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Cell and Tumor Biology |
Departments of 1 Molecular Biology and 2 Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio and 3 Department of Pathology, New York University School of Medicine, New York, New York
Requests for reprints: George R. Stark, Department of Molecular Biology, New York University School of Medicine, New York, NY. Phone: 216-444-3900; Fax: 216-444-3279; E-mail: starkg{at}ccf.org.
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Abstract |
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Key Words: expression analysis • tumor arrays • immunohistochemistry • MRAS • RANTES
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Introduction |
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It has been reported widely that the activation of STAT3 is likely to contribute importantly to the development of cancer. A constitutively active (DNA binding) variant of STAT3 induces oncogenic transformation and tumorigenesis (5). Constitutively tyrosine phosphorylated, active STAT3 has been observed in transformation by v-Src, v-Eyk, v-Ros, and v-Fps (6,7), and STAT3 activation has been seen at a high frequency in many human tumors, including breast and head and neck carcinomas, lymphomas, leukemias, melanomas, and pancreatic, lung, ovarian, and brain tumors (7, 8). In addition, STAT3 can be activated by several different oncogenic kinases, such as v-SRC, c-SRC, v-ABL, and v-FPS (9, 10). Abrogation of constitutive STAT3 activity by dominant-negative STAT3 mutant proteins induces apoptosis and growth arrest in breast cancer cell lines (11), suggesting an important role for constitutively active STAT3 in breast cancer development, possibly through an aberrant epidermal growth factor receptor pathway or activation of SRC. SRC_mediated activation of STAT3 also correlates with the development of prostate and ovarian carcinomas (12), and autocrine stimulation by IL-6 induces prostate cancer cell growth that is accompanied by the activation of STAT3 (13). Furthermore, IL-6 is required for glioma development in a mouse model (14).
From our previous work (15), we know that STAT1 can drive the constitutive expression of several genes in the complete absence of tyrosine phosphorylation, a function quite distinct from its role in inducible, phosphorylation-dependent gene expression in response to IFNs and other cytokines. In the work reported here, we show that unphosphorylated STAT3 also drives gene expression and that the increase in STAT3 levels that follow its IL-6–dependent activation by tyrosine phosphorylation drives a distinct subset of genes. Furthermore, mRNAs or proteins whose expression is driven by overexpression of unphosphorylated STAT3 (e.g., MET and MRAS) are present at high levels in many cancers.
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Materials and Methods |
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Expression Array Experiments. Total RNAs were extracted from cells with Trizol (Life Technologies). Approximately 15 µg of RNA were used to obtain cRNA according to standard Affymetrix protocols (17). The cRNAs were hybridized with human (U133A) or mouse (U74Av2) arrays and data were analyzed using the Affymetrix gene chip software. Expression was normalized against the Affymetrix spike RNA levels as well as against glyceraldehyde phosphate dehydrogenase (GAPDH) and actin mRNA levels in the all samples. The expression of genes in HiSTAT3wt or HiY705F MEFs was compared with STAT3-null MEFs as the baseline. The expression of genes in hTERT-HME1 cells overexpressing wild-type or Y705F STAT3 was compared with hTERT-HME1 cells as the baseline.
Expression Analysis Using a Tumor Tissue Array. Cancer Profiling Array I (Clontech) consists of 241 cDNAs, synthesized from human tumors and normal tissues (http://www.bdbiosciences.com/clontech/techinfo/manuals/PDF/PT3578-1.pdf and http://www.bdbiosciences.com/clontech/techinfo/manuals/PDF/7841-1.pdf). Each pair was independently normalized, based on the expression of three housekeeping genes. Human stat3, met, and mras cDNAs were radiolabeled using a [
-32P]-dCTP and hybridized overnight at 68°C using ExpressHyb Hybridization Solution (Clontech), washed, and exposed to Phosphor Screen (Molecular Dynamics, Eugene, OR). Signal intensities were calculated for individual spots using a STORM-840 phosphoimager (Molecular Dynamics).
Western Analysis. Cells at 80% confluence in 100-mm dishes were washed once with PBS and the cell pellets were lysed for 20 minutes at 4°C in 100 µL lysis buffer [ 50 mmol/L HEPES (pH 7.0), 250 mmol/L NaCl, 0.1% NP40, 10% glycerol, 1 mmol/L phenylmethanesulfonyl fluoride, 2 µg/mL aprotinin, 25 µg/mL leupeptin, 5 µg/mL pepstatin A, and 1 mmol/L DTT]. Extracts containing equal quantities of proteins, determined by the Bradford method (Bio-Rad, Hercules, CA), were separated by SDS-PAGE (10% acrylamide) and transferred to polyvinylidenedifluoride membranes (Millipore, Bedford, MA). Membranes were probed with antibodies specific for STAT3, Cyclin B1, CDC2, PLK-1, or Ran GAP1. Horseradish peroxidase–coupled goat anti-rabbit or anti-mouse immunoglobulins were used for visualization, using the enhanced chemiluminescence Western detection system (Perkin-Elmer Life Sciences, Boston, MA).
Northern Analysis. Twenty micrograms of total RNA were fractionated in a 1% agarose/formaldehyde gel and transferred to a Hybond-XL membrane (Amersham Biosciences UK Limited, Buckinghamshire, United Kingdom). The RNAs were cross-linked to the membrane by using a UV cross-linker before hybridization. [-32P]-dCTP (6,000 Ci/mmol, NEN, Boston, MA) was used to generate 32P-labeled cDNA probes by random priming (Roche Molecular Biochemicals, Laval, Quebec, Canada). The membrane was prehybridized for 6 hours with 5x saline-sodium phosphate-EDTA (75 mmol/L NaCl, 50 mmol/L NaH2P04, and 4 mmol/L EDTA) plus 2% SDS and 100 µg/mL ssDNA at 65°C. After the addition of specific probes, hybridization took place for 36 hours at 65°C. The membranes were washed thrice with 2x saline-sodium phosphate-EDTA plus 0.1% SDS. Selected genes from the array were also examined by the Northern procedure. Mouse and human cDNA probes for these genes were cut from I.M.A.G.E. clones, obtained from Invitrogen (Carlsbad, CA) or the American Type Culture Collection (Manassas, VA). Templates for the mouse and human gapdh cDNAs were obtained by reverse transcription-PCR. Transfers were normalized for loading by comparing the intensities of the 18 S and 28 S rRNA bands or the gapdh mRNA levels on the same membranes.
Electrophoretic Mobility Shift Analysis. hTERT-HME1 cells, untreated or treated with IL-6, were lysed in 10 mmol/L HEPES (pH 7.9), 60 mmol/L KCl, 1 mmol/L EDTA, 0.1 mmol/L EGTA, 0.075% NP40, 1 mmol/L Na3VO4, 5 mmol/L NaF, 1 mmol/L DTT, 1 mmol/L phenylmethanesulfonylfluoride, 2 µg/mL aprotinin, 25 µg/mL leupeptin, and 5 µg/mL pepstatin. After incubation for 15 minutes on ice, debris was removed by centrifugation at 16,000 x g at 4C for 30 minutes. Protein concentrations were determined by the Bradford method. Binding reactions contained 1 L of lysate (5-10 g of protein), 1 µL of sonicated salmon sperm DNA (0.5 mg/mL), 1.4 µL of 5 shift buffer [100 mmol/L HEPES (pH 7.9), 200 mmol/L KCl, 30 mmol/L MgCl2, 0.5% NP40, 5 mmol/L DTT, and 5 mmol/L phenylmethylsulfonyl fluoride], 1.5 µL of bovine serum albumin (1 mg/mL), 3.8 µL of H2O, and 0.3 µL of probe, end-labeled with T4 polynucleotide kinase and [
-32P]-ATP. The probe was the SIE consensus sequence (top strand 5'-TCGACATTTCCCGTAAATC-3') from the c-fos gene promoter (18); 104 dpm of labeled probe was used in each binding reaction. Protein-DNA complexes were separated by electrophoresis in gels composed of 4% acrylamide-bisacrylamide (29:1), 0.5x TBE (45 mmol/L Tris-HCl, 44 mmol/L boric acid, and 1 mmol/L EDTA), and 5% glycerol. For supershift analyses, whole cell extracts were preincubated for 20 minutes at room temperature with polyclonal antibodies specific for STAT3 (C-20) before adding radiolabeled probe.
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Results |
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Overexpressed Wild-Type and Y705F STAT3 Drive Gene Expression. An array-based analysis of gene expression revealed that the relative levels of more than a thousand mRNAs changed in response to the overexpression of wild-type or Y705F STAT3. In hTERT-HME1 cells, 1,420 mRNAs changed, positively or negatively, by 
2-fold in response to overexpressed wild-type STAT3 and 1,191 mRNAs changed by the same amount in response to overexpressed Y705F STAT3 (data not shown). Furthermore, 869 mRNAs changed in common by 2-fold in both cell populations, and 84 of these changed by 4-fold (examples in Table 1A; full list available upon request). These mRNAs include several that are induced to very high levels (10-to 40-fold). Analysis of the mouse cell lines provided complementary data. In addition to the obvious cell-type differences in the two experiments, mouse cells overexpressing wild-type or Y705F STAT3 are compared with STAT3-null cells, rather than to cells with low level expression of STAT3, which was the baseline in the human system. In MEFs, 1,054 mRNAs changed by 2-fold in cells overexpressing wild-type STAT3 and 1,268 mRNAs changed by the same amount in cells overexpressing Y705F STAT3. Furthermore, 413 mRNAs changed in common by 2-fold in both cell types, and 115 of these changed by 4-fold (Table 1B, full list available upon request). Some of the genes that respond to unphosphorylated STAT3 are known to be regulated also by phosphorylated STAT3 homodimers [e.g., socs-2 (19), c-myc, dp1 (20), c-fos, c-jun (21), and bcl-x (22)]. (22)]. In the case of STAT1, the lmp2 gene is known to respond both to homodimers of phosphorylated STAT1 and to unphosphorylated STAT1-IRF1 heterodimers through distinct but overlapping DNA elements (15). On the other hand, several genes not shown in Table 1B were induced in MEFs only in response to overexpressed Y705F and not wild-type STAT3 [e.g., small inducible cytokine a5 (scyA5), tiap, meiosis-specific nuclear structural protein 1 (mns1), the p70/p85 S6 kinase gene, formin, P21-activated kinase-3 (mpak-3), heat shock protein 86, thymopoietin, and TFIIH]. Several genes were induced in MEFs only in response to overexpressed wild-type STAT3 but not Y705F (e.g., Survivin, BUB1, and TACC3). Some of the gene chip data have been confirmed in both cell systems Fig. 2. Most of the genes identified in the gene chip analyses were confirmed by Northern, Western, or reverse transcription-PCR analyses. Those genes confirmed by Northern or Western analyses are shown in Fig. 2; for example, genes confirmed in hTERT-HME1 cells by Northern analysis include bcl2-related protein a1 (bcl2a1), Ran GTPase activating protein 1(Ran GAP1), tis11d, met, and rantes (Fig. 2A); genes confirmed by Western analysis in MEFs include cyclin B1, polo-like kinase 1 (plk-1), Ran GAP1, cdc2, and cdc25c (Fig. 2B) and by Northern analysis survivin, tacc3, bub1, serine/threonine kinase 6 (s/t kinase 6), Ran GAP1, met, tis11d, and plk-1 (Fig. 2C). Others, which were confirmed by reverse transcription-PCR are not shown.
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Discussion |
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Mechanism of Transcriptional Activation by Unphosphorylated STAT3. Changes in gene expression in response to unphosphorylated STAT3 may be due either to the direct effect of STAT3 binding to a responsive promoter or to an indirect effect (e.g., if a gene regulated directly by STAT3 encodes a transcription factor that activates additional genes). In Table 1, it can be seen that overexpression of wild-type and Y705F STAT3 have similar but distinct effects on gene expression. It is unlikely that the differences are due to the formation of dimers of unphosphorylated STAT3 in the case of the wild-type protein because no stimulus has been given to the cells, there was no detectable tyrosine phosphorylation (data not shown) and the pattern of gene expression is quite distinct from the pattern induced by IL-6, which does cause the formation of dimers. By analogy with the limited information currently available on how unphosphorylated STAT1 drives gene expression (15), it seems possible that STAT3 forms heterodimers with other transcription factors (yet to be identified) and that such heterodimers might recognize half of a GAS element plus a DNA element to which the non-STAT partner can bind. The substitution of tyrosine by phenylalanine may affect the structure or affinity for DNA of such heterodimers and thus may affect gene expression independently of the ability of residue 705 to become phosphorylated.
The crystal structure of STAT3 dimers bound to DNA indicates that, in addition to several well characterized conserved domains (linker, SRC homology 2, and transactivation), STAT3 also has a large NH2-terminal coiled coil domain that projects laterally from the core structure (27, 28). This feature represents a large exposed surface that can bind to other proteins that interact with STAT3 or with other STATs (29, 30). There is limited coincidence between the sets of genes induced by unphosphorylated STAT3 in the human (Table 1A) and mouse (Table 1B) systems but, for example, met, tis11d, and serine/threonine kinase 6 are induced in both situations. The lack of greater coincidence is perhaps not too surprising, given the many differences between the two experiments (species, cell type, comparison with normal levels of STAT3 in the human experiment and with STAT3-null cells in the mouse, analysis of clones of mouse cells versus a population of human cells, differences in growth rates of the cells studied in the mouse experiment).
Functions of Induced Genes. Target genes of unphosphorylated STAT3 (cdc2, cyclin B1 mras, and e2f-1) are overexpressed in colon and breast carcinomas.4 E2F-1 is a transcription factor that activates the synthesis of mRNAs encoding proteins needed during the cell cycle. Most E2F-1–regulated genes encode proteins involved in DNA replication or cell cycle progression. The products of some E2F-1–regulated genes, such as cyclin D1 and cyclin E (31, 32), cdc2 and cyclin B1 (33, 34) contribute to the G1-S and G2-M transitions and inhibit apoptosis. Recently, clear evidence has been obtained that CDC2, Cyclin B1, and E2F-1 are overexpressed in mucosa-associated lymphoid tissues and head and neck carcinomas (23, 24). The product of another STAT3 target gene (MRAS) contributes to cellular transformation and differentiation (35, 36). Our findings reveal an important role for STAT3 in activating oncogene expression.
Expression and Location of STAT3 in Cancer Cells. We investigated STAT3 immunoreactivity in a variety of neoplastic tissue specimens obtained from different sources (National Cancer Institute TARP3, Zymed MaxArray, Cleveland Clinic Foundation Surgical Pathology specimens). Based on these limited data (not shown), we can say that STAT3 was detected in the majority of neoplasms examined (carcinomas of breast, prostate, colon, lung, brain and ovary, melanomas, lymphomas, and glioblastomas). Most of the STAT3 immunoreactivity was in the nucleus. This finding is consistent with observations in cell culture systems (37).
It is difficult to determine whether the level of a particular protein is altered in tumors compared with the corresponding normal tissues. Analysis of tissue extracts by the Northern, reverse transcription-PCR, or Western methods yields results that are readily quantified but lack specificity because of the cellular heterogeneity of tissues. For example, the most abundant cell type in normal colonic mucosa is the colonic epithelial cell, but some regions of the colon have a high frequency of lymphoid nodules and mucosal lymphocytes. Many genes of interest in cancer, such as regulators of cell cycle and apoptosis, are expressed by lymphocytes and contribute to the total signal in homogenates. Similarly, tumor-infiltrating lymphocytes, present in many neoplasms, will contribute to the expression seen in tumor tissues.
Immunocytochemistry and in situ hybridization enable one to distinguish the cells of interest from others, making them highly specific techniques. However, most in situ techniques used for human pathology specimens employ chromogenic detection and rely upon enzyme-linked and other amplification techniques to achieve the high sensitivity required for visualization. Large differences but not small differences in stain intensity are readily distinguished by the naked eye. Also, as noted above, the lability of specific proteins or phosphoproteins in tumors can only be addressed by rapid acquisition after surgery and rapid preservation of the specimens.
Upon long-term treatment of hTERT-HME1 cells with IL-6, the total amount of STAT3 was increased, whereas the level of phosphorylated STAT3 was similar to the very low level in untreated cells (Fig. 3A and B). Immunofluorescence analysis in these experiments showed that STAT3 was increased both in the cytoplasm and in the nucleus, but mostly in the nucleus (data not shown). Also, as noted above, the lability of specific proteins or phosphoproteins in tumors can only be addressed by rapid acquisition after surgery and rapid preservation of the specimens.
STAT3 and Cancer. The role of STAT3 in cancer has been assumed until now to be due solely to the activation of gene expression in response to STAT3 dimers, formed through tyrosine phosphorylation in response to oncogeneic tyrosine kinases such as SRC (11). It is now clear that the constitutive activation of STAT3 drives in turn the constitutive overexpression of STAT3, and it is possible that stimuli other than STAT3 dimers can also drive STAT3 expression. To analyze the impact of gene expression driven by unphosphorylated STAT3 in tumors, it will be helpful to determine the relative expression of proteins that are driven by the total amount of STAT3 or by STAT3 dimers, respectively, to help discriminate among different mechanisms in different tumors. For example, if genes that respond to unphosphorylated STAT3 are expressed in certain cancers but genes that respond to STAT3 dimers are not, it would indicate that the STAT3 overexpression in these cases is caused by a signal distinct from STAT3 dimers. Such information would be useful in seeking appropriate applications for drugs currently in development that target the formation or function of STAT3 dimers (38).
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Dr. Robert J. Arceci, John Hopkins University, for human stat3 wild-type and Y705F cDNAs; Dr. Lawrence A. Quilliam, Indiana University School of Medicine, for the antibody against MRAS; Yulan Qing for assistance with analysis of the array data; William Taylor, Mairead Commane, and Jacqueline Bromberg for helpful discussions; Linda Vargo, Digital Imaging Core, Cleveland Clinic, for assistance with the immunohistochemistry; and Drs. Jacqueline Bromberg and Ganes C. Sen for critical reading of this article.
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Footnotes |
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4 J.B. Yang and G.R. Stark, unpublished observation. 
Received 7/26/04. Revised 6/10/04. Accepted 11/10/04.
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, ß, or using oligonucleotide arrays. Proc Natl Acad Sci U S A 1998;95:15623–8.-activated STAT1 in the liver: involvement of SOCS2 and SOCS3. FEBS Lett 2000;480:132–6.[CrossRef][Medline]
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 K. W. Kim, R. W. Mutter, C |
