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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
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To date, Stat5 activation has been demonstrated primarily in hematopoietic malignancies where Stat5 activation is associated with specific genetic abnormalities, such as the Bcr-Ablfusion protein in chronic myelogenous leukemia (7) . A variety of cytokines and growth factors have been reported to stimulate Stat5 activation, including EGF. Like Stat3, Stat5 has been shown to regulate proliferation and inhibition of apoptosis in cancer cells. A constitutively active Stat5 mutant induced properties characteristic of transformed cells (8) . However, previous studies have generally not distinguished Stat5a and Stat5b in carcinogenesis, and there are no reports of Stat5 activation in epithelial tumor specimens. Stat5a and Stat5b are derived from distinct, yet closely linked genes on chromosome 11 and exhibit 93% identity at the amino acid level. Stat5a/b demonstrate similar patterns of expression, and are activated by the same cytokines and growth factors. The association of Stat5 with transformation and tumor progression suggests that Stat5 may play a role in human carcinogenesis.
Early genetic changes that contribute to carcinogenesis can be detected in the histologically normal mucosa in SCCHN patients. This "condemned mucosa" is subjected to field cancerization by carcinogenic agents (e.g., tobacco and alcohol), predisposing SCCHN patients to the development of multiple primary tumors (9
, 10)
. Overexpression of the EGFR and its autocrine ligand, TGF-
, has been detected in transformed squamous epithelium, adjacent histologically 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 in SCCHN carcinogenesis (11, 12, 13)
. Dysregulation of TGF-/EGFR appears to be primarily a result of transcriptional activation and not gene amplication or prolongation of mRNA half-life (14)
. The detection of increased expression of EGFR and activation of Stat3 in this "at risk" mucosa from head and neck cancer patients implicates EGFR-mediated STAT activation as an early event in SCCHN carcinogenesis (15)
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The vast majority of cancers that arise in the mucosa of the upper aerodigestive tract (>90%) are squamous cell carcinomas. The development of SCCHN has been linked to carcinogen exposure, generally tobacco and alcohol, as well as to genetic alterations in the affected tissues. Early genetic changes that contribute to SCCHN carcinogenesis can be detected in the histologically normal-appearing mucosa in the area of "field cancerization." Such a broad mucosal diathesis in these patients is supported by the high frequency of multiple primary tumors. Patients who survive the initial SCCHN tumor will most likely succumb to a second primary tumor of the aerodigestive tract. Identification of the critical signaling pathways will facilitate the design of novel prevention and treatment strategies. The present study was undertaken to determine the role of Stat5 activation in SCCHN tumorigenesis and test the hypothesis that Stat5 isoforms could serve as therapeutic targets.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Samples of normal oropharyngeal mucosa were obtained from ten gender and age-matched (±5 years) control subjects without cancer undergoing nononcological surgical procedures, such as uvulopalatopharyngoplasty for obstructive sleep apnea syndrome. Tissues were collected under the auspices of an Institutional Review Board-approved protocol with informed consent obtained from all of the subjects. For the xenograft studies, we used the cell lines OSC-19 (16)
or 1483 (17)
, which are well-characterized SCCHN cell lines that can form tumors in athymic nude mice. In culture, they were maintained in supplemented DMEM as described previously (16)
. Sf-9 cells (Invitrogen) and Sf-9 cells transfected with Stat5a or Stat5b were cultured in Grace’s complete insect cell medium containing 10% fetal bovine serum and 50 µg/ml gentamicin as described previously (18)
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Immunoblotting and Immunoprecipitation.
Whole cell extracts were mixed with 2x SDS sample buffer [125 mmol/liter Tris-HCL (pH 6.8), 4% SDS, 20% glycerol, and 10% 2 mercaptoethanol] at 1:1 ratio and were heated for 5 min at 100°C. Proteins (50 µg/lane) were separated by 12.5% SDS-PAGE and transferred onto a nitrocellulose membrane (MSI, Westboro, MA). Prestained molecular weight markers (Life Technologies, Inc., Gaithersburg, MD) were included in each gel. Membranes were blocked for 30 min in TBST and 5% BSA. After blocking, membranes were incubated with a primary antibody, rabbit antihuman Stat5a or Stat5b polyclonal antibodies (Transduction Labs, Lexington, KY), or rabbit antihuman Cyclin D1 polyclonal antibody or mouse antihuman Bcl-xL monoclonal antibody (Santa Cruz Biotechnology), in TBST and 1% BSA. After washing the membranes three times with TBST (5 min each), they were incubated with horseradish peroxidase-conjugated secondary antibody in TBST and 1% BSA for 30 min. Subsequently, membranes were washed three times with TBST and developed using the enhanced chemiluminescence detection system (Amersham Life Sciences Inc., Arlington Heights, IL). Stat5 activation was determined by immunoblotting with a phosphospecific antibody that cannot distinguish Stat5a from Stat5b (Upstate Biotechnology). Stat5a or Stat5b phosphorylation was determined by immunoprecipitation with antiphosphotyrosine monoclonal antibody (PY20; Transduction Laboratories, Inc.), followed by immunoblotting with anti- Stat5a or Stat5b (Upstate Biotechnology, Inc., Lake Placid, NY). Interaction of Stat5a or Stat5b with EGFR was determined by immunoprecipitation with anti-EGFR (Santa Cruz Biotechnology), or Stat5a or Stat5b antibodies, followed by immunoblotting with anti-Stat5a or Stat5b antisera.
Animal Studies.
Female athymic nude mice 
/ (4–6 weeks old; 20 ± 2 g; Harlan-Sprague Dawley) were implanted with 1 x 106 cells (OSC-19 or 1483) into the right and left flank with a 26-gauge needle/1-ml tuberculin syringe. Ten days later, when the tumor nodules were established (
2 x 2 mm in diameter), the tumor implanted on one flank was treated with Stat5b antisense oligonucleotides, and the tumor on the contralateral flank was treated with Stat5b sense oligonucleotides, Stat5a antisense oligonucleotides, or no treatment. Antisense oligonucleotides were injected on days 11–15, 18–22, and 25–29. There were 5–7 mice in each treatment group. For the EGFR antisense gene therapy studies, the tumor on one flank was treated with intratumoral injection of EGFR antisense DNA (25 µg three times a week). The tumor on the contralateral flank was treated with the same dose of EGFR sense DNA as described previously. Phosphorothioated 21-mer oligodeoxynucleotides were synthesized on an Applied Biosystem 394 synthesizer by ß-cyanothylphysphoramidite chemistry to minimize degradation of the oligonucleotides by endogenous nucleases. The antisense oligonucleotides were directed against the translation start site (AUG codon) and surrounding nucleotides of the human Stat5a or Stat5b genes. The Stat5a antisense oligonucleotide sequence was 5' TGA ACG GCC ATG GCG GGC TGG 3' and the corresponding sense oligonucleotide sequence was 5' CCA GCC CGC CAT GGC GCT TCA 3'. The Stat5b antisense oligonucleotide sequence was 5' CCA CAC AGC CAT GTT TAC CCG 3' and the corresponding sense oligonucleotide sequence was 5' CGG GTA AAC ATG GCT GTG TGG 3'. Intratumoral injection of antisense oligonucleotides (7.92 nM or 50 µg) in a volume of 50 µl was delivered five times per week for a total of 15 treatments. Tumor volumes were measured in conjunction with each treatment and calculated as length x (width)2/2. Mice were sacrificed after the last treatment, and tumors were harvested for analysis. Experiments were repeated twice to ensure reproducibility. Animal care was in strict compliance with institutional guidelines established by the University of Pittsburgh, the Guide for the Care and Use of Laboratory Animals [National Academy of Sciences (1996)], and the Association for Assessment and Accreditation of Laboratory Animal Care International.
Statistics.
Comparisons of Stat5 expression, phosphorylation, and activation levels among tissue types were conducted using a two-sample t test. Tumor growth experiments compared the tumor volume in one flank to the paired tumor volume in the opposite flank with the signed rank test.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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for patient characteristics). Repeat EMSA analysis was performed on a subset of samples, and the variability was found to be <10% (data not shown). DNA binding of Stat5 was found to be 3-fold higher in tumors and 1.8-fold higher in normal mucosa from cancer subjects (harvested several centimeters away from the tumor) compared with normal mucosa from noncancer subjects (P = 0.000523 and P = 0.017, respectively). In addition, the level of Stat5 activation in the tumors was 1.7-fold higher in the SCCHN tumors compared with levels in the corresponding normal mucosa from the same SCCHN patients (P = 0.000135). Because it is not possible to distinguish Stat5a from Stat5b activation on gel shift assay, we performed supershift analysis to confirm that the constitutive Stat5 complexes contained both Stat5a and Stat5b isoforms. Immunoblotting with a phosphospecific Stat5 antibody was performed to confirm the increased Stat5 activation levels in SCCHN tissues detected by gel shift (Fig. 1)
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, Stat5b phosphorylation was only detected in SCCHN tumors and was not found in the corresponding normal mucosa from SCCHN patients or control mucosa from subjects without cancer. In contrast, expression levels of Stat5a and phosphorylated Stat5a in SCCHN tumors was comparable with the levels detected in normal mucosa from SCCHN subjects, as well as in normal mucosa from patients without cancer (Fig. 3)
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2 x 2 mm in diameter), the tumor implanted on one flank was treated with EGFR antisense DNA and the tumor on the contralateral flank with EGFR sense DNA. Tumors were harvested after the last treatment, and Stat5 activation levels were determined by EMSA. As shown in Fig. 4
A, tumors treated with EGFR antisense DNA demonstrated decreased Stat5 activation levels (as determined by EMSA or immunoblotting) compared with tumors treated with EGFR sense DNA, thus linking Stat5 activation, in part, to EGFR stimulation in vivo.
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. Therefore, EGFR-mediated Stat5 activation may occur, in part, via direct interaction between the tyrosine kinase domain of the receptor and SH2 domain of Stat5a/b.
Targeting Stat5b, but not Stat5a, Inhibits Tumor Growth and Target Gene Expression in Vivo.
We reported recently that blocking Stat5b, but not Stat5a, using either dominant-negative or antisense strategies inhibited the growth of SCCHN cells in vitro (27)
. The detection of elevated Stat5b phosphorylation exclusively in SCCHN tumor specimens suggests that Stat5b may play a critical role in the progression of head and neck cancer. To determine the consequences of down-modulating Stat5b in vivo, we treated established SCCHN xenografts with antisense oligonucleotides targeting the translation start site of Stat5b as described previously (27)
. Controls included Stat5b oligonucleotides in the sense orientation, antisense oligonucleotides targeting the translation start site of Stat5a, or no treatment. Three groups of mice were randomly selected to receive 25 µg of Stat5b antisense oligonucleotides injected into each established tumor five times a week. Injections were administered on days 11–15, 18–22, and 25–29 after tumor implantation. As shown in Fig. 5
, tumor volumes were consistently lower in the tumors that received Stat5b antisense oligonucleotides compared with tumors treated with corresponding Stat5b sense oligonucleotides or Stat5a antisense oligonucleotides. Similar results were obtained using two other SCCHN xenograft models (data not shown). After the last treatment, mice were sacrificed and tumors harvested for analysis. Western blotting of tumor lysates revealed decreased expression of Stat5a or Stat5b in the respective antisense-treated tumors demonstrating down-modulation of the specific Stat5 isoform being targeted (Fig. 6A)
. The specificity of the treatments was additionally demonstrated by immunoblotting, which showed that Stat5b antisense treatment did not decrease Stat5a expression, nor did Stat5a antisense treatment block expression of Stat5b protein. STATs, including Stat5, have been shown to exert their effects by modulation of gene expression. Stat5 response elements have been identified in several genes, including bcl-xL and cyclin D1 (28)
. Analysis of the tumor lysates demonstrated that expression of both Bcl-xL and Cyclin D1 were decreased in Stat5b antisense-treated tumors compared with levels in tumors treated with Stat5b sense DNA. In contrast, treatment with Stat5a antisense oligonucleotides did not abrogate Cyclin D1 or BcL-xL expression (Fig. 6B)
. To investigate the mechanism of tumor growth in inhibition after Stat5b targeting, xenografts were stained for DNA fragmentation and proliferation indicies. Targeting Stat5b, but not Stat5a, resulted in decreased tumor cell proliferation as determined by staining and blotting for PCNA (Fig. 7
; data not shown). In contrast, there was no evidence of apoptosis modulation after targeting of either Stat5 isoform (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We demonstrate here that expression and activation of Stat5b, downstream of EGFR, contribute to SCCHN carcinogenesis in vivo and may serve as a therapeutic target in cancers that demonstrate constitutive Stat5 activation. Many reports have not distinguished activation of Stat5a from Stat5b, and such a failure to determine the role of each Stat5 gene may obscure key differences. Studies of knockout mice have contributed to our understanding of the physiological roles of these closely linked STAT proteins. Stat5a-deficient mice exhibited defective mammary gland development and lactogenesis (29) . In contrast, studies of Stat5b-deficient mice indicated that Stat5b mediates an essential function in growth hormone actions (30) . Although previous reports have suggested potentially distinct roles for Stat5 isoforms, this study provides clear evidence that Stat5b, but not Stat5a, contributes to tumor progression in a human epithelial cancer. Whereas levels of Stat5a expression and phosphorylation were similar in tumor tissue and paired normal mucosa from head and neck cancer subjects, as well as control mucosa from subjects without cancer, Stat5b expression and phosphorylation was elevated consistently in SCCHN tumors but not in their epithelial counterparts. Additional investigation demonstrated that specific targeting of Stat5b using an antisense oligonucleotide approach abrogated tumor progression and target gene expression in vivo, whereas targeting Stat5a had no effect on tumor growth or gene expression.
In hematopoietic malignancies, Stat5 activation has been linked to transformation mediated by fusion genes including NPM/ALK, TEL/JAK2, and TEL/ABL (31 , 32) . However, the role of Stat5 activation in epithelial tumor formation and progression has been largely unexplored. Nonspecific epithelial cell defects in the prostates of Stat5a-deficient mice have been described (33) . Using a murine breast cancer model, it was reported recently that loss of Stat5a by genetic manipulation delayed mammary cancer progression (34) . Stat5 has been implicated in the estrogen-regulated control of T47D cells (35) . Unlike Stat3, which has been shown to transform mammalian fibroblasts when constitutively activated (36) , Stat5 activation alone has not been reported to be an essential event in malignant transformation. Src kinase has been shown to phosphorylate and activate either Stat5a or Stat5b, although only Stat5b was translocated to the nucleus after phosphorylation (37) . Using NIH-3T3 cells, Stat5b also accelerated v-Src-induced tumorigenicity, cell motility, and cell growth (38) . These studies suggest that Stat5b activation may potentiate the malignant phenotype, which is primarily induced by other transforming events.
The mechanism of increased Stat5 activation in human cancers has not been completely defined, and may depend on the specific cell type and activating stimuli in the tumor microenvironment. Src has been shown to contribute to Stat5 activation in a vulvar squamous cell carcinoma cell line (25) . We report here EGFR-Stat5 interactions in SCCHN cells, and we have detected Src-Stat5 complexes (either Stat5a or Stat5b) in SCCHN cell lines (data not shown). Activation of Stat5b by EGF has been reported to require EGFR overexpression (23) .
Increased expression of EGFR is characteristic of most epithelial malignancies, including SCCHN, where autocrine or paracrine activation of EGFR is thought to contribute to tumor progression (reviewed in Ref. 39 ). In the present study, we have demonstrated that targeting EGFR in a SCCHN xenograft model, using an antisense gene therapy approach, abrogated constitutive Stat5 activation, thus linking EGFR to Stat5 in vivo. Additional investigation showed that increased expression and phosphorylation of Stat5b was associated with SCCHN tumorigenesis where targeting Stat5b decreased tumor progression in vivo. The antitumor effects of Stat5b blockade can be explained, in part, by down-regulation of target genes that control growth and apoptosis. Specifically, antisense targeting of Stat5b resulted in decreased expression of Cyclin D1 and Bcl-xL. Previous studies have demonstrated that the antiapoptotic gene encoding Bcl-xL is a downstream target of both Stat3 and Stat5 (40 , 41) . Similarly, Cyclin D1/D2 are critical cell cycle control genes that have been reported to be a target of Stat5 (42) . The present study suggests that blockade of Stat5b in vivo leads to tumor growth inhibition primarily as a result of decreased proliferation, and not increased apoptosis. Because both STATs 3 and 5 are activated in SCCHN, and appear to contribute to growth regulation, additional studies to elucidate mechanisms of STAT activation are required. These cumulative results implicate decreased Stat5 activation as a potential antitumor mechanism of EGFR blocking approaches, and suggest that specific abrogation of Stat5b may play a role in molecular targeting strategies for cancer therapy.
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at The Eye and Ear Institute, Suite 500, 200 Lothrop Street, Pittsburgh, PA 15213. Phone: (412) 647-5280; Fax: (412) 647-0108; E-mail: jgrandis{at}pitt.edu 
2 The abbreviations used are: STAT, signal transducers and activators of transcription; EGFR, epidermal growth factor receptor; EGF, epidermal growth factor; SCCHN, squamous cell carcinoma of the head and neck; TGF, transforming growth factor; EMSA, 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 antigen.
Received 5/29/03. Revised 7/17/03. Accepted 7/23/03.
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REFERENCES |
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; A–C) Stat5b sense oligonucleotides (
; A), Stat5a antisense oligonucleotides (
; B), or no oligonucleotides (
; C), 10 days after tumor cell implantation. Statistical analysis (exact two-tailed signed rank test) was performed comparing tumor volumes in the Stat5b antisense-treated flank with the tumor volume of the opposite flank. Significant differences were observed at all time points on days 15–30 (P < 0.0001).
