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Constitutive Activation of Stat5b Contributes to Carcinogenesis in Vivo

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Constitutive Activation of Stat5b Contributes to Carcinogenesis in Vivo [CANCER RESEARCH 63, 6763–6771, October 15, 2003] Constitutive Activation of Stat5b Contributes to Carcinogenesis in Vivo Sichuan Xi, Qing Zhang, William E. Gooding, Thomas E. Smithgall, and Jennifer Rubin Grandis1 Departments of Otolaryngology [S. X., J. R. G.], Pharmacology [Q. Z., J. R. G.], and Molecular Genetics and Biochemistry [T. E. S.], University of Pittsburgh School of Medicine, and Department of Biostatistics, University of Pittsburgh Cancer Institute [W. E. G.], Pittsburgh, Pennsylvania 15213 ABSTRACT EGF. Like Stat3, Stat5 has been shown to regulate proliferation and inhibition of apoptosis in cancer cells. A constitutively active Stat5 The development of more effective prevention and treatment strategies mutant induced properties characteristic of transformed cells (8). for solid tumors is limited by an incomplete understanding of the critical However, previous studies have generally not distinguished Stat5a growth pathways that are activated in carcinogenesis. Signal transducers and activators of transcription (STAT) proteins have been linked to and Stat5b in carcinogenesis, and there are no reports of Stat5 acti- transformation and tumor progression. Studies to date have not eluci- vation in epithelial tumor specimens. Stat5a and Stat5b are derived dated clear and distinct roles for Stat5 genes (Stat5a and Stat5b) in human from distinct, yet closely linked genes on chromosome 11 and exhibit epithelial cancers. We analyzed the role of Stat5a/b isoforms in squamous 93% identity at the amino acid level. Stat5a/b demonstrate similar cell carcinoma of the head and neck using expression and activation patterns of expression, and are activated by the same cytokines and studies in human tissues and in a xenograft model after selective targeting. growth factors. The association of Stat5 with transformation and In a xenograft model, blockade of Stat5b, but not Stat5a, using antisense tumor progression suggests that Stat5 may play a role in human oligonucleotides resulted in tumor growth inhibition and abrogation of carcinogenesis. Stat5 target genes in vivo. Blockade of the epidermal growth factor Early genetic changes that contribute to carcinogenesis can be receptor resulted in partial abrogation of Stat5 activation, thus linking detected in the histologically normal mucosa in SCCHN patients. This epidermal growth factor receptor to Stat5 in vivo. In tissues from 33 individuals with head and neck cancer, Stat5 activation levels were cor- “condemned mucosa” is subjected to field cancerization by carcino- related with progression to a malignant phenotype, where increased ex- genic agents (e.g., tobacco and alcohol), predisposing SCCHN pa- pression and phosphorylation of Stat5b were detected consistently in tients to the development of multiple primary tumors (9, 10). Over- tumors compared with their epithelial counterparts. Thus, constitutive expression of the EGFR and its autocrine ligand, TGF-␣, has been activation of Stat5b contributes to squamous cell tumorigenesis and may detected in transformed squamous epithelium, adjacent histologically serve as a therapeutic target. normal epithelium from SCCHN patients, as well as in premalignant dysplastic lesions, compared with levels in control mucosa from patients without cancer, suggesting that this pathway is activated early INTRODUCTION in SCCHN carcinogenesis (11–13). Dysregulation of TGF-␣/EGFR Cumulative evidence supports a role for activation of STATs2 in appears to be primarily a result of transcriptional activation and not oncogenesis as reflected by elevated STAT-DNA binding activity in gene amplication or prolongation of mRNA half-life (14). The detec- a variety of primary tumor specimens and cell lines (1, 2). Several tion of increased expression of EGFR and activation of Stat3 in this potential mechanisms of STAT activation have been implicated in “at risk” mucosa from head and neck cancer patients implicates human cancer cells including activation of upstream receptor tyrosine EGFR-mediated STAT activation as an early event in SCCHN carci- kinases, such as the EGFR, as well as nonreceptor kinases. Autocrine nogenesis (15). stimulation of EGFR results in receptor dimerization, phosphoryla- The vast majority of cancers that arise in the mucosa of the upper tion, and recruitment of STATs to tyrosine residues in the cytoplasmic aerodigestive tract (Ͼ90%) are squamous cell carcinomas. The de- domain. Interaction between STAT protein src-homology 2 domains velopment of SCCHN has been linked to carcinogen exposure, gen- and the activated EGFR leads to STAT phosphorylation, dimerization, erally tobacco and alcohol, as well as to genetic alterations in the and nuclear translocation. In the nucleus, STAT dimers bind to target affected tissues. Early genetic changes that contribute to SCCHN gene promoters and regulate gene expression (3–6). Seven STAT carcinogenesis can be detected in the histologically normal-appearing genes have been identified: Stat1, -2, -3, -4, -5a, -5b, and -6. Consti- mucosa in the area of “field cancerization.” Such a broad mucosal tutive activation of STATs 1, 3, and 5 has been demonstrated in a diathesis in these patients is supported by the high frequency of variety of diverse human tumor cell lines. In general, STATs 3 and 5 multiple primary tumors. Patients who survive the initial SCCHN are involved in the development and progression of cancers, whereas tumor will most likely succumb to a second primary tumor of the Stat1 demonstrates a tumor suppressor function (2). aerodigestive tract. Identification of the critical signaling pathways To date, Stat5 activation has been demonstrated primarily in he- will facilitate the design of novel prevention and treatment strategies. matopoietic malignancies where Stat5 activation is associated with The present study was undertaken to determine the role of Stat5 specific genetic abnormalities, such as the Bcr-Abl fusion protein in activation in SCCHN tumorigenesis and test the hypothesis that Stat5 chronic myelogenous leukemia (7). A variety of cytokines and growth isoforms could serve as therapeutic targets. factors have been reported to stimulate Stat5 activation, including MATERIALS AND METHODS Received 5/29/03; revised 7/17/03; accepted 7/23/03. The costs of publication of this article were defrayed in part by the payment of page Tissues and Cells. Samples of squamous cell carcinoma and normal mu- charges. This article must therefore be hereby marked advertisement in accordance with cosa distant from the tumor (generally, several centimeters away) were ob- 18 U.S.C. Section 1734 solely to indicate this fact. tained from 33 subjects undergoing primary surgical resection for head and 1 To whom requests for reprints should be addressed, at The Eye and Ear Institute, neck cancer at the University of Pittsburgh Medical Center from 1998 to 2001 Suite 500, 200 Lothrop Street, Pittsburgh, PA 15213. Phone: (412) 647-5280; Fax: (412) 647-0108; E-mail: [email protected]. (Table 1). Samples of normal oropharyngeal mucosa were obtained from ten 2 The abbreviations used are: STAT, signal transducers and activators of transcription; gender and age-matched (Ϯ5 years) control subjects without cancer undergo- EGFR, epidermal growth factor receptor; EGF, epidermal growth factor; SCCHN, squa- ing nononcological surgical procedures, such as uvulopalatopharyngoplasty for mous cell carcinoma of the head and neck; TGF, transforming growth factor; EMSA, obstructive sleep apnea syndrome. Tissues were collected under the auspices of electrophoretic mobility shift assay; TBST, Tris-buffered saline [10 mmol/liter Tris-HCL (pH 7.5) and 150 mmol/liter NaCl] with 0.5% Tween 20; PCNA, proliferating cell nuclear an Institutional Review Board-approved protocol with informed consent ob- antigen. tained from all of the subjects. For the xenograft studies, we used the cell lines 6763 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2003 American Association for Cancer Research. STAT5 ISOFORMS IN CARCINOGENESIS Table 1 Clinicopathologic characteristics of 33 head and neck cancer patients control on that gel as described by us previously for Stat3 activation determi- evaluated prospectively for Stat5 activation/expression nations (15). Gender Immunoblotting and Immunoprecipitation. Whole cell extracts were Male 25 (76%) mixed with 2ϫ SDS sample buffer [125 mmol/liter Tris-HCL (pH 6.8), 4% Female 8 (24%) SDS, 20% glycerol, and 10% 2 mercaptoethanol] at 1:1 ratio and were heated Age Mean, 64 years; Median, 63 years; range, 4786 years for 5 min at 100°C. Proteins (50 ␮g/lane) were separated by 12.5% SDS- Tumor site PAGE and transferred onto a nitrocellulose membrane (MSI, Westboro, MA). Oral cavity 16 (49%) Prestained molecular weight markers (Life Technologies, Inc., Gaithersburg, Oropharynx 5 (15%) Larynx 12 (36%) MD) were included in each gel. Membranes were blocked for 30 min in TBST T stage and 5% BSA. After blocking, membranes were incubated with a primary 1–2 11 (33%) antibody, rabbit antihuman Stat5a or Stat5b polyclonal antibodies (Transduc- 3–4 18 (55%) tion Labs, Lexington, KY), or rabbit antihuman Cyclin D1 polyclonal antibody Recurrence 4 (12%) N stage or mouse antihuman Bcl-xL monoclonal antibody (Santa Cruz Biotechnology), 0–1 27 (82%) in TBST and 1% BSA. After washing the membranes three times with TBST 2 6 (18%) (5 min each), they were incubated with horseradish peroxidase-conjugated Tumor differentiation secondary antibody in TBST and 1% BSA for 30 min. Subsequently, mem- Well 8 (24%) Well-moderate
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