neck squamous cell carcinomas. In these tumor cells in culture, epidermal growth factor receptor stimulation initiates signaling via persistent activation of selective STAT proteins. To determine the timing of Stat3 activation in head and neck carcinogenesis, we studied the expression and constitutive activation of Stat3 in tumors and normal mucosa from patients with head and neck cancer compared with mucosa from controls without cancer. Stat3 was up-regulated and constitutively activated in both primary human head and neck tumors as well as in normal mucosa from these cancer patients compared with control normal mucosa from patients without cancer. In vivo liposome-mediated gene therapy with a Stat3 antisense plasmid efficiently inhibited Stat3 activation, increased tumor cell apoptosis, and decreased Bcl-x(L) expression in a head and neck xenograft model. These findings provide evidence that constitutively activated Stat3 is an early event in head and neck carcinogenesis that contributes to the loss of growth control by an anti-apoptotic mechanism.

MeSH Terms
Animals Apoptosis Carcinoma, Squamous Cell/genetics,pathology,therapy DNA-Binding Proteins/genetics,metabolism ErbB Receptors/metabolism Female Genetic Therapy Head and Neck Neoplasms/genetics,pathology,therapy Humans Liposomes Mice Mice, Nude Neoplasm Transplantation Oligonucleotides, Antisense/pharmacology STAT3 Transcription Factor Signal Transduction Trans-Activators/genetics,metabolism Transforming Growth Factors/metabolism Tumor Cells, Cultured
Chemicals
DNA-Binding Proteins Liposomes Oligonucleotides, Antisense STAT3 Transcription Factor STAT3 protein, human Stat3 protein, mouse Trans-Activators Transforming Growth Factors ErbB Receptors
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Grandis J R
Department of Otolaryngology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. [email protected]
Drenning S D
Zeng Q
Watkins S C
Melhem M F
Endo S
Johnson D E
Huang L
He Y
Kim J D
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.97.8.4227
Email
[email protected]
Published
2000-04-11
Pages
4227-32
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC18206
Subset
IM
Grants
NCI NIH HHS · R01 CA077308 · United States
NCI NIH HHS · CA01760 · United States
NCI NIH HHS · CA72526 · United States
NCI NIH HHS · CA77308 · United States
External Links
PubMed source DOI: 10.1073/pnas.97.8.4227 PMC Full Text View journal details
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