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Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity Alice N

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Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity Alice N Published OnlineFirst June 27, 2016; DOI: 10.1158/1541-7786.MCR-16-0114 Signal Transduction Molecular Cancer Research Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity Alice N. Weaver1, M. Benjamin Burch2,Tiffiny S. Cooper1, Deborah L. Della Manna1, Shi Wei3, Akinyemi I. Ojesina4, Eben L. Rosenthal5, and Eddy S. Yang1 Abstract Oral squamous cell carcinoma (OSCC) is a cancer subtype Notch pathway upregulation was significantly correlated with that lacks validated prognostic and therapeutic biomarkers, and patient mortality status and with expression of the proinvasive human papillomavirus status has not proven beneficial in gene FGF1. In vitro Notch activation in HNSCC cells increased predicting patient outcomes. A gene expression pathway anal- transcription of FGF1 and induced a marked increase in cell ysis was conducted using OSCC patient specimens to identify migration and invasion, which was fully abrogated by FGF1 molecular targets that may improve management of this dis- knockdown. These results reveal that increased Notch pathway ease. RNA was isolated from 19 OSCCs treated surgically at the signaling plays a role in cancer progression and patient out- University of Alabama at Birmingham (UAB; Birmingham, AL) comes in OSCC. Accordingly, the Notch–FGF interaction and evaluated using the NanoString nCounter system. Results should be further studied as a prognostic biomarker and were confirmed using the oral cavity subdivision of the Head potential therapeutic target for OSCC. and Neck Squamous Cell Carcinoma Cancer (HNSCC) study generated by The Cancer Genome Atlas (TCGA) Research Implications: Patients with squamous cell carcinoma of the Network. Further characterization of the in vitro phenotype oral cavity who succumb to their disease are more likely to produced by Notch pathway activation in HNSCC cell lines have upregulated Notch signaling, which may mediate a more included gene expression, proliferation, cell cycle, migration, invasive phenotype through increased FGF1 transcription. Mol invasion, and radiosensitivity. In both UAB and TCGA samples, Cancer Res; 14(9); 883–91. Ó2016 AACR. Introduction decreased recurrence and improved overall survival in this sub- type. In contrast, relapse is still common in patients with OSCC Head and neck squamous cell carcinoma (HNSCC) is a mul- and survival remains below 70% (1, 2). One reason for this tifactorial and heterogeneous disease encompassing multiple limited progress may be the lack of reliable biomarkers for OSCCs. anatomic sites but most commonly arising from the oral cavity HPV is not associated with therapeutic sensitivity or outcomes in [oral squamous cell carcinoma (OSCC)] or oropharynx tumors from the oral cavity, and therapies targeting EGFR, which [oropharyngeal squamous cell carcinoma (OPSCC)]. The major- is commonly activated in this disease, produce only a modest ity of HNSCC patients present with locally advanced disease, response (3, 4). In the absence of effective treatments, there is a requiring intense multimodality therapy associated with signifi- strong need to identify molecular targets and predictive markers to cant acute and long-term toxicities. Increasing incidence of improve the management of OSCC. human papillomavirus (HPV) in OPSCCs has corresponded with Recently, the Notch signaling pathway has emerged as a can- didate to fill this void. Notch signaling plays an important role in 1Department of Radiation Oncology, University of Alabama at Bir- cell proliferation, differentiation, and apoptosis during embryo- mingham, Birmingham, Alabama. 2Department of Otolaryngology- genesis (5, 6). The canonical pathway is activated by the binding Head and Neck Surgery, University of Alabama at Birmingham, Bir- 3 of Delta or Jag ligands expressed on the cell surface to Notch mingham, Alabama. Department of Pathology, University of Alabama trans at Birmingham, Birmingham, Alabama. 4Department of Epidemiology, receptors located on the surface of a neighboring cell. This University of Alabama at Birmingham, Birmingham, Alabama. interaction induces g-secretase–mediated cleavage of the Notch 5Department of Otolaryngology-Head and Neck Surgery, Stanford intracellular domain (NICD), which translocates into the nucleus University, Palo Alto, California. (7). NICD complexes with and activates CBF1-SU(H)-LAG1 Note: Supplementary data for this article are available at Molecular Cancer (CSL) and recruits other coactivators such as Mastermind-like Research Online (http://mcr.aacrjournals.org/). (MAML) proteins (8). The resulting complex activates transcrip- Corresponding Author: Eddy S. Yang, University of Alabama at Birmingham, 619 tion of Notch target genes, including HEY1/2, HES1/5, NFkB, 19th Street South, Birmingham, AL 35249. Phone: 205-934-2762; Fax: 205-975- MYC, CCND1, BCL2, and CCR7, in a cell type-specific manner. 0784; E-mail: [email protected] Aberrant Notch signaling has been found in a number of solid doi: 10.1158/1541-7786.MCR-16-0114 and hematologic malignancies and can function in either an Ó2016 American Association for Cancer Research. oncogenic or tumor-suppressive capacity depending on cell type www.aacrjournals.org 883 Downloaded from mcr.aacrjournals.org on September 26, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst June 27, 2016; DOI: 10.1158/1541-7786.MCR-16-0114 Weaver et al. and context (9). For example, Notch signaling activates transcrip- Table 1. Patient demographics Cip1 Kip1 tion of cell-cycle regulators p21 and p27 in epithelial cells OSCC OSCC but not in other tissue types, suggesting the Notch pathway may patients patients w/o CSM w/ CSM function as a tumor suppressor in squamous cell carcinomas Characteristics N ¼ 14 % N ¼ 5% P (10, 11). In support of this theory, two separate exome sequencing Gender studies of HNSCC revealed 10% to 15% of tumors had inactivat- M 11 79 4 80 1.00 ing mutations in NOTCH1 (12, 13). However, this model has F321120 been challenged by evidence that HNSCCs display a bimodal Average age, y 60.57 64.80 0.61 pattern of Notch alterations, including a subset of tumors with Site of origin Mandibular alveolar ridge 2 14 0 0 0.90 increased expression of ligands JAG1 and JAG2, as well as the NOTCH1 NOTCH3 – in vitro Gingivobuccal sulcus 1 7 0 0 and receptors (14 18). In addition, Floor of mouth 5 36 2 40 work has shown a relationship between Notch1 activity and Buccal mucosa 1 7 0 0 clinically relevant characteristics, such as cancer stem cell–like Mandible 2 14 1 20 properties and TNFa-mediated inflammation (15, 16, 18). Floor of mouth þ Mandible 2 14 1 20 HNSCC candidate biomarker studies typically focus on iden- Unknown 1 7 1 20 Nodal disease tifying individual genes or proteins that correlated with patient Yes 13 93 4 80 1.00 outcomes and tumor biology. We hypothesized that dysregula- No 1 7 1 20 tion at the pathway level may significantly alter signaling activity, Average size, cm 3.67 3.60 0.92 tumor behavior, and patient outcomes, which may not be detect- T stage (AJCC) able in individual biomarker studies. Thus, we conducted a gene T2 8 57 0 0 0.04 expression pathway analysis to identify cell signaling abnormal- T4 6 43 5 100 Bone invasion ities associated with cancer-specific mortality in OSCC. We report fi Yes 6 43 4 80 0.30 asigni cant association between Notch pathway upregulation No 8 57 1 20 and mortality in two independent OSCC datasets. A positive Perineural invasion association between Notch activation and upregulation of the Yes 1 7 2 40 0.15 proinvasive gene FGF1 wasalsoobservedinOSCCsamples No 13 93 3 60 from the University of Alabama at Birmingham (UAB; Birming- Margins positive Yes 5 36 1 20 0.61 ham, AL) and validated using The Cancer Genome Atlas In vitro No 9 64 5 80 (TCGA) dataset. , activation of Notch signaling in Adjuvant XRT human head and neck cancer cells altered the expression of Yes 7 50 4 80 0.34 Notch pathway genes in a pattern comparable with that No 7 50 1 20 observed in patients with a high Notch pathway score and Average follow-up (mo) 27.09 28.44 0.92 produced a similar increase in transcription of FGF1.These Average PFS (mo) 26.44 25.44 0.94 Average OS (mo) 60.92 37.98 0.11 in vitro gene expression changes were accompanied by signif- icantly increased cell migration and invasion in Notch-activat- Abbreviations: AJCC, American Joint Committee on Cancer; F, female; M, male; FGF1 OS, overall survival; PFS, progression free survival; w/, with; w/o, without; XRT, ed cells, which was reversed upon knockdown. Our radiotherapy. results suggest that upregulation of the Notch pathway may be a marker of invasive phenotype in OSCC. Materials and Methods for 18 hours at 4 C prior to plating. FGF1 expression was inhibited by transfection with FGF1 siRNA (Santa Cruz Biotechnology, sc- Human tissue samples 39444) using Lipofectamine RNAiMAX (Invitrogen, REF 13778- Tissue samples were obtained from the UAB surgical pathology 150) as per manufacturer's instructions. Control siRNA-A (Santa archives (2000–2009) with Institutional Review Board approval Cruz Biotechnology, sc-37007) was used for comparison. Cells and represent histologically confirmed OSCC. All patients were were transfected for 48 hours, then trypsinized, centrifuged, and treated surgically in the Department of Otolaryngology-Head and replated for use in experiments. Where indicated, FGF1 knock- Neck Surgery at the UAB Hospital. Selected patients had previ- down was complemented by recombinant FGF1 (R&D Systems, ously untreated primary disease. Formalin-fixed paraffin-embed- 232-FA-025), which was added to growth media at 100 ng/mL. ded tissue samples from a cohort of 19 primary OSCC tumors were used (Table 1). RNA isolation and NanoString PanCancer Pathways analysis For patient samples, RNA was harvested from areas of >70% Cell culture and reagents tumor, as identified by a pathologist, using the High Pure FFPET HNSCC cell lines UM-SCC1 and UM-SCC6 were obtained RNA Isolation Kit (Roche, REF 06 650 775 001) as per the courtesy of Thomas E.
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