[en] Pleomorphic adenoma gene 1 (PLAG1) proto-oncogene overexpression is implicated in various human neoplasias, including salivary gland pleomorphic adenomas. To further assess the oncogenic capacity of PLAG1, two independent PLAG1 transgenic mouse strains were established, PTMS1 and PTMS2, in which activation of PLAG1 overexpression is Cre mediated. Crossbreeding of PTMS1 or PTMS2 mice with MMTV-Cre transgenic mice was done to target PLAG1 overexpression to salivary and mammary glands, in the P1-Mcre/P2-Mcre offspring. With a prevalence of 100% and 6%, respectively, P1-Mcre and P2-Mcre mice developed salivary gland tumors displaying various pleomorphic adenoma features. Moreover, histopathologic analysis of salivary glands of 1-week-old P1-Mcre mice pointed at early tumoral stages in epithelial structures. Malignant characteristics in the salivary gland tumors and frequent lung metastases were found in older tumor-bearing mice. PLAG1 overexpression was shown in all tumors, including early tumoral stages. The tumors revealed an up-regulation of the expression of two distinct, imprinted gene clusters (i.e., Igf2/H19 and Dlk1/Gtl2). With a latency period of about 1 year, 8% of the P2-Mcre mice developed mammary gland tumors displaying similar histopathologic features as the salivary gland tumors. In conclusion, our results establish the strong and apparently direct in vivo tumorigenic capacity of PLAG1 and indicate that the transgenic mice constitute a valuable model for pleomorphic salivary gland tumorigenesis and potentially for other glands as well.
Disciplines :
Oncology
Author, co-author :
Declercq, Jeroen; Laboratory for Molecular Oncology, Department of Human Genetics, K.U. Leuven, Belgium
Van Dyck, Frederik; Department of Human Genetics, Flanders interuniversity Institute for Biotechnology, K.U. Leuven, Belgium
Braem, Caroline V; Department of Human Genetics, Flanders interuniversity Institute for Biotechnology, K.U. Leuven, Belgium
Van Valckenborgh, Isabelle C; Department of Human Genetics, Flanders interuniversity Institute for Biotechnology, K.U. Leuven, Belgium
Voz, Marianne ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire ; Department of Human Genetics, Flanders interuniversity Institute for Biotechnology, K.U. Leuven, Belgium
Wassef, Michel; Service Central de Cytologie and Anatomie Pathologique, Hôpital Lariboisière, France
Van Damme, Boudewijn; Department of Morphology and Molecular Pathology, K.U. Leuven, Leuven, Belgium
Fiette, Laurence; Unité de Recherche et d'Expertise en Histotechnologie et Pathologie, Institut Pasteur, Paris, France ; Platform of Veterinary Diagnosis, CMU, CH 1211, Geneva 4, Switzerland
Van de Ven, Wim J M; Department of Human Genetics, Flanders interuniversity Institute for Biotechnology, K.U. Leuven, Belgium ; Laboratory for Molecular Oncology, Department of Human Genetics, K.U. Leuven, B-3000 Leuven, Belgium
Language :
English
Title :
Salivary gland tumors in transgenic mice with targeted PLAG1 proto-oncogene overexpression.
Publication date :
01 June 2005
Journal title :
Cancer Research
ISSN :
0008-5472
eISSN :
1538-7445
Publisher :
American Association for Cancer Research (AACR), United States
Kas K, Voz ML, Roijer E, et al. Promoter swapping between the genes for a novel zinc finger protein and β-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nat Genet 1997;15:170-4.
Voz ML, Astrom AK, Kas K, et al. The recurrent translocation t(5;8)(p13;q12) in pleomorphic adenomas results in upregulation of PLAG1 gene expression under control of the LIFR promoter. Oncogene 1998;16:1409-16.
Astrom A, D'Amore ES, Sainati L, et al. Evidence of involvement of the PLAG1 gene in lipoblastomas. Int J Oncol 2000;16:1107-10.
Hibbard MK, Kozakewich HP, Dal Cin P, et al. PLAG1 fusion oncogenes in lipoblastoma. Cancer Res 2000;60:4869-72.
Morerio C, Rapella A, Rosanda C, et al. PLAG1-HAS2 fusion in lipoblastoma with masked 8q intrachromosomal rearrangement Cancer Genet Cytogenet 2005;156:183-4.
Zatkova A, Rouillard JM, Hartmann W, et al. Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma. Genes Chromosomes Cancer 2004;39:126-37.
Castilla LH, Perrat P, Martinez NJ, et al. Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. PNAS 2004;101:4924-9.
Liu P, Tarle SA, Hajra A, et al. Fusion between transcription factor CBF β/PEBP2 β and a myosin heavy chain in acute myeloid leukemia. Science 1993;261:1041-4.
Landrette SF, Kuo YH, Hensen K, et al. Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11. Blood 2005;105:2900-7.
Kas K, Voz ML, Hensen K, Meyen E, Van de Ven WJ. Transcriptional activation capacity of the novel PLAG family of zinc finger proteins. J Biol Chem 1998;273:23026-32.
Astrom AK, Voz ML, Kas K, et al. Conserved mechanism of PLAG1 activation in salivary gland tumors with and without chromosome 8q12 abnormalities: identification of SII as a new fusion partner gene. Cancer Res 1999;59:918-23.
Voz ML, Agten NS, Van de Ven WJ, Kas K. PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II. Cancer Res 2000;60:106-13.
Braem CV, Kas K, Meyen E, et al. Identification of a karyopherin α 2 recognition site in PLAG1, which functions as a nuclear localization signal. J Biol Chem 2002;277:19673-8.
Van Dyck F, Delvaux ELD, Van de Ven WJM, Chavez MV. Repression of the transactivating capacity of the oncoprotein PLAG1 by SUMOylation. J Biol Chem 2004;279:36121-31.
Voz ML, Mathys J, Hensen K, et al. Microarray screening for target genes of the proto-oncogene PLAG1. Oncogene 2004;23:179-91.
Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz ML. The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities. Cancer Res 2002;62:1510-7.
Niwa H, Yamamura K, Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 1991;108:193-9.
Adra CN, Boer PH, McBurney MW. Cloning and expression of the mouse pgk-1 gene and the nucleotide sequence of its promoter. Gene 1987;60:65-74.
Wagner KU, McAllister K, Ward T, et al. Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res 2001;10:545-53.
Seshi B. Cell blotting: techniques for staining and microscopical examination of cells blotted on nitrocellulose paper. Anal Biochem 1986;157:331-42.
Mikaelian I, Blades N, Churchill GA, et al. Proteotypic classification of spontaneous and transgenic mammary neoplasms. Breast Cancer Res 2004;6:R668-79.
Debiec-Rychter M, Van Valckenborgh I, Van den Broeck C, et al. Histologic localization of PLAG1 (pleomorphic adenoma gene 1) in pleomorphic adenoma of the salivary gland: cytogenetic evidence of common origin of phenotypically diverse cells. Lab Invest 2001;81:1289-97.
Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156-9.
Hensen K, Braem C, Declercq J, et al. Targeted disruption of the murine Plag1 proto-oncogene causes growth retardation and reduced fertility. Dev Growth Differ 2004;46:459-70.
Lallemand Y, Luria V Haffner-Krausz R, Lonai P. Maternally expressed PGK-Cre transgene as a tool for early and uniform activation of the Cre site-specific recombinase. Transgenic Res 1998;7:105-12.
Attie JN, Sciubba JJ. Tumors of major and minor salivary glands: clinical and pathologic features. Curr Probl Surg 1981;18:65-155.
Olsen KD, Lewis JE. Carcinoma ex pleomorphic adenoma: a clinicopathologic review. Head Neck 2001;23:705-12.
Mizui T, Ishimaru JI, Miyamoto K, Toida M. Malignant transformation of a gigantic pleomorphic adenoma of the submandibular gland: a case report. J Oral Maxillofac Surg 2000;58:1422-4.
Roijer E, Nordkvist A, Strom A-K, et al. Translocation, deletion/amplification, and expression of HMGIC and MDM2 in a carcinoma ex pleomorphic adenoma. Am J Pathol 2002;160:433-40.
Zhao XD, Yang WJ, Wang L, et al. Development of salivary gland tumors in pleomorphic adenoma gene 1 transgenic mice. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003;20:390-5.
Babinet C. Transgenic mice: an irreplaceable tool for the study of mammalian development and biology. J Am Soc Nephrol 2000;11:588-94.
Takada S, Paulsen M, Tevendale M, et al. Epigenetic analysis of the Dlk1-Gtl2 imprinted domain on mouse chromosome 12: implications for imprinting control from comparison with Igf2-H19. Hum Mol Genet 2002;11:77-86.
Takada S, Tevendale M, Baker J, et al. Delta-like and gtl2 are reciprocally expressed, differentially methylated linked imprinted genes on mouse chromosome 12. Curr Biol 2000;10:1135-8.
Paulsen M, Takada S, Youngson NA, et al. Comparative sequence analysis of the imprinted Dlk1-Gtl2 locus in three mammalian species reveals highly conserved genomic elements and refines comparison with the Igf2-H19 region. Genome Res 2001;11:2085-94.
Moorehead RA, Sanchez OH, Baldwin RM, Khokha R. Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma. Oncogene 2003;22:853-7.
Jaisser F. Inducible gene expression and gene modification in transgenic mice. J Am Soc Nephrol 2000;11:S95-100.
