This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kijima, T. Articles by Grandis, J. R. Search for Related Content PubMed PubMed Citation Articles by Kijima, T. Articles by Grandis, J. R.

STAT3 Activation Abrogates Growth Factor Dependence and Contributes to Head and Neck Squamous Cell Carcinoma Tumor Growth in Vivo¹

Departments of Otolaryngology [T. K., H. N., S. D. D., A. L. W., S. X., J. R. G.], Pharmacology [J. R. G., R. A. S.], Medicine [R. A. S.], and Biostatistics [W. E. G.], University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213

Epidermal growth factor receptor (EGFR) is up-regulated and contributes to the loss of growth control in squamous cell carcinoma of the head and neck (SCCHN). Previously, we reported an association between autocrine stimulation of EGFR and constitutive signal transducers and activators of transcription (STAT) 3 activation in SCCHN cells in vitro and in vivo. Here, we evaluated the role of activated STAT3 in tumor progression and EGFR-independent mitogenic signaling. We found that SCCHN cells stably transfected with a dominant active STAT3 construct expressed elevated levels of STAT3 target genes, including Bcl-X_L and cyclin D1, and demonstrated increased proliferation in vitro and more rapid tumor growth rates in vivo. Cell cycle analysis demonstrated an increased proportion of STAT3 construct transfectants in G₂-M. These findings provide evidence that constitutive STAT3 activation contributes to tumor growth in SCCHN, independent of the EGFR autocrine axis.

This article has been cited by other articles:

				L. A. Byers, B. Sen, B. Saigal, L. Diao, J. Wang, M. Nanjundan, T. Cascone, G. B. Mills, J. V. Heymach, and F. M. Johnson Reciprocal Regulation of c-Src and STAT3 in Non-Small Cell Lung Cancer Clin. Cancer Res., November 15, 2009; 15(22): 6852 - 6861. [Abstract] [Full Text] [PDF]

				J. J. Ranger, D. E. Levy, S. Shahalizadeh, M. Hallett, and W. J. Muller Identification of a Stat3-Dependent Transcription Regulatory Network Involved in Metastatic Progression Cancer Res., September 1, 2009; 69(17): 6823 - 6830. [Abstract] [Full Text] [PDF]

				C. Li, Y. Zang, M. Sen, R. J. Leeman-Neill, D. SK. Man, J. R. Grandis, and D. E. Johnson Bortezomib up-regulates activated signal transducer and activator of transcription-3 and synergizes with inhibitors of signal transducer and activator of transcription-3 to promote head and neck squamous cell carcinoma cell death Mol. Cancer Ther., August 1, 2009; 8(8): 2211 - 2220. [Abstract] [Full Text] [PDF]

				D. L. Wheeler, M. Iida, and E. F. Dunn The Role of Src in Solid Tumors Oncologist, July 1, 2009; 14(7): 667 - 678. [Abstract] [Full Text] [PDF]

				B. Sen, B. Saigal, N. Parikh, G. Gallick, and F. M. Johnson Sustained Src Inhibition Results in Signal Transducer and Activator of Transcription 3 (STAT3) Activation and Cancer Cell Survival via Altered Janus-Activated Kinase-STAT3 Binding Cancer Res., March 1, 2009; 69(5): 1958 - 1965. [Abstract] [Full Text] [PDF]

				H. Zou, S. M. Thomas, Z.-W. Yan, J. R. Grandis, A. Vogt, and L.-Y. Li Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells FASEB J, February 1, 2009; 23(2): 425 - 432. [Abstract] [Full Text] [PDF]

				Z. Zhang, J. Xing, L. Ma, R. Gong, Y. E. Chin, and S. Zhuang Transglutaminase-1 Regulates Renal Epithelial Cell Proliferation through Activation of Stat-3 J. Biol. Chem., January 30, 2009; 284(5): 3345 - 3353. [Abstract] [Full Text] [PDF]

				J. Wang, R. R. Seethala, Q. Zhang, W. Gooding, C. van Waes, H. Hasegawa, and R. L. Ferris Autocrine and Paracrine Chemokine Receptor 7 Activation in Head and Neck Cancer: Implications for Therapy J Natl Cancer Inst, April 2, 2008; 100(7): 502 - 512. [Abstract] [Full Text] [PDF]

				S. Choi and J.N. Myers Molecular Pathogenesis of Oral Squamous Cell Carcinoma: Implications for Therapy Journal of Dental Research, January 1, 2008; 87(1): 14 - 32. [Abstract] [Full Text] [PDF]

				F. M. Johnson, B. Saigal, H. Tran, and N. J. Donato Abrogation of Signal Transducer and Activator of Transcription 3 Reactivation after Src Kinase Inhibition Results in Synergistic Antitumor Effects Clin. Cancer Res., July 15, 2007; 13(14): 4233 - 4244. [Abstract] [Full Text] [PDF]

				A. Jewett, C. Head, and N.A. Cacalano Emerging Mechanisms of Immunosuppression in Oral Cancers Journal of Dental Research, December 1, 2006; 85(12): 1061 - 1073. [Abstract] [Full Text] [PDF]

				S. Kalyankrishna and J. R. Grandis Epidermal Growth Factor Receptor Biology in Head and Neck Cancer J. Clin. Oncol., June 10, 2006; 24(17): 2666 - 2672. [Abstract] [Full Text] [PDF]

				N. Jing, Q. Zhu, P. Yuan, Y. Li, L. Mao, and D. J. Tweardy Targeting signal transducer and activator of transcription 3 with G-quartet oligonucleotides: a potential novel therapy for head and neck cancer. Mol. Cancer Ther., February 1, 2006; 5(2): 279 - 286. [Abstract] [Full Text] [PDF]

				T. L. Lee, J. Yeh, C. Van Waes, and Z. Chen Epigenetic modification of SOCS-1 differentially regulates STAT3 activation in response to interleukin-6 receptor and epidermal growth factor receptor signaling through JAK and/or MEK in head and neck squamous cell carcinomas Mol. Cancer Ther., January 1, 2006; 5(1): 8 - 19. [Abstract] [Full Text] [PDF]

				K. H. Dragnev, W. J. Petty, S. Shah, A. Biddle, N. B. Desai, V. Memoli, J. R. Rigas, and E. Dmitrovsky Bexarotene and Erlotinib for Aerodigestive Tract Cancer J. Clin. Oncol., December 1, 2005; 23(34): 8757 - 8764. [Abstract] [Full Text] [PDF]

				E. R. Camp, J. Summy, T. W. Bauer, W. Liu, G. E. Gallick, and L. M. Ellis Molecular Mechanisms of Resistance to Therapies Targeting the Epidermal Growth Factor Receptor Clin. Cancer Res., January 1, 2005; 11(1): 397 - 405. [Abstract] [Full Text] [PDF]

				C. D. Andl, T. Mizushima, K. Oyama, M. Bowser, H. Nakagawa, and A. K. Rustgi EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes Am J Physiol Gastrointest Liver Physiol, December 1, 2004; 287(6): G1227 - G1237. [Abstract] [Full Text] [PDF]

				W. J. Petty, K. H. Dragnev, V. A. Memoli, Y. Ma, N. B. Desai, A. Biddle, T. H. Davis, W. C. Nugent, N. Memoli, M. Hamilton, et al. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition Represses Cyclin D1 in Aerodigestive Tract Cancers Clin. Cancer Res., November 15, 2004; 10(22): 7547 - 7554. [Abstract] [Full Text] [PDF]

				H. Siavash, N.G. Nikitakis, and J.J. Sauk SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION: INSIGHTS INTO THE MOLECULAR BASIS OF ORAL CANCER Critical Reviews in Oral Biology & Medicine, September 1, 2004; 15(5): 298 - 307. [Abstract] [Full Text] [PDF]

				M. R. D. Quadros, F. Peruzzi, C. Kari, and U. Rodeck Complex Regulation of Signal Transducers and Activators of Transcription 3 Activation in Normal and Malignant Keratinocytes Cancer Res., June 1, 2004; 64(11): 3934 - 3939. [Abstract] [Full Text] [PDF]

				Z. Wang, T. Cook, S. Alber, K. Liu, I. Kovesdi, S. K. Watkins, Y. Vodovotz, T. R. Billiar, and D. Blumberg Adenoviral Gene Transfer of the Human Inducible Nitric Oxide Synthase Gene Enhances the Radiation Response of Human Colorectal Cancer Associated with Alterations in Tumor Vascularity Cancer Res., February 15, 2004; 64(4): 1386 - 1395. [Abstract] [Full Text] [PDF]

				B. E. Barton, J. G. Karras, T. F. Murphy, A. Barton, and H. F-S. Huang Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines Mol. Cancer Ther., January 1, 2004; 3(1): 11 - 20. [Abstract] [Full Text]

				S. Xi, Q. Zhang, K. F. Dyer, E. C. Lerner, T. E. Smithgall, W. E. Gooding, J. Kamens, and J. R. Grandis Src Kinases Mediate STAT Growth Pathways in Squamous Cell Carcinoma of the Head and Neck J. Biol. Chem., August 22, 2003; 278(34): 31574 - 31583. [Abstract] [Full Text] [PDF]

				C.-W. Ni, H.-J. Hsieh, Y.-J. Chao, and D. L. Wang Shear Flow Attenuates Serum-induced STAT3 Activation in Endothelial Cells J. Biol. Chem., May 23, 2003; 278(22): 19702 - 19708. [Abstract] [Full Text] [PDF]

				P. L. Leong, G. A. Andrews, D. E. Johnson, K. F. Dyer, S. Xi, J. C. Mai, P. D. Robbins, S. Gadiparthi, N. A. Burke, S. F. Watkins, et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth PNAS, April 1, 2003; 100(7): 4138 - 4143. [Abstract] [Full Text] [PDF]