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n2:pmcid: PMC0
bibo:doi: 10.1038%2Fonc.2009.279
n4:contains: _:vb8183778 _:vb8183711 _:vb8183701 _:vb8183738 _:vb8183719

Subject Item: _:vb8183701
rdf:type: n4:Section
dc:title: introduction
n4:contains: _:vb8183702 _:vb8183703 _:vb8183704 _:vb8183705 _:vb8183706 _:vb8183707 _:vb8183708 _:vb8183709 _:vb8183710

Subject Item: _:vb8183702
rdf:type: n2:Context
rdf:value: EGFR overexpression in HNSCC has been correlated with tumor progression, resistance to conventional therapy and poor prognosis (Grandis and Tweardy, >>1993<<). Preclinical studies demonstrated the anti-tumor effects of EGFR targeting and the FDA approved the EGFR monoclonal antibody cetuximab for clinical use in HNSCC based on the results of a phase III trial (Bonner et al., 2006). However,
n2:mentions: n3:8412192

Subject Item: _:vb8183703
rdf:type: n2:Context
rdf:value: Preclinical studies demonstrated the anti-tumor effects of EGFR targeting and the FDA approved the EGFR monoclonal antibody cetuximab for clinical use in HNSCC based on the results of a phase III trial (Bonner et al., >>2006<<). However, while combining EGFR targeting with radiation prolonged overall survival, it did not reduce the incidence of metastasis. Despite the nearly ubiquitous expression of EGFR in HNSCC, there is only a 13% response rate when
n2:mentions: n3:16467544

Subject Item: _:vb8183704
rdf:type: n2:Context
rdf:value: Despite the nearly ubiquitous expression of EGFR in HNSCC, there is only a 13% response rate when cetuximab is administered as a single agent (Vermorken et al., >>2007<<). The tumor features that contribute to resistance to EGFR targeting are incompletely understood.
n2:mentions: n3:17538161

Subject Item: _:vb8183705
rdf:type: n2:Context
rdf:value: This mutation eliminates exons 2-7 resulting in a distorted ligand-binding region (Bigner et al., >>1990<<; Sugawa et al., 1990).
n2:mentions: n3:2253244

Subject Item: _:vb8183706
rdf:type: n2:Context
rdf:value: This mutation eliminates exons 2-7 resulting in a distorted ligand-binding region (Bigner et al., 1990; Sugawa et al., >>1990<<). EGFRvIII does not bind ligand but is constitutively activated in a ligand-independent manner. The presence of EGFRvIII in human tumors has been associated with tumor growth, metastasis, and survival in several malignancies including
n2:mentions: n3:2236070

Subject Item: _:vb8183707
rdf:type: n2:Context
rdf:value: The presence of EGFRvIII in human tumors has been associated with tumor growth, metastasis, and survival in several malignancies including glioma, carcinomas of the breast, lung and HNSCC (Pedersen et al., >>2001<<). Furthermore, EGFRvIII has been reported to increase resistance to anti-tumor agents including EGFR inhibitors (Sok et al., 2006).
n2:mentions: n3:11484948

Subject Item: _:vb8183708
rdf:type: n2:Context
rdf:value: Furthermore, EGFRvIII has been reported to increase resistance to anti-tumor agents including EGFR inhibitors (Sok et al., >>2006<<).
n2:mentions: n3:16951222

Subject Item: _:vb8183709
rdf:type: n2:Context
rdf:value: Moreover, EGFRvIII decreased HNSCC cell apoptosis in response to cisplatin and decreased growth inhibition following treatment with cetuximab (Sok et al., >>2006<<). While these results support the role of EGFRvIII in mediating tumor growth in response to EGFR targeting, the contribution of EGFRvIII to invasion and the precise downstream pathways that are induced by EGFRvIII are incompletely
n2:mentions: n3:16951222

Subject Item: _:vb8183710
rdf:type: n2:Context
rdf:value: EGFRvIII expression in glioma has been reported to correlate with expression of phosphotyrosine STAT3 (Mizoguchi et al., >>2006<<). The lethality of HNSCC is associated with the tendency of these cancers to invade surrounding structures and metastasize. The present study was undertaken to test the hypothesis that EGFRvIII induces HNSCC invasion and subsequently,
n2:mentions: n3:17146292

Subject Item: _:vb8183711
rdf:type: n4:Section
dc:title: materials and methods
n4:contains: _:vb8183712 _:vb8183713 _:vb8183714 _:vb8183715 _:vb8183716 _:vb8183717 _:vb8183718

Subject Item: _:vb8183712
rdf:type: n2:Context
rdf:value: NR6 cells expressing human EGFRvIII (NR6M) were generated as described previously (Batra et al., >>1995<<). EGFRvIII-transfected HNSCC cells (vIII-1 to 4) and vector control transfected HNSCC cells (control-1 to 4) were generated as descried previously (Sok et al., 2006). All cells were maintained in DMEM (Mediatech, Inc., Herndon, VA) with
n2:mentions: n3:8845302

Subject Item: _:vb8183713
rdf:type: n2:Context
rdf:value: EGFRvIII-transfected HNSCC cells (vIII-1 to 4) and vector control transfected HNSCC cells (control-1 to 4) were generated as descried previously (Sok et al., >>2006<<). All cells were maintained in DMEM (Mediatech, Inc., Herndon, VA) with 10% heat-inactivated fetal bovine serum (Invitrogen, Carlsbad, CA) and incubated at 37°C in the presence of 5% CO2. To establish hypoxic conditions (1% O2), cells
n2:mentions: n3:16951222

Subject Item: _:vb8183714
rdf:type: n2:Context
rdf:value: To detect the deleted region of EGFRvIII, standard RT-PCR was performed as described previously (Sok et al., >>2006<<).
n2:mentions: n3:16951222

Subject Item: _:vb8183715
rdf:type: n2:Context
rdf:value: Bromberg (Memorial Sloan-Kettering Cancer Center, New York, NY) and pRL-TK (Promega, Madison, WI) a Renilla luciferase construct, using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions (Besser et al., >>1999<<). The transfection media was replaced to complete DMEM after 4 h of transfection.
n2:mentions: n3:9891073

Subject Item: _:vb8183716
rdf:type: n2:Context
rdf:value: and the mutant control decoy sequences (double-stranded deoxyribonucleotides with phosphorothioate modifications in the first three bases and last three bases of the sequences) were generated as described previously (Leong et al., >>2003<<). The mutant control decoy, carrying a single base mutation, that does not abrogate STAT3 DNA binding activity, was used as a control as in previous studies (Leong et al., 2003; Xi et al., 2005).
n2:mentions: n3:12640143

Subject Item: _:vb8183717
rdf:type: n2:Context
rdf:value: The mutant control decoy, carrying a single base mutation, that does not abrogate STAT3 DNA binding activity, was used as a control as in previous studies (Leong et al., >>2003<<; Xi et al., 2005).
n2:mentions: n3:12640143

Subject Item: _:vb8183718
rdf:type: n2:Context
rdf:value: The mutant control decoy, carrying a single base mutation, that does not abrogate STAT3 DNA binding activity, was used as a control as in previous studies (Leong et al., 2003; Xi et al., >>2005<<). The siRNA sequences targeting STAT3 human mRNA (D-003544-01, sense 5’-CCAACGACCUGCAGCAAUAUU-3’, and antisense 5’-PUAUUGCUGCAGGUCGUUGGUU-3’; Dharmacon, Lafayette, CO) were transfected into HNSCC cells for STAT3 silencing. The
n2:mentions: n3:15592503

Subject Item: _:vb8183719
rdf:type: n4:Section
dc:title: results
n4:contains: _:vb8183736 _:vb8183737 _:vb8183728 _:vb8183729 _:vb8183730 _:vb8183731 _:vb8183732 _:vb8183733 _:vb8183734 _:vb8183735 _:vb8183720 _:vb8183721 _:vb8183722 _:vb8183723 _:vb8183724 _:vb8183725 _:vb8183726 _:vb8183727

Subject Item: _:vb8183720
rdf:type: n2:Context
rdf:value: We previously reported that EGFRvIII is expressed in approximately 40% of HNSCC tumors (Sok et al., >>2006<<). For reasons that are incompletely understood, expression of EGFRvIII in human tumors is routinely lost in tissue culture (Bigner et al., 1990).
n2:mentions: n3:16951222

Subject Item: _:vb8183721
rdf:type: n2:Context
rdf:value: For reasons that are incompletely understood, expression of EGFRvIII in human tumors is routinely lost in tissue culture (Bigner et al., >>1990<<). Therefore, to study the consequences of EGFRvIII in HNSCC, we stably transfected EGFR vIII into a representative HNSCC cell line (UM-22B) as described previously (Nishikawa et al., 1994; Sok et al., 2006). Four independent clones that
n2:mentions: n3:2253244

Subject Item: _:vb8183722
rdf:type: n2:Context
rdf:value: Therefore, to study the consequences of EGFRvIII in HNSCC, we stably transfected EGFR vIII into a representative HNSCC cell line (UM-22B) as described previously (Nishikawa et al., >>1994<<; Sok et al., 2006).
n2:mentions: n3:8052651

Subject Item: _:vb8183723
rdf:type: n2:Context
rdf:value: Therefore, to study the consequences of EGFRvIII in HNSCC, we stably transfected EGFR vIII into a representative HNSCC cell line (UM-22B) as described previously (Nishikawa et al., 1994; Sok et al., >>2006<<). Four independent clones that stably expressed EGFRvIII were isolated (vIII-1 to 4) as well as four vector-transfected control clones (control-1 to 4). Due to the high level of wild-type EGFR in HNSCC cell lines and tissues, commercially
n2:mentions: n3:16951222

Subject Item: _:vb8183724
rdf:type: n2:Context
rdf:value: These results are consistent with findings in human HNSCC where all HNSCC tumors that express EGFRvIII also express wild-type EGFR, with a higher level of wild-type EGFR compared to EGFRvIII (Sok et al., >>2006<<).
n2:mentions: n3:16951222

Subject Item: _:vb8183725
rdf:type: n2:Context
rdf:value: We previously reported that EGFRvIII induces HNSCC cell proliferation in vitro and tumor growth in vivo (Sok et al., >>2006<<). EGFRvIII has been shown to induce motility in murine fibroblasts (Pedersen et al., 2004).
n2:mentions: n3:16951222

Subject Item: _:vb8183726
rdf:type: n2:Context
rdf:value: EGFRvIII has been shown to induce motility in murine fibroblasts (Pedersen et al., >>2004<<). To determine the consequences of EGFRvIII on directional HNSCC cell motility, cell migration (wound-healing) assays were performed. Briefly, a wound was created in a confluent monolayer of HNSCC cells. Images captured at the creation of
n2:mentions: n3:14696090

Subject Item: _:vb8183727
rdf:type: n2:Context
rdf:value: We previously reported that HNSCC cells expressing EGFRvIII are relatively resistant to the growth inhibitory effects of cetuximab in vitro and in vivo (Sok et al., >>2006<<). Since the addition of cetuximab to radiation did not prevent metastasis in HNSCC patients, we next determined the effects of cetuximab on EGFRvIII-mediated invasion (Bonner et al., 2006). As shown in Figure 2C, while cetuximab abrogated
n2:mentions: n3:16951222

Subject Item: _:vb8183728
rdf:type: n2:Context
rdf:value: Since the addition of cetuximab to radiation did not prevent metastasis in HNSCC patients, we next determined the effects of cetuximab on EGFRvIII-mediated invasion (Bonner et al., >>2006<<). As shown in Figure 2C, while cetuximab abrogated EGF-induced invasion of vector control-transfected HNSCC cells, treatment of EGFRvIII-expressing HNSCC cells with cetuximab failed to decrease invasion. While EGF induced invasion of
n2:mentions: n3:16467544

Subject Item: _:vb8183729
rdf:type: n2:Context
rdf:value: A correlation between EGFRvIII expression and expression of phosphotyrosine STAT3 has been noted in glioblastomas (Mizoguchi et al., >>2006<<). We previously reported that STAT3 is activated downstream of wild-type EGFR in HNSCC (Grandis et al., 1998). To determine whether STAT3 is differentially activated by EGFRvIII, we analyzed expression of tyrosine phosphorylated STAT3 by
n2:mentions: n3:17146292

Subject Item: _:vb8183730
rdf:type: n2:Context
rdf:value: We previously reported that STAT3 is activated downstream of wild-type EGFR in HNSCC (Grandis et al., >>1998<<). To determine whether STAT3 is differentially activated by EGFRvIII, we analyzed expression of tyrosine phosphorylated STAT3 by immunoblotting in addition to STAT3 transcriptional activity in the EGFRvIII-expressing HNSCC cells compared
n2:mentions: n3:9769331

Subject Item: _:vb8183731
rdf:type: n2:Context
rdf:value: Further, EGFRvIII expression was associated with increased tumor growth in a xenograft model, thus confirming our previous findings (Sok et al., >>2006<<) (data not shown).
n2:mentions: n3:16951222

Subject Item: _:vb8183732
rdf:type: n2:Context
rdf:value: STAT3 has been implicated in several oncogenic processes including proliferation, survival, and invasion and may represent a therapeutic target for cancer (Germain and Frank, >>2007<<). To determine whether STAT3 is required for EGFRvIII-mediated cell motility and invasion, we performed wound healing and invasion assays in the presence or absence of siRNA targeting STAT3, under conditions where siRNA did not modulate
n2:mentions: n3:17908954

Subject Item: _:vb8183733
rdf:type: n2:Context
rdf:value: In addition to downmodulation of STAT3 expression using siRNA, we also blocked STAT3 in the cells with a transcription factor decoy directed against STAT3 as described previously (Leong et al., >>2003<<). The STAT3 decoy interferes with STAT3-mediated DNA binding and abrogates STAT3 target gene expression. As shown in Figures 4D and 4E, treatment with the STAT3 decoy resulted in reduction of both migration and invasion in vIII-4 cells
n2:mentions: n3:12640143

Subject Item: _:vb8183734
rdf:type: n2:Context
rdf:value: Others have reported that PI3K/AKT is activated downstream of EGFRvIII in glioma (Antonyak et al., >>1998<<; Li et al., 2004).
n2:mentions: n3:9446590

Subject Item: _:vb8183735
rdf:type: n2:Context
rdf:value: Others have reported that PI3K/AKT is activated downstream of EGFRvIII in glioma (Antonyak et al., 1998; Li et al., >>2004<<). To determine whether motility and invasion are also mediated by this pathway, in addition to STAT3, we examined the expression of AKT phosphorylation in EGFRvIII and vector-transfected control HNSCC cells and found that similar to
n2:mentions: n3:15077177

Subject Item: _:vb8183736
rdf:type: n2:Context
rdf:value: Hypoxia potently induces expression of hypoxia inducible factor (HIF-1α), which has been shown to be a STAT3 target gene (Niu et al., >>2008<<). EGFRvIII has been reported to contribute to hypoxia-mediated tumor growth in conjunction with radiation therapy but has not been previously linked to HIF-1α expression (Weppler et al., 2007). We therefore examined the expression of
n2:mentions: n3:18644974

Subject Item: _:vb8183737
rdf:type: n2:Context
rdf:value: EGFRvIII has been reported to contribute to hypoxia-mediated tumor growth in conjunction with radiation therapy but has not been previously linked to HIF-1α expression (Weppler et al., >>2007<<). We therefore examined the expression of HIF-1α following treatment of HNSCC cells expressing EGFRvIII (or vector-transfected controls) with EGF and/or cetuximab. As shown in Figure 6, hypoxia-induced expression of HIF-1α was abrogated
n2:mentions: n3:17512071

Subject Item: _:vb8183738
rdf:type: n4:Section
dc:title: discussion
n4:contains: _:vb8183740 _:vb8183741 _:vb8183742 _:vb8183743 _:vb8183739 _:vb8183756 _:vb8183757 _:vb8183758 _:vb8183759 _:vb8183752 _:vb8183753 _:vb8183754 _:vb8183755 _:vb8183748 _:vb8183749 _:vb8183750 _:vb8183751 _:vb8183744 _:vb8183745 _:vb8183746 _:vb8183747 _:vb8183772 _:vb8183773 _:vb8183774 _:vb8183775 _:vb8183768 _:vb8183769 _:vb8183770 _:vb8183771 _:vb8183764 _:vb8183765 _:vb8183766 _:vb8183767 _:vb8183760 _:vb8183761 _:vb8183762 _:vb8183763 _:vb8183776 _:vb8183777

Subject Item: _:vb8183739
rdf:type: n2:Context
rdf:value: We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where expression of this altered receptor mediates growth and resistance to chemotherapy or EGFR targeting using cetuximab (Sok et al., >>2006<<). Patients with HNSCC succumb to their disease due to invasion into surrounding tissues and regional and distant metastasis.
n2:mentions: n3:16951222

Subject Item: _:vb8183740
rdf:type: n2:Context
rdf:value: Although the addition of cetuximab to radiation was shown to improve survival, it did not decrease metastasis (Bonner et al., >>2006<<). The present study was undertaken to determine the effects of EGFRvIII on the migration and invasion of HNSCC cells and the signaling pathways that mediate these properties. Our results suggest that EGFRvIII increases HNSCC motility and
n2:mentions: n3:16467544

Subject Item: _:vb8183741
rdf:type: n2:Context
rdf:value: EGFRvIII has not been observed in normal tissue, but it has been detected in carcinomas of the brain, breast, ovary (Moscatello et al., >>1995<<), lung (Garcia de Palazzo et al., 1993), prostate (Olapade-Olaopa et al., 2000) and head and neck (Sok et al., 2006).
n2:mentions: n3:7585629

Subject Item: _:vb8183742
rdf:type: n2:Context
rdf:value: EGFRvIII has not been observed in normal tissue, but it has been detected in carcinomas of the brain, breast, ovary (Moscatello et al., 1995), lung (Garcia de Palazzo et al., >>1993<<), prostate (Olapade-Olaopa et al., 2000) and head and neck (Sok et al., 2006).
n2:mentions: n3:8391918

Subject Item: _:vb8183743
rdf:type: n2:Context
rdf:value: EGFRvIII has not been observed in normal tissue, but it has been detected in carcinomas of the brain, breast, ovary (Moscatello et al., 1995), lung (Garcia de Palazzo et al., 1993), prostate (Olapade-Olaopa et al., >>2000<<) and head and neck (Sok et al., 2006).
n2:mentions: n3:10638988

Subject Item: _:vb8183744
rdf:type: n2:Context
rdf:value: been observed in normal tissue, but it has been detected in carcinomas of the brain, breast, ovary (Moscatello et al., 1995), lung (Garcia de Palazzo et al., 1993), prostate (Olapade-Olaopa et al., 2000) and head and neck (Sok et al., >>2006<<). Expression of EGFRvIII has been correlated with poor prognosis in brain tumors (Diedrich et al., 1995).
n2:mentions: n3:16951222

Subject Item: _:vb8183745
rdf:type: n2:Context
rdf:value: Expression of EGFRvIII has been correlated with poor prognosis in brain tumors (Diedrich et al., >>1995<<). Further, EGFRvIII can to transform fibroblasts in vitro (Pedersen et al., 2004) and enhance the tumorigenicity of cancer cells in vivo, supporting its oncogenic function (Tang et al., 2000).
n2:mentions: n3:8568531

Subject Item: _:vb8183746
rdf:type: n2:Context
rdf:value: Further, EGFRvIII can to transform fibroblasts in vitro (Pedersen et al., >>2004<<) and enhance the tumorigenicity of cancer cells in vivo, supporting its oncogenic function (Tang et al., 2000).
n2:mentions: n3:14696090

Subject Item: _:vb8183747
rdf:type: n2:Context
rdf:value: Further, EGFRvIII can to transform fibroblasts in vitro (Pedersen et al., 2004) and enhance the tumorigenicity of cancer cells in vivo, supporting its oncogenic function (Tang et al., >>2000<<).
n2:mentions: n3:10773015

Subject Item: _:vb8183748
rdf:type: n2:Context
rdf:value: Nagane et al. reported that EGFRvIII-expressing cells demonstrated less apoptosis in response to cisplatin treatment (Nagane et al., >>1998<<). Others have reported that EGFRvIII induced glioma cell migration and invasion via induction of metalloproteases and extracellular matrix components (Lal et al., 2002); (Cai et al., 2005). The precise signaling events that mediate
n2:mentions: n3:9576951

Subject Item: _:vb8183749
rdf:type: n2:Context
rdf:value: Others have reported that EGFRvIII induced glioma cell migration and invasion via induction of metalloproteases and extracellular matrix components (Lal et al., >>2002<<); (Cai et al., 2005).
n2:mentions: n3:12067969

Subject Item: _:vb8183750
rdf:type: n2:Context
rdf:value: Others have reported that EGFRvIII induced glioma cell migration and invasion via induction of metalloproteases and extracellular matrix components (Lal et al., 2002); (Cai et al., >>2005<<). The precise signaling events that mediate EGFRvIII-induced migration and invasion need further investigation. Moscatello et al. reported that EGFRvIII activates PI3-K pathway instead of the Ras-Raf-MEK pathway, which is preferentially
n2:mentions: n3:15986432

Subject Item: _:vb8183751
rdf:type: n2:Context
rdf:value: Moscatello et al. reported that EGFRvIII activates PI3-K pathway instead of the Ras-Raf-MEK pathway, which is preferentially activated by wild-type EGFR (Moscatello et al., >>1998<<). Further investigation suggested that constitutive PI3-K/AKT activation by EGFRvIII may contribute to chemoresistance and radioresistance in these cells (Li et al., 2004; Narita et al., 2002). Antonyak et al. showed that c-Jun N-terminal
n2:mentions: n3:9417065

Subject Item: _:vb8183752
rdf:type: n2:Context
rdf:value: Further investigation suggested that constitutive PI3-K/AKT activation by EGFRvIII may contribute to chemoresistance and radioresistance in these cells (Li et al., >>2004<<; Narita et al., 2002).
n2:mentions: n3:15077177

Subject Item: _:vb8183753
rdf:type: n2:Context
rdf:value: Further investigation suggested that constitutive PI3-K/AKT activation by EGFRvIII may contribute to chemoresistance and radioresistance in these cells (Li et al., 2004; Narita et al., >>2002<<). Antonyak et al. showed that c-Jun N-terminal Kinase (JNK) was constitutively activated by EGFRvIII and was down-regulated by PI3-K inhibition (Antonyak et al., 1998). To date, signaling through PI3-K/AKT has not been correlated with
n2:mentions: n3:12438278

Subject Item: _:vb8183754
rdf:type: n2:Context
rdf:value: Antonyak et al. showed that c-Jun N-terminal Kinase (JNK) was constitutively activated by EGFRvIII and was down-regulated by PI3-K inhibition (Antonyak et al., >>1998<<). To date, signaling through PI3-K/AKT has not been correlated with tumor cell migration or invasion mediated by EGFRvIII. We found that although EGFRvIII-expressing HNSCC cell expressed increased levels of phosphorylated AKT, abrogation
n2:mentions: n3:9446590

Subject Item: _:vb8183755
rdf:type: n2:Context
rdf:value: While Mizoguchi et al. reported a correlation of expression levels of EGFRvIII and phosphotyrosine STAT3 in glioblastoma (Mizoguchi et al., >>2006<<), Andersen et al. recently reported that glioma cells that express EGFRvIII fail to induce IRF-1 via STAT3 phosphorylation (Andersen et al., 2008).
n2:mentions: n3:17146292

Subject Item: _:vb8183756
rdf:type: n2:Context
rdf:value: levels of EGFRvIII and phosphotyrosine STAT3 in glioblastoma (Mizoguchi et al., 2006), Andersen et al. recently reported that glioma cells that express EGFRvIII fail to induce IRF-1 via STAT3 phosphorylation (Andersen et al., >>2008<<). Cumulative evidence has implicated STAT3 as an critical oncogene where elevated expression levels of tyrosine phosphorylated STAT3 are detected in numerous human cancers (Bowman et al., 2000).
n2:mentions: n3:17918184

Subject Item: _:vb8183757
rdf:type: n2:Context
rdf:value: Cumulative evidence has implicated STAT3 as an critical oncogene where elevated expression levels of tyrosine phosphorylated STAT3 are detected in numerous human cancers (Bowman et al., >>2000<<). Studies in HNSCC demonstrate that STAT3 is activated downstream of receptor and non-receptor tyrosine kinases including EGFR and Src family kinases as well as IL-6/gp130 (Kijima et al., 2002), (Xi et al., 2003), (Sriuranpong et al.,
n2:mentions: n3:10851046

Subject Item: _:vb8183758
rdf:type: n2:Context
rdf:value: Studies in HNSCC demonstrate that STAT3 is activated downstream of receptor and non-receptor tyrosine kinases including EGFR and Src family kinases as well as IL-6/gp130 (Kijima et al., >>2002<<), (Xi et al., 2003), (Sriuranpong et al., 2003).
n2:mentions: n3:12193474

Subject Item: _:vb8183759
rdf:type: n2:Context
rdf:value: Studies in HNSCC demonstrate that STAT3 is activated downstream of receptor and non-receptor tyrosine kinases including EGFR and Src family kinases as well as IL-6/gp130 (Kijima et al., 2002), (Xi et al., >>2003<<), (Sriuranpong et al., 2003).
n2:mentions: n3:12771142

Subject Item: _:vb8183760
rdf:type: n2:Context
rdf:value: Studies in HNSCC demonstrate that STAT3 is activated downstream of receptor and non-receptor tyrosine kinases including EGFR and Src family kinases as well as IL-6/gp130 (Kijima et al., 2002), (Xi et al., 2003), (Sriuranpong et al., >>2003<<). Targeting STAT3 in HNSCC preclinical HNSCC models inhibited tumor growth but not the growth of normal epithelial cells (Leong et al., 2003).
n2:mentions: n3:12782602

Subject Item: _:vb8183761
rdf:type: n2:Context
rdf:value: Targeting STAT3 in HNSCC preclinical HNSCC models inhibited tumor growth but not the growth of normal epithelial cells (Leong et al., >>2003<<). Expression of tyrosine phosphorylated STAT3 in the primary HNSCC tumor has been correlated with nodal metastasis, advanced tumor stage and decreased survival (Masuda et al., 2002). The results of the present study suggest that
n2:mentions: n3:12640143

Subject Item: _:vb8183762
rdf:type: n2:Context
rdf:value: Expression of tyrosine phosphorylated STAT3 in the primary HNSCC tumor has been correlated with nodal metastasis, advanced tumor stage and decreased survival (Masuda et al., >>2002<<). The results of the present study suggest that activation of STAT3 downstream of EGFRvIII in HNSCC contributes to the increased migration and invasion.
n2:mentions: n3:12067972

Subject Item: _:vb8183763
rdf:type: n2:Context
rdf:value: STAT3 target genes include cell cycle regulators (Sinibaldi et al., >>2000<<), anti-apoptotic genes (Oritani et al., 1999) and pro-angiogenic factors (Huang et al., 2002), each of which has been implicated in tumorigenic processes including invasion and metastasis.
n2:mentions: n3:11114718

Subject Item: _:vb8183764
rdf:type: n2:Context
rdf:value: STAT3 target genes include cell cycle regulators (Sinibaldi et al., 2000), anti-apoptotic genes (Oritani et al., >>1999<<) and pro-angiogenic factors (Huang et al., 2002), each of which has been implicated in tumorigenic processes including invasion and metastasis.
n2:mentions: n3:9949178

Subject Item: _:vb8183765
rdf:type: n2:Context
rdf:value: STAT3 target genes include cell cycle regulators (Sinibaldi et al., 2000), anti-apoptotic genes (Oritani et al., 1999) and pro-angiogenic factors (Huang et al., >>2002<<), each of which has been implicated in tumorigenic processes including invasion and metastasis.
n2:mentions: n3:12483533

Subject Item: _:vb8183766
rdf:type: n2:Context
rdf:value: STAT3 has been shown to contribute to cancer migration and invasion thorough regulation of genes that stimulate these processes including matrix metalloproteinases (e.g. MMP-2 and MMP-9), VEGF and/or bFGF (Dechow et al., >>2004<<); (Qiu et al., 2007).
n2:mentions: n3:15249664

Subject Item: _:vb8183767
rdf:type: n2:Context
rdf:value: has been shown to contribute to cancer migration and invasion thorough regulation of genes that stimulate these processes including matrix metalloproteinases (e.g. MMP-2 and MMP-9), VEGF and/or bFGF (Dechow et al., 2004); (Qiu et al., >>2007<<). In addition to the transcriptionally mediated effects of STAT3 on cell migration and invasion, transcription-independent pathways have also been described for the effects of STAT3 on cell motility.
n2:mentions: n3:17459060

Subject Item: _:vb8183768
rdf:type: n2:Context
rdf:value: Specifically, STAT3 has been found to directly interact with cell motility components such as focal adhesion components, FAK, paxillin (Silver et al., >>2004<<), p130CAS (Kira et al., 2002), or cytoskeltal microtubles (Ng et al., 2006).
n2:mentions: n3:15150111

Subject Item: _:vb8183769
rdf:type: n2:Context
rdf:value: Specifically, STAT3 has been found to directly interact with cell motility components such as focal adhesion components, FAK, paxillin (Silver et al., 2004), p130CAS (Kira et al., >>2002<<), or cytoskeltal microtubles (Ng et al., 2006).
n2:mentions: n3:11812786

Subject Item: _:vb8183770
rdf:type: n2:Context
rdf:value: Specifically, STAT3 has been found to directly interact with cell motility components such as focal adhesion components, FAK, paxillin (Silver et al., 2004), p130CAS (Kira et al., 2002), or cytoskeltal microtubles (Ng et al., >>2006<<). We did not detect increased expression of MMP-2, MMP-9 or VEGF in association with the EGFRvIII-mediated migration and invasion observed in these cells (data not shown), suggesting that other STAT3 target genes or STAT3 interacting
n2:mentions: n3:16401721

Subject Item: _:vb8183771
rdf:type: n2:Context
rdf:value: We have developed a highly specific transcription factor decoy approach to block STAT3 signaling and demonstrated that it inhibits tumor growth in vitro and in vivo in HNSCC preclinical models (Leong et al., >>2003<<). Using the same STAT3 decoy, others have reported antitumor effects in a murine model of cutaneous squamous cell carcinoma (Sano et al., 2005). Toxicology studies in non-human primates were recently completed and demonstrated no evidence
n2:mentions: n3:12640143

Subject Item: _:vb8183772
rdf:type: n2:Context
rdf:value: Using the same STAT3 decoy, others have reported antitumor effects in a murine model of cutaneous squamous cell carcinoma (Sano et al., >>2005<<). Toxicology studies in non-human primates were recently completed and demonstrated no evidence of toxicity (Sen et al., 2008). In the present study, treatment of EGFRvIII-expressing HNSCC cells with the STAT3 decoy abrogated cell
n2:mentions: n3:15592573

Subject Item: _:vb8183773
rdf:type: n2:Context
rdf:value: In addition to the decoy, others have reported the use of siRNA, peptidomimetic strategies, and G-quartet oligonucleotides to inhibit STAT3 in cancer models (Leeman et al., >>2006<<).
n2:mentions: n3:16503733

Subject Item: _:vb8183774
rdf:type: n2:Context
rdf:value: These cumulative results suggest that STAT3 activation is critical for cancer progression mediated by both wild-type EGFR and EGFRvIII, which are often co-expressed in HNSCC tumors (Sok et al., >>2006<<). Knockdown or blockade of STAT3 preferentially abrogated the migration and invasion of HNSCC cells that expressed EGFRvIII implicating STAT3 as a critical pathway in mediating HNSCC invasion in tumors that express this altered receptor.
n2:mentions: n3:16951222

Subject Item: _:vb8183775
rdf:type: n2:Context
rdf:value: Therapeutic agents with selective activity against EGFRvIII are presently under clinical investigation including the immunotoxin MR1-1, the chimeric antibody 806 (Li et al., >>2007<<) and irreversible HER1/HER2 inhibitors (Ji et al., 2006) that appear to have selective activity against EGFRvIII.
n2:mentions: n3:17256054

Subject Item: _:vb8183776
rdf:type: n2:Context
rdf:value: Therapeutic agents with selective activity against EGFRvIII are presently under clinical investigation including the immunotoxin MR1-1, the chimeric antibody 806 (Li et al., 2007) and irreversible HER1/HER2 inhibitors (Ji et al., >>2006<<) that appear to have selective activity against EGFRvIII. The EGFR monoclonal antibody cetuximab is the only FDA-approved EGFR targeting strategy for HNSCC.
n2:mentions: n3:16672372

Subject Item: _:vb8183777
rdf:type: n2:Context
rdf:value: We previously reported that HNSCC xenografts expressing EGFRvIII were resistant to the growth inhibitory effects of cetuximab (Sok et al., >>2006<<). Here we demonstrate that EGFRvIII cells are resistant to anti-invasive effects of cetuximab in HNSCC. Further, EGFRvIII expression results in an increase in phosphorylation of STAT3 in HNSCC cells. These results suggest that HNSCC
n2:mentions: n3:16951222

Subject Item: _:vb8183778
rdf:type: n4:Section
dc:title: supplementary material
n4:contains: _:vb8183779

Subject Item: _:vb8183779
rdf:type: n2:Context
rdf:value: QFACS procedures and labeling of monoclonal antibodies have been previously described (Wikstrand et al., >>1997<<) using the Quantum Simply Cellular kit from Bangs Laboratories (Fishers, IN).
n2:mentions: n3:9307304

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n2:RelevantScore: 4
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n2:RelevantScore: 4
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n2:RelevantScore: 4
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n2:RelevantScore: 4
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 4
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 4
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
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n2:RelevantScore: 3
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n2:RelevantScore: 3
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
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Subject Item: _:vb437867214
rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
n2:hasRelevantPaperId: n3:21865152

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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
n2:hasRelevantPaperId: n3:18297114

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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
n2:hasRelevantPaperId: n3:15144956

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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
n2:hasRelevantPaperId: n3:18784101

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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
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n2:RelevantScore: 3
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n2:RelevantScore: 3
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 3
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 2
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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rdf:type: n2:RelevantBibliographicResource
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