Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
권호 표지

Somatic Mutations of the ENPP2 (Autotaxin/lysoPLD) Gene in Breast Cancer

  • Song, Jae-Hwi (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Kim, Jeong-Kyu (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Noh, Ji-Heon (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Jung, Kwang-Hwa (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Eun, Jung-Woo (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Kim, Chang-Jae (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Bae, Hyun-Jin (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Xie, Hong-Jian (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Ahn, Young-Min (Department of Kidney System, College of Oriental Medicine, Kyung Hee University) ;
  • Lee, Sug-Hyung (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Yoo, Nam-Jin (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Lee, Jung-Young (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Park, Won-Sang (Lab of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Nam, Suk-Woo (Lab of Pathology, College of Medicine, The Catholic University of Korea)
  • Published : 2007.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

ENPP2, a 125 kDa secreted lysophopholipase D which originally identified as a tumor-motogen, Autotaxin, enhances cellular locomotion, cell proliferation, angiogenesis and cell survival by generating the signal molecule lysophosphatic acid or sphingosine-1-phosphate. Previous studies have suggested that expression of Autotaxin is associated with invasive phenotype in advanced breast carcinomas. Thus, to determine whether genetic alterations of ENPP2 gene are involved in the development or progression of breast cancer, we analyzed its somatic mutation in 85 breast carcinomas by single-stranded conformational polymorphism and sequencing. Overall, six ENPP2 mutations were found (7.0%), comprising five missense and one nonsense mutation (s). To our knowledge, this is the first report on ENPP2 mutation in breast carcinoma, and the data indicate that ENPP2 is occasionally mutated in breast carcinomas, and suggest that ENPP2 mutation may contribute to the tumor development in some breast carcinomas.

Keywords

References

  1. Stracke, M. L. et al. Ientification, purification, and partial sequence analysis of autotaxin, a novel motility- stimulating protein. J Biol Chem 267:2524-2529 (1992)
  2. Stracke, M. L. et al. Autotaxin is an N-linked glycoprotein but the sugar moieties are not needed for its stimulation of cellular motility. Melanoma Res 5:203-209 (1995) https://doi.org/10.1097/00008390-199508000-00001
  3. Stracke, M. L., Clair, T. & Liotta, L. A. Autotaxin, tumor motility-stimulating exophosphodiesterase. Adv Enzyme Regul 37:135-144 (1997) https://doi.org/10.1016/S0065-2571(96)00017-9
  4. Mills, G. B. & Moolenaar, W. H. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 3:582-591 (2003) https://doi.org/10.1038/nrc1143
  5. Umezu-Goto, M. et al. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158:227-233 (2002) https://doi.org/10.1083/jcb.200204026
  6. Tokumura, A. et al. Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 277:39436-39442 (2002) https://doi.org/10.1074/jbc.M205623200
  7. Clair, T. et al. Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res 63:5446-5453 (2003)
  8. Brindley, D. N. Lipid phosphate phosphatases and related proteins: signaling functions in development, cell division, and cancer. J Cell Biochem 92:900-912 (2004) https://doi.org/10.1002/jcb.20126
  9. Chen, M. & O'Connor, K. L. Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells. Oncogene 24:5125-5130 (2005) https://doi.org/10.1038/sj.onc.1208729
  10. Hama, K. et al. Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1. J Biol Chem 279:17634-17639 (2004) https://doi.org/10.1074/jbc.M313927200
  11. Nam, S. W. et al. Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic potential of ras-transformed cells. Oncogene 19:241-247 (2000) https://doi.org/10.1038/sj.onc.1203263
  12. Nam, S. W. et al. Autotaxin (NPP-2), a metastasisenhancing motogen, is an angiogenic factor. Cancer Res 1561:6938-6944 (2001)
  13. Kehlen, A. et al. Expression, regulation and function of autotaxin in thyroid carcinomas. Int J Cancer 109: 833-838 (2004) https://doi.org/10.1002/ijc.20022
  14. Song, J. et al. Autotaxin (lysoPLD/NPP2) protects fibroblasts from apoptosis through its enzymatic product, lysophosphatidic acid, utilizing albumin-bound substrate. Biochem Biophys Res Commun 337:967-975 (2005) https://doi.org/10.1016/j.bbrc.2005.09.140
  15. Exton, J. H. Regulation of phospholipase D. FEBS Lett 531:58-61 (2002) https://doi.org/10.1016/S0014-5793(02)03405-1
  16. Jenkins, G. M. & Frohman, M. A. Phospholipase D: a lipid centric review. Cell Mol Life Sci 62:2305-2316 (2005) https://doi.org/10.1007/s00018-005-5195-z
  17. Huang, P. & Frohman, M. A. The potential for phospholipase D as a new therapeutic target. Expert Opin Ther Targets 11:707-716 (2007) https://doi.org/10.1517/14728222.11.5.707
  18. Clair, T., Lee, H. Y., Liotta, L. A. & Stracke, M. L. Autotaxin is an exoenzyme possessing 5'-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities. J Biol Chem 272:996-1001 (1997) https://doi.org/10.1074/jbc.272.2.996
  19. Lee, H. Y. et al. Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin. J Biol Chem 271:24408-24412 (1996) https://doi.org/10.1074/jbc.271.40.24408
  20. Koh, E. et al. Site-directed mutations in the tumorassociated cytokine, autotaxin, eliminate nucleotide phosphodiesterase, lysophospholipase D, and motogenic activities. Cancer Res 63:2042-2045 (2003)
  21. Noh, J. H. et al. Identification of large-scale molecular changes of Autotaxin (ENPP2) knock-down by small interfering RNA in breast cancer cells. Mol Cell Biochem 288:91-106 (2006) https://doi.org/10.1007/s11010-006-9124-8
  22. Lee, J. Y. et al. A simple, precise and economical microdissection technique for analysis of genomic DNA from archival tissue sections. Virchows Arch 433:305-309 (1998) https://doi.org/10.1007/s004280050253
  23. Gijsbers, R., Ceulemans, H., Stalmans, W. & Bollen, M. Structural and catalytic similarities between nucleotide pyrophosphatases/phosphodiesterases and alkaline phosphatases. J Biol Chem 276:1361-1368 (2001) https://doi.org/10.1074/jbc.M007552200
  24. van. Meeteren, L. A. & Moolenaar, W. H. Regulation and biological activities of the autotaxin-LPA axis. Prog Lipid Res 46:145-160 (2007) https://doi.org/10.1016/j.plipres.2007.02.001
  25. Yang, S. Y. et al. Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells. Clin Exp Metastasis 19:603-608 (2002) https://doi.org/10.1023/A:1020950420196