Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine endometrial cancers.

BACKGROUND Gas6, the protein product of the growth arrest-specific gene 6 (gas6), a member of the vitamin K-dependent protein family, was identified as a ligand for the Axl/Sky family of receptor tyrosine kinases. Gas6 acts as a growth-potentiating factor for thrombin-induced proliferation of vascular smooth muscle cells. The aim of the present study was to test for the presence of Gas6 and its receptors Axl and Sky, related to specific growth in uterine endometrial cancers, and to evaluate their plausible growth potential and mechanism. MATERIALS AND METHODS Sixty patients underwent curative resection for uterine endometrial cancers. In uterine endometrial cancers, the mRNA levels and histoscores of Gas6, Axl and Sky were determined by competitive RT-PCR using recombinant RNA and immunohistochemical studies, respectively. The rate of proliferation by immunochemistry for Ki67 and the rate of apoptosis by TUNEL were determined. RESULTS The mRNA levels and the histoscores of Gas6 and Axl in well-differentiated endometrial cancers (G1 EC) were significantly higher than in normal uterine endometrium (NE) and in moderately and poorly differentiated endometrial cancers (G2 + G3 EC). The rate of apoptosis in G1 EC was significantly lower than that in NE and in G2 + G3 EC. CONCLUSIONS Gas6 and Axl signal transduction is aberrantly stimulated in well-differentiated endometrial cancers, plausibly related to tumor progression due to protection from apoptosis in cancers cells.

[1]  M. Capogrossi,et al.  Acidification Prevents Endothelial Cell Apoptosis by Axl Activation , 2002, Circulation research.

[2]  T. Tamaya,et al.  Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases, Axl and Sky, in human uterine endometrium and ovarian endometriosis. , 2002, Molecular human reproduction.

[3]  G. D'aiuto,et al.  Dynamic coupling of 99mTc-MIBI efflux and apoptotic pathway activation in untreated breast cancer patients , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[4]  B. Varnum,et al.  Gas 6 promotes Axl-mediated survival in pulmonary endothelial cells. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[5]  E. Dreher,et al.  Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  M. E. Ruaro,et al.  Gas6 Induces Growth, β-Catenin Stabilization, and T-Cell Factor Transcriptional Activation in Contact-Inhibited C57 Mammary Cells , 2001, Molecular and Cellular Biology.

[7]  M. Hung,et al.  Axl-Gas6 Interaction Counteracts E1A-Mediated Cell Growth Suppression and Proapoptotic Activity , 1999, Molecular and Cellular Biology.

[8]  H. Kung,et al.  Comparative tyrosine‐kinase profiles in colorectal cancers: Enhanced arg expression in carcinoma as compared with adenoma and normal mucosa , 1999, International journal of cancer.

[9]  E. Ruaro,et al.  Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras , 1999, Oncogene.

[10]  S. Yamashita,et al.  Expression of the Axl receptor tyrosine kinase in human thyroid carcinoma. , 1999, Thyroid : official journal of the American Thyroid Association.

[11]  S. Goff,et al.  Tyro-3 family receptors are essential regulators of mammalian spermatogenesis , 1999, Nature.

[12]  J. Weber,et al.  Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system 1 Published on the World Wide Web on 2 December 1998. 1 , 1999, Brain Research.

[13]  T. Tamaya,et al.  Effect of medroxyprogesterone acetate on sex hormone-binding globulin mRNA expression in the human endometrial cancer cell line Ishikawa. , 1998, European journal of endocrinology.

[14]  E. Attar,et al.  GAS6 Induces Axl-mediated Chemotaxis of Vascular Smooth Muscle Cells* , 1998, The Journal of Biological Chemistry.

[15]  S. Goff,et al.  Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation , 1997, Oncogene.

[16]  M. Nisolle,et al.  Immunohistochemical analysis of proliferative activity and steroid receptor expression in peritoneal and ovarian endometriosis. , 1997, Fertility and sterility.

[17]  E. Liu,et al.  Human chondrocyte expression of growth-arrest-specific gene 6 and the tyrosine kinase receptor axl: potential role in autocrine signaling in cartilage. , 1997, Arthritis and rheumatism.

[18]  E. Ruaro,et al.  Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts , 1997, Molecular and cellular biology.

[19]  P. Godowski,et al.  Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation , 1997, Oncogene.

[20]  K. Kawamoto,et al.  Requirement of gamma-carboxyglutamic acid residues for the biological activity of Gas6: contribution of endogenous Gas6 to the proliferation of vascular smooth muscle cells. , 1997, The Biochemical journal.

[21]  H. Hanafusa,et al.  Identification of the Product of Growth Arrest-specific Gene 6 as a Common Ligand for Axl, Sky, and Mer Receptor Tyrosine Kinases* , 1996, The Journal of Biological Chemistry.

[22]  K. Kawamoto,et al.  Prevention of growth arrest‐induced cell death of vascular smooth muscle cells by a product of growth arrest‐specific gene, gas6 , 1996, FEBS letters.

[23]  E. Ruaro,et al.  Gas6, the ligand of Axl tyrosine kinase receptor, has mitogenic and survival activities for serum starved NIH3T3 fibroblasts. , 1996, Oncogene.

[24]  E. Liu,et al.  Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase , 1996, Molecular and cellular biology.

[25]  P. Godowski,et al.  Reevaluation of the roles of protein S and gas6 as ligands for the receptor tyrosine kinase Rse/Tyro 3 , 1995, Cell.

[26]  E. Liu,et al.  Receptor tyrosine kinases expressed in metastatic colon cancer , 1995, International journal of cancer.

[27]  H. Yamane,et al.  Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6 , 1995, Nature.

[28]  C. Basilico,et al.  The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding , 1995, Molecular and cellular biology.

[29]  D. Huhn,et al.  Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis. , 1994, Blood.

[30]  G. Lemke,et al.  Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase. , 1994, Oncogene.

[31]  H. Snodgrass,et al.  Cloning and Mrna Expression Analysis of a Novel Human Protooncogene, C-merr , 2022 .

[32]  A. Goddard,et al.  rse, a novel receptor-type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain. , 1994, The Journal of biological chemistry.

[33]  K. Kuma,et al.  Cloning of the cDNA for a novel receptor tyrosine kinase, Sky, predominantly expressed in brain. , 1994, Oncogene.

[34]  C. Schneider,et al.  The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade , 1993, Molecular and cellular biology.

[35]  G. D'aiuto,et al.  Human urokinase receptor concentration in malignant and benign breast tumors by in vitro quantitative autoradiography: comparison with urokinase levels. , 1993, Cancer research.

[36]  J. V. Vanden Heuvel,et al.  Construction of recombinant RNA templates for use as internal standards in quantitative RT-PCR. , 1993, BioTechniques.

[37]  A. Schulz,et al.  A novel putative tyrosine kinase receptor with oncogenic potential. , 1991, Oncogene.

[38]  R. Espinosa,et al.  axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase , 1991, Molecular and cellular biology.

[39]  M. Key,et al.  Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. , 1991, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[40]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[41]  M Schemper,et al.  Estrogen receptor analysis on biopsies and fine-needle aspirates from human breast carcinoma. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. , 1986, The American journal of pathology.

[42]  B. Dahlbäck,et al.  Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Vihko,et al.  Steroidal regulation of endometriosis tissue: lack of induction of 17 beta-hydroxysteroid dehydrogenase activity by progesterone, medroxyprogesterone acetate, or danazol. , 1985, Fertility and sterility.

[44]  H Stein,et al.  Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. , 1984, Journal of immunology.

[45]  K. Schweppe,et al.  Ultrastructural comparison of endometriotic implants and eutopic endometrium. , 1984, American journal of obstetrics and gynecology.

[46]  S. Hsu,et al.  Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. , 1981, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[47]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[48]  P. Whitehead,et al.  A rapid technique for the detection of amylase isoenzymes using an enzyme sensitive "test-paper". , 1976, Analytical biochemistry.

[49]  A. Kraus,et al.  Axl receptor tyrosine kinase expression in human lung cancer cell lines correlates with cellular adhesion. , 2001, European journal of cancer.

[50]  G. Majno,et al.  Apoptosis, oncosis, and necrosis. An overview of cell death. , 1995, The American journal of pathology.

[51]  [Carcinoma]. , 1955, Die Medizinische.