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• W2046020700 abstract "Annexin A1 (ANXA1) protein expression was evaluated by Western blot in a series of 32 head and neck squamous cell carcinomas (HNSCCs) in a search for molecular alterations that could serve as useful diagnostic/prognostic markers. ANXA1 down-regulation was observed in 24 cases (75%) compared with patient-matched normal epithelium. In relation to clinicopathological variables, ANXA1 down-regulation was significantly associated with advanced T stages (P = 0.029), locoregional lymph node metastases (P = 0.038), advanced disease stage (P = 0.006), hypopharyngeal localization (P = 0.038), and poor histological differentiation (P = 0.005). ANXA1 expression was also analyzed by immunohistochemistry in paraffin-embedded sections from 22 of 32 HNSCCs and 8 premalignant lesions. All dysplastic tissues showed significantly reduced ANXA1 expression compared to a strong positive signal observed in adjacent normal epithelia (except basal and suprabasal cells). A close association was observed between ANXA1 expression and the histological grade in HNSCC. Well-differentiated tumors presented a positive ANXA1 signal in highly keratinized areas whereas moderately and poorly differentiated tumors exhibited very weak or negative staining. Our findings clearly identify ANXA1 as an effective differentiation marker for the histopathological grading of HNSCCs and for the detection of epithelial dysplasia. Annexin A1 (ANXA1) protein expression was evaluated by Western blot in a series of 32 head and neck squamous cell carcinomas (HNSCCs) in a search for molecular alterations that could serve as useful diagnostic/prognostic markers. ANXA1 down-regulation was observed in 24 cases (75%) compared with patient-matched normal epithelium. In relation to clinicopathological variables, ANXA1 down-regulation was significantly associated with advanced T stages (P = 0.029), locoregional lymph node metastases (P = 0.038), advanced disease stage (P = 0.006), hypopharyngeal localization (P = 0.038), and poor histological differentiation (P = 0.005). ANXA1 expression was also analyzed by immunohistochemistry in paraffin-embedded sections from 22 of 32 HNSCCs and 8 premalignant lesions. All dysplastic tissues showed significantly reduced ANXA1 expression compared to a strong positive signal observed in adjacent normal epithelia (except basal and suprabasal cells). A close association was observed between ANXA1 expression and the histological grade in HNSCC. Well-differentiated tumors presented a positive ANXA1 signal in highly keratinized areas whereas moderately and poorly differentiated tumors exhibited very weak or negative staining. Our findings clearly identify ANXA1 as an effective differentiation marker for the histopathological grading of HNSCCs and for the detection of epithelial dysplasia. Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of tumors, afflicting 500,000 patients worldwide each year.1Sankaranarayanan R Masuyer E Swaminathan R Ferlay J Whelan S Head and neck cancer: a global perspective on epidemiology and prognosis.Anticancer Res. 1998; 18: 4779-4786PubMed Google Scholar The survival rate for patients with HNSCC has remained unchanged in recent years despite advances in diagnosis and treatment. Our ability to prognosticate advanced cases of HNSCC is especially poor owing to variations in the biological behavior of the tumors and inadequacies of the present staging system. Novel markers that can distinguish differences in tumor condition and behavior are needed for the diagnosis and treatment of such cancers. The development of molecular profiling techniques for genomic and proteomic analysis has introduced a new approach to cancer research aimed at discovering differential gene and protein expression associated with cancer development and progression.Annexins are a structurally related family of calcium- and phospholipid-binding proteins that have been implicated in a broad range of molecular and cellular processes,2Gerke V Moss SE Annexins: from structure to function.Physiol Rev. 2002; 82: 331-371Crossref PubMed Scopus (1610) Google Scholar including the modulation of phospholipase A2 and kinase activities in signal transduction, the maintenance of cytoskeleton and extracellular matrix integrity, tissue growth and differentiation, inflammation, and blood coagulation. Human annexins and their cognate orthologues comprise the A subfamily of vertebrate annexins represented by 12 members, designated by the ANX symbol stem-suffixed with a subfamily classification A1 through A11 or A13.3Morgan RO Jenkins NA Gilbert DJ Copeland NG Balsara BR Testa JR Fernandez MP Novel human and mouse ANXA10 are linked to the genome duplications during early chordate evolution.Genomics. 1999; 60: 40-49Crossref PubMed Scopus (56) Google Scholar Annexin A1 (ANXA1) has long been considered a putative mediator of glucocorticoid immunosuppressive activity and a mouse gene knockout model appears to support this interpretation.4Hannon R Croxtall JD Getting SJ Roviezzo F Yona S Paul-Clark MJ Gavins FN Perretti M Morris JF Buckingham JC Flower RJ Aberrant inflammation and resistance to glucocorticoids in annexin 1−/− mouse.EMBO J. 2003; 17: 253-255Google ScholarThe term annexinopathies has been used to define those human diseases in which abnormal levels and pleiotropic effects of annexins contribute to the pathogenesis,5Rand JH The annexinopathies: a new category of diseases.Biochim Biophys Acta. 2000; 1498: 169-173Crossref PubMed Scopus (69) Google Scholar although annexins have yet to be directly implicated in the etiology of any genetic disease. Thus, overexpression of ANXA2 may contribute to the phenotype in a hemorrhagic form of acute promyelocytic leukemia, whereas underexpression of ANXA5 accompanies the anti-phospholipid syndrome and preeclampsia. The altered expression of annexins has also been associated with cell line transformation (http://genome-www.stanford.edu/nci60/),6Ross DT Scherf U Eisen MB Perou CM Rees C Spellman P Iyer V Jeffrey SS Van de Rijn M Waltham M Pergamenschikov A Lee JC Lashkari D Shalon D Myers TG Weinstein JN Botstein D Brown PO Systematic variation in gene expression patterns in human cancer cell lines.Nat Genet. 2000; 24: 227-235Crossref PubMed Scopus (1812) Google Scholar tumor progression,7Xin W Rhodes DR Ingold C Chinnaiyan AM Rubin MA Dysregulation of the annexin family protein family is associated with prostate cancer progression.Am J Pathol. 2003; 162: 255-261Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar and metastasis,8Hippo Y Yashiro M Ishii M Taniguchi H Tsutsumi S Hirakawa K Kodama T Aburatani H Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes.Cancer Res. 2001; 61: 889-895PubMed Google Scholar, 9Wu W Tang X Hu W Lotan R Hong WK Mao L Identification and validation of metastasis-associated proteins in head and neck cancer cell lines by two-dimensional electrophoresis and mass spectrometry.Clin Exp Metastasis. 2002; 19: 319-326Crossref PubMed Scopus (175) Google Scholar and interpreted to suggest either a homeostatic or possible tumor suppressive role for annexins. ANXA1 is overexpressed in breast cancer10Ahn SH Sawada H Ro JY Nicolson GL Differential expression of annexin I in human mammary ductal epithelial cells in normal and benign and malignant breast tissues.Clin Exp Metastasis. 1997; 15: 151-156Crossref PubMed Scopus (109) Google Scholar and hepatocellular carcinoma11Masaki T Tokuda M Ohnishi M Watanabe S Fujimura T Miyamoto K Itano T Matsui H Arima K Shirai M Maeba T Sogawa K Konishi R Taniguchi K Hatanaka Y Hatase O Nishioka M Enhanced expression of the protein kinase substrate annexin in human hepatocellular carcinoma.Hepatology. 1996; 24: 72-81PubMed Google Scholar but markedly down-regulated in esophageal, prostate, and gastric carcinomas.6Ross DT Scherf U Eisen MB Perou CM Rees C Spellman P Iyer V Jeffrey SS Van de Rijn M Waltham M Pergamenschikov A Lee JC Lashkari D Shalon D Myers TG Weinstein JN Botstein D Brown PO Systematic variation in gene expression patterns in human cancer cell lines.Nat Genet. 2000; 24: 227-235Crossref PubMed Scopus (1812) Google Scholar, 8Hippo Y Yashiro M Ishii M Taniguchi H Tsutsumi S Hirakawa K Kodama T Aburatani H Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes.Cancer Res. 2001; 61: 889-895PubMed Google Scholar, 12Paweletz CP Ornstein DK Roth MJ Bichsel VE Gillespie JW Calvert VS Vocke CD Hewitt SM Duray PH Herring J Wang QH Hu N Linehan WM Taylor PR Liotta LA Emmert-Buck MR Petricoin III, EF Loss of annexin 1 correlates with early onset of tumorigenesis in esophageal and prostate carcinoma.Cancer Res. 2000; 60: 6293-6297PubMed Google Scholar, 13Kang JS Calvo BF Maygarden SJ Caskey LS Mohler JL Ornstein DK Dysregulation of annexin I protein expression in high-grade prostatic intraepithelial neoplasia and prostate cancer.Clin Cancer Res. 2002; 8: 117-123PubMed Google Scholar, 14Xia SH Hu LP Hu H Ying WT Xu X Cai Y Han YL Chen BS Wei F Qian XH Cai YY Shen Y Wu M Wang MR Three isoforms of annexin I are preferentially expressed in normal esophageal epithelia but down-regulated in esophageal squamous cell carcinomas.Oncogene. 2002; 21: 6641-6648Crossref PubMed Scopus (88) Google Scholar, 15Zhou G Li H DeCamp D Chen S Shu H Gong Y Flaig M Gillespie JW Hu N Taylor PR Emmert-Buck MR Liotta LA Petricoin III, EF Zhao Y 2D differential in-gel electrophoresis for the identification of esophageal scans cell cancer-specific protein markers.Mol Cell Proteomics. 2002; 1: 117-124Crossref PubMed Google Scholar ANXA2 is overexpressed in brain glial tumors16Roseman BJ Bollen A Hsu J Lamborn K Israel MA Annexin II marks astrocytic brain tumors of high histologic grade.Oncol Res. 1994; 6: 561-567PubMed Google Scholar and pancreatic carcinoma17Vishwanatha JK Chiang Y Kumble KD Hollingsworth MA Pour PM Enhanced expression of annexin II in human pancreatic carcinoma cells and primary pancreatic cancers.Carcinogenesis. 1993; 14: 2575-2579Crossref PubMed Scopus (124) Google Scholar and down-regulated in prostate cancer.18Chetcuti A Margan SH Russell P Mann S Millar DS Clark SJ Rogers J Handelsman DJ Dong Q Loss of annexin II heavy and light chains in prostate cancer and its precursors.Cancer Res. 2001; 61: 6331-6334PubMed Google Scholar Possible tumor suppressor roles have been proposed for ANXA6 in melanoma19Francia G Mitchell SD Moss SE Hanby AM Marshall JF Hart IR Identification by differential display of annexin-VI, a gene differentially expressed during melanoma progression.Cancer Res. 1996; 56: 3855-3858PubMed Google Scholar and squamous cell carcinoma,20Theobald J Hanby A Patel K Moss SE Annexin VI has tumour-suppressor activity in human A431 squamous epithelial carcinoma cells.Br J Cancer. 1995; 71: 786-788Crossref PubMed Scopus (56) Google Scholar for ANXA7 in melanoma,21Kataoka TR Ito A Asada H Watabe K Nishiyama K Nakamoto K Itami S Yoshikawa K Ito M Nojima H Kitamura Y Annexin VII as a novel marker for invasive phenotype of malignant melanoma.Jpn J Cancer Res. 2000; 91: 75-83Crossref PubMed Scopus (34) Google Scholar and for ANXA10 in hepatocellular carcinoma.22Liu SH Lin CY Peng SY Jeng YM Pan HW Lai PL Liu CL Hsu HC Down-regulation of annexin A10 in hepatocellular carcinoma is associated with vascular invasion, early recurrence, and poor prognosis in synergy with p53 mutation.Am J Pathol. 2002; 160: 1831-1837Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar ANXA4 has been associated with chemoresistance.23Han EK Tahir SK Cherian SP Collins N Ng SC Modulation of paclitaxel resistance by annexin IV in human cancer cell lines.Br J Cancer. 2000; 83: 83-88Crossref PubMed Scopus (97) Google ScholarThe magnitude and specificity of annexin changes in various cancers underscores their potential value as molecular markers and their possible role in carcinogenesis itself. The above-cited studies identify ANXA1 as a promising candidate, but some contradictory findings in metastatic conditions and cultured cell lines require more direct analysis of primary tumor tissue to resolve the cellular conditions originating these changes. We therefore evaluated ANXA1 protein expression in a study set of invasive HNSCC tumors together with patient-matched normal epithelium and premalignant lesions from head and neck squamous epithelia using both Western blot and immunohistochemistry (IHC) analysis.Materials and MethodsTissue SpecimensSurgical tissue specimens from 32 patients with HNSCC who consecutively underwent resection of their tumors at the Hospital Central de Asturias were obtained for this prospective study, following institutional review board guidelines. Informed consent was obtained from each patient. None of them had received radio/chemotherapy before intervention. Biopsies were sharply excised, placed in sterile tubes, and frozen immediately in liquid nitrogen. Clinically normal adjacent mucosa was also collected. All tissue samples were stored at −80°C until analysis. A portion of the surgical tissue specimen was fixed in buffered formaldehyde, dehydrated in graded alcohol solutions, and embedded in paraffin for use in histological analysis and IHC studies.The characteristics of the patients studied and the clinicopathological features of their tumors (site, pT stage, pN stage, disease stage, and histopathological grade) are shown in Table 1. The stage of disease was determined after the surgical resection of the tumor according to the current tumor-node-metastasis staging (TNM) system of the International Union Against Cancer. The histological grade was determined according to the degree of differentiation of the tumor (Broders' classification). All patients were habitual tobacco and alcohol consumers.Table 1Summary of Clinicopathological Parameters of HNSCC Patients and Their Tumors, with Corresponding ANXA1 Protein Expression Results as Number and Percentage of the Patient Population, with Statistical AssessmentFeatureNo. of patientsANXA1 down-regulated (%)P value*Chi-square test.Mean age at resection (median):59 (61)Sex Male31 (97%) Female1 (3%)Site Oropharynx9 (28%)6 (67)0.038 Supraglottic larynx12 (38%)10 (83) Glottic larynx4 (12%)1 (25) Hypopharynx7 (22%)7 (100)pT stage T1–T26 (19%)2 (33)0.029 T316 (50%)13 (81) T410 (31%)9 (90)pN stage N013 (41%)7 (54)0.038†Fisher's test. N1–319 (59%)17 (89)Disease stage I–II5 (16%)1 (20)0.006 III8 (25%)6 (75) IV19 (59%)17 (89)Histopathologic grade Well-differentiated16 (50%)8 (50)0.005 Moderately-differentiated9 (28%)9 (100) Poorly-differentiated7 (22%)7 (100)Total3224 (75)* Chi-square test.† Fisher's test. Open table in a new tab Premalignant LesionsTissue was obtained from archival, paraffin-embedded blocks from the Hospital Central de Asturias. Representative sections from tissue were used for IHC study and the diagnosis was confirmed for each lesion by a pathologist (AHZ). The distribution of patients according to the histological nature of their lesions was: hyperplasia/hyperkeratosis (three cases), mild dysplasia (one case), moderate dysplasia (two cases) and severe dysplasia/carcinoma in situ (two cases).Protein Extraction and Western BlottingFor protein extraction, freshly frozen tissue from each sample was microdissected by cryostat sectioning to ensure that it contained at least 75% epithelial tumor cells. Each sample was frozen and thawed three times and mechanically lysed in ice-cold lysis buffer containing 50 mmol/L HEPES pH 7.9, 250 mmol/L NaCl, 5 mmol/L ethylenediaminetetraacetic acid, 0.2% (v/v) Nonidet P-40, 10% glycerol plus a phosphatase- and protease-inhibitor mixture (25 mmol/L β-glycerophosphate, 1 mmol/L Na3VO4, 1 mmol/L phenylmethyl sulfonyl fluoride, 10 μg/ml leupeptin, 10 μg/ml aprotinin).Whole protein extract concentration of the supernatant was estimated by Bradford's method using a protein assay kit (Bio-Rad, Hercules, CA). Equal amounts of protein extract (100 μg per lane) were boiled in Laemmli sample buffer, separated on sodium dodecyl sulfate polyacrylamide gel (10%), and transferred to polyvinylidene difluoride membranes using a Semidry Trans Blot (Bio-Rad). Membranes were immunoblotted with mouse IgG anti-ANXA1 monoclonal antibody (1:4000 dilution) (Zymed Laboratories, San Francisco, CA). Anti-mouse IgG secondary antibodies were used at 1:5000 dilution. For protein load control, anti-β-actin mouse monoclonal antibody (Sigma-Aldrich, St. Louis, MO) was used. Anti-mouse IgG secondary antibody was used at 1:25,000 dilution. Both immunoreactive bands were visualized in one reaction by the enhanced chemiluminescence Western blotting analysis system (Amersham-Pharmacia-Biotech, Piscataway, NJ).Immunohistochemical StudyThe formalin-fixed, paraffin-embedded tissues were cut into 4-μm sections and dried on capillary-gap glass slides (ChemMate; BioTEK Solutions, Santa Barbara, CA). The sections were deparaffinized with standard xylene and hydrated through graded alcohols into water. Antigen retrieval was performed using proteinase K. Staining was done at room temperature on an automatic staining workstation (TechMate 1000, BioTEK Solutions) by using the Envision peroxidase mouse system (Envision Plus; DAKO, Carpinteria, CA). Slides were placed for 20 minutes in a 3% hydrogen peroxide blocking medium and then allowed to react with mouse IgG anti-annexin I monoclonal antibody (Transduction Laboratories, Lexington, KY) at 1:200 dilution for 30 minutes. Immunodetection was performed with the Envision system and diaminobenzidine chromogen as substrate (DAKO). Counterstaining with hematoxylin for 1 minute was the final step. After staining, the slides were dehydrated through graded alcohols and mounted with a coverslip using a standard medium. Appropriate positive controls were used (normal laryngeal epithelium). Negative controls with an omission of the antiserum from the primary incubation were also included. The slides were viewed randomly, without clinical data, by two of the authors.Statistical AnalysisThe molecular results data distributed among different clinical groups of tumors were tested for significance by the chi-square and Fisher's exact tests with the help of the statistical software package SPSS (SPSS Inc., Chicago, IL). P < 0.05 values were considered statistically significant.ResultsLoss of ANXA1 Protein in HNSCC TumorsImmunoblot analysis of ANXA1 protein expression in patient-matched normal and tumor epithelium from 32 different patients with primary HNSCC was performed using a commercially available mouse monoclonal antibody against ANXA1. Complete or substantial loss of this 39-kd protein was observed in 24 cases (75%) of tumors examined, whereas strong expression of ANXA1 was detected in adjacent normal epithelium (Figure 1). Normalization for protein loading was achieved using anti-β-actin antibodies (Figure 1).Table 1 presents the association of ANXA1 down-regulation with clinicopathological parameters. Loss of ANXA1 was found at each primary head and neck anatomical site with statistically significant differences (P = 0.038). We found an association of normal ANXA1 expression with glottic laryngeal localization (three of four) whereas all hypopharynx tumors (seven of seven) showed a marked reduction of ANXA1 protein levels. Loss of ANXA1 correlated with advanced T and N stages, being more frequent in large tumors (90%) than in small HNSCCs (33%) (P = 0.029) and also in HNSCCs with locoregional lymph node metastasis (89%) above N0-stage tumors (54%), with differences attaining statistical significance (P = 0.038). Down-regulation of ANXA1 was significantly associated with patients in advanced disease stage, 89% in stage IV versus 20% in stage I and II (P = 0.006). With regard to histopathological grade, a relationship was observed between ANXA1 protein levels and histological differentiation. Normal ANXA1 expression was observed in well-differentiated tumors whereas ANXA1 expression was down-regulated in all moderate and poorly differentiated tumors (P = 0.005).ANXA1 Expression Correlates with Histological Differentiation Grade in HNSCCWe next performed IHC analysis in 22 of the HNSCC specimens to confirm the observations from Western blot analysis and to localize the sites of ANXA1 expression. All sections selected for study contained both normal and malignant epithelia. ANXA1 expression was detected in all cell layers of normal epithelium, except basal and suprabasal cells, with strong positive signal toward the most external layers of epithelia (Figure 2A). ANXA1 staining was preferentially membrane-localized, although both nuclear and cytoplasmic staining were noted in the superficial layers. We also observed positive staining in both endothelial and infiltrated neutrophils, whereas stroma cells showed negligible ANXA1 expression. In contrast, cancer tissue specimens showed a markedly reduced ANXA1 expression, as compared with the corresponding normal epithelia (Figure 2, C and D). We detected an abnormal distribution of ANXA1 that correlated significantly with histopathological grade in HNSCC. We observed ANXA1 staining only in cancerous cells surrounding the horn pearl in the highly keratinized areas of well-differentiated HNSCC (Figure 2E), whereas tumor cells with poor differentiation exhibited negative staining (Figure 2F).Figure 2Immunohistochemical analysis of ANXA1. A: All cell layers (except basal and suprabasal layers) were positively stained in normal epithelium. B: ANXA1 immunostain distinguished between normal and dysplastic epithelia. The left side shows markedly reduced ANXA1 expression in dysplastic compared to normal epithelium (top right). C and D: ANXA1 staining distinguished between normal epithelium and invasive HNSCC tumors. The left side shows absence of immunoreactivity in infiltrated tumor cells whereas normal epithelium exhibited strong ANXA1 signal (top and right sides). E: ANXA1 staining strongly correlated with histological differentiation grade in HNSCC. ANXA1 was irregularly expressed (as patches) in well-differentiated HNSCC. F: Poorly differentiated tumors were consistently negative for ANXA1 immunostaining. Original magnifications: ×200 (A–C); × 100 (D); ×50 (E); ×400 (F).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Loss of ANXA1 Expression in Early Stages of TumorigenesisIHC analysis was performed on a study set of eight premalignant lesions (distributed as described in Materials and Methods) to determine whether the loss of ANXA1 expression occurred early in the development of tumorigenesis in HNSCC. All selected sections included normal epithelia as internal control. A marked reduction of ANXA1 expression was detected as weak staining on the most superficial layers of dysplastic tissue, in marked contrast to the strong ANXA1 signal detected in corresponding normal epithelium (Figure 2B). ANXA1 staining was also negative in hyperplasia with hyperkeratosis of squamous epithelia.DiscussionMuch of the complex fundamental biology of HNSCC remains poorly understood, despite intensive study. Like other epithelial neoplasms, head and neck carcinogenesis appears to evolve through a multistep process involving biomolecular changes, ensuing premalignant lesions, and consequent invasive cancer.24Califano J van der Riet P Westra W Nawroz H Clayman G Piantadosi S Corio R Lee D Greenberg B Koch W Sidransky D Genetic progression model for head and neck cancer: implications for field cancerization.Cancer Res. 1996; 56: 2488-2492PubMed Google Scholar Thus, epithelial carcinogenesis has been divided into three phases of initiation, promotion and progression that involve genetic alteration, dysregulated epithelial differentiation, abnormal proliferation and altered regulatory effects associated with the abnormal expression of cellular factors that regulate growth and development. The identification of molecular alterations associated with these events could yield insight into the mechanisms of initiation and progression of neoplasia and provide new tools for diagnosis, treatment, and prevention. Annexins are commonly dysregulated in cancers6Ross DT Scherf U Eisen MB Perou CM Rees C Spellman P Iyer V Jeffrey SS Van de Rijn M Waltham M Pergamenschikov A Lee JC Lashkari D Shalon D Myers TG Weinstein JN Botstein D Brown PO Systematic variation in gene expression patterns in human cancer cell lines.Nat Genet. 2000; 24: 227-235Crossref PubMed Scopus (1812) Google Scholar and their frequent down-regulation has suggested a possible homeostatic or tumor suppressor role.7Xin W Rhodes DR Ingold C Chinnaiyan AM Rubin MA Dysregulation of the annexin family protein family is associated with prostate cancer progression.Am J Pathol. 2003; 162: 255-261Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 20Theobald J Hanby A Patel K Moss SE Annexin VI has tumour-suppressor activity in human A431 squamous epithelial carcinoma cells.Br J Cancer. 1995; 71: 786-788Crossref PubMed Scopus (56) Google Scholar, 25Srivastava M Bubendorf L Srikantan V Fossom L Nolan L Glasman M Leighton X Fehrle W Pittaluga S Raffeld M Koivisto P Willi N Gasser TC Kononen J Sauter G Kallioniemi OP Srivastava S Pollard HB ANX7, a candidate tumor suppressor gene for prostate cancer.Proc Natl Acad Sci USA. 2001; 98: 4575-4580Crossref PubMed Scopus (126) Google Scholar, 26Shridhar V Sen A Chien J Staub J Avula R Kovats S Lee J Lillie J Smith DI Identification of underexpressed genes in early- and late-stage primary ovarian tumors by suppression subtraction hybridization.Cancer Res. 2002; 62: 262-270PubMed Google Scholar We prioritized ANXA1 for follow-up analysis on the basis that this protein is normally well expressed in a wide range of organs and tissues, is specifically implicated in epithelial differentiation and growth regulation,27Violette SM King I Browning JL Pepinsky RB Wallner BP Sartorelli AC Role of lipocortin I in the glucocorticoid induction of the terminal differentiation of a human squamous carcinoma.J Cell Physiol. 1990; 142: 70-77Crossref PubMed Scopus (99) Google Scholar, 28Croxtall JD Gilroy DW Solito E Choudhury Q Ward BJ Buckingham JC Flower RJ Attenuation of glucocorticoid functions in an Anx-A1−/− cell line.Biochem J. 2003; 371: 927-935Crossref PubMed Scopus (55) Google Scholar and is markedly down-regulated in certain cancers7Xin W Rhodes DR Ingold C Chinnaiyan AM Rubin MA Dysregulation of the annexin family protein family is associated with prostate cancer progression.Am J Pathol. 2003; 162: 255-261Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 8Hippo Y Yashiro M Ishii M Taniguchi H Tsutsumi S Hirakawa K Kodama T Aburatani H Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes.Cancer Res. 2001; 61: 889-895PubMed Google Scholar, 26Shridhar V Sen A Chien J Staub J Avula R Kovats S Lee J Lillie J Smith DI Identification of underexpressed genes in early- and late-stage primary ovarian tumors by suppression subtraction hybridization.Cancer Res. 2002; 62: 262-270PubMed Google Scholar including esophageal squamous cell carcinomas.12Paweletz CP Ornstein DK Roth MJ Bichsel VE Gillespie JW Calvert VS Vocke CD Hewitt SM Duray PH Herring J Wang QH Hu N Linehan WM Taylor PR Liotta LA Emmert-Buck MR Petricoin III, EF Loss of annexin 1 correlates with early onset of tumorigenesis in esophageal and prostate carcinoma.Cancer Res. 2000; 60: 6293-6297PubMed Google Scholar, 14Xia SH Hu LP Hu H Ying WT Xu X Cai Y Han YL Chen BS Wei F Qian XH Cai YY Shen Y Wu M Wang MR Three isoforms of annexin I are preferentially expressed in normal esophageal epithelia but down-regulated in esophageal squamous cell carcinomas.Oncogene. 2002; 21: 6641-6648Crossref PubMed Scopus (88) Google Scholar, 15Zhou G Li H DeCamp D Chen S Shu H Gong Y Flaig M Gillespie JW Hu N Taylor PR Emmert-Buck MR Liotta LA Petricoin III, EF Zhao Y 2D differential in-gel electrophoresis for the identification of esophageal scans cell cancer-specific protein markers.Mol Cell Proteomics. 2002; 1: 117-124Crossref PubMed Google Scholar ANXA1 is a pleiotropic 39-kd protein, member of the annexin superfamily, of principal interest as one of the mediators of the anti-inflammatory actions of glucocorticoids. Subsequent research has shown that the protein plays a major regulatory role in cell-growth regulation and differentiation, neutrophil migration, central nervous system responses to cytokines, neuroendocrine secretion, and mediation of apoptosis.28Croxtall JD Gilroy DW Solito E Choudhury Q Ward BJ Buckingham JC Flower RJ Attenuation of glucocorticoid functions in an Anx-A1−/− cell line.Biochem J. 2003; 371: 927-935Crossref PubMed Scopus (55) Google Scholar ANXA1 has also been shown to be a substrate for epidermal growth factor receptor kinase, a recognized indicator of poor prognosis and reduced survival in head and neck cancer.DNA and protein microarray studies highlight the changes in ANXA1 expression in various cancers and identify other genes with similar expression profiles6Ross DT Scherf U Eisen MB Perou CM Rees C Spellman P Iyer V Jeffrey SS Van de Rijn M Waltham M Pergamenschikov A Lee JC Lashkari D Shalon D Myers TG Weinstein JN Botstein D Brown PO Systematic variation in gene expression patterns in human cancer cell lines.Nat Genet. 2000; 24: 227-235Crossref PubMed Scopus (1812) Google Scholar that may help to elucidate regulatory changes relevant to both ANXA1 function and tumor classification. 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• W2046020700 title "Annexin A1 Down-Regulation in Head and Neck Cancer Is Associated with Epithelial Differentiation Status" @default.
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