Molecular Oncology
Volume 2, Issue 3 , Pages 241-249 , October 2008

Exon 2 deletion splice variant of γ-glutamyl carboxylase causes des-γ-carboxy prothrombin production in hepatocellular carcinoma cell lines

Received 17 March 2008 ,Revised 11 June 2008 ,Accepted 15 June 2008.

References 

  1. Ando E, et al. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. Cancer. 2002;95:588–595
  2. Bartel F, Taubert H, Harris LC. Alternative and aberrant splicing of MDM2 mRNA in human cancer. Cancer Cell. 2002;2:9–15
  3. Brenner B, Sanchez-Vega B, Wu SM, Lanir N, Stafford DW, Solera J. A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood. 1998;92:4554–4559
  4. Brinkman BM. Splice variants as cancer biomarkers. Clin. Biochem. 2004;37:584–594
  5. Chalfant CE, Rathman K, Pinkerman RL, Wood RE, Obeid LM, Ogretmen B, et al. De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J. Biol. Chem. 2002;277:12587–12595
  6. Fujikawa T, et al. Des-{gamma}-carboxyl Prothrombin-promoted Vascular Endothelial Cell Proliferation and Migration. J. Biol. Chem. 2007;282:8741–8748
  7. Furukawa M, Nakanishi T, Okuda H, Ishida S, Obata H. Changes of plasma des-gamma-carboxy prothrombin levels in patients with hepatocellular carcinoma in response to vitamin K. Cancer. 1992;69:31–38
  8. Gotoh M, Nakatani T, Masuda T, Mizuguchi Y, Sakamoto M, Tsuchiya R, et al. Prediction of invasive activities in hepatocellular carcinomas with special reference to alpha-fetoprotein and des-gamma-carboxyprothrombin. Jpn. J. Clin. Oncol. 2003;33:522–526
  9. Grazi GL, Mazziotti A, Legnani C, Jovine E, Miniero R, Gallucci A, et al. The role of tumor markers in the diagnosis of hepatocellular carcinoma, with special reference to the des-gamma-carboxy prothrombin. Liver Transpl. Surg. 1995;1:249–255
  10. Hammes A, Guo JK, Lutsch G, Leheste JR, Landrock D, Ziegler U, et al. Two splice variants of the Wilms’ tumor 1 gene have distinct functions during sex determination and nephron formation. Cell. 2001;106:319–329
  11. Huisse MG, Leclercq M, Belghiti J, Flejou JF, Suttie JW, Bezeaud A, et al. Mechanism of the abnormal vitamin K-dependent gamma-carboxylation process in human hepatocellular carcinomas. Cancer. 1994;74:1533–1541
  12. Inoue S, Nakao A, Harada A, Nonami T, Takagi H. Clinical significance of abnormal prothrombin (DCP) in relation to postoperative survival and prognosis in patients with hepatocellular carcinoma. Am. J. Gastroenterol. 1994;89:2222–2226
  13. Jin W, Cote GJ. Enhancer-dependent splicing of FGFR1 alpha-exon is repressed by RNA interference-mediated down-regulation of SRp55. Cancer Res. 2004;64:8901–8905
  14. Jin W, McCutcheon IE, Fuller GN, Huang ES, Cote GJ. Fibroblast growth factor receptor-1 alpha-exon exclusion and polypyrimidine tract-binding protein in glioblastoma multiforme tumors. Cancer Res. 2000;60:1221–1224
  15. Kassahun WT, Fangmann J, Harms J, Hauss J, Bartels M. Liver resection and transplantation in the management of hepatocellular carcinoma: a review. Exp. Clin. Transplant. 2006;4:549–558
  16. Kim MM, Rivera MA, Botchkina IL, Shalaby R, Thor AD, Blackburn EH. A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. Proc. Natl. Acad. Sci. U.S.A. 2001;98:7982–7987
  17. Kuniyasu H, Oue N, Tsutsumi M, Tahara E, Yasui W. Heparan sulfate enhances invasion by human colon carcinoma cell lines through expression of CD44 variant exon 3. Clin. Cancer Res. 2001;7:4067–4072
  18. Kuromatsu R, Tanaka M, Shimauchi Y, Shimada M, Tanikawa K, Watanabe K, et al. Usefulness of ED036 kit for measuring serum PIVKA-II levels in small hepatocellular carcinoma. J. Gastroenterol. 1997;32:507–512
  19. Li ZQ, He FY, Stehle CJ, Wang Z, Kar S, Finn FM, et al. Vitamin K uptake in hepatocytes and hepatoma cells. Life Sci. 2002;70:2085–2100
  20. Liebman HA, Furie BC, Tong MJ, Blanchard RA, Lo KJ, Lee SD, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N. Engl. J. Med. 1984;310:1427–1431
  21. Liu Y, Nelson AN, Lipsky JJ. Vitamin K-dependent carboxylase: mRNA distribution and effects of vitamin K-deficiency and warfarin treatment. Biochem. Biophys. Res. Commun. 1996;224:549–554
  22. Liu HX, Cartegni L, Zhang MQ, Krainer AR. A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nat. Genet. 2001;27:55–58
  23. Marrero J, Martinez FJ, Hyzy R. Advances in critical care hepatology. Am J Respir Crit. Care Med. 2003;168:1421–1426
  24. McCullough AJ, Berget SM. G triplets located throughout a class of small vertebrate introns enforce intron borders and regulate splice site selection. Mol. Cell. Biol. 1997;17:4562–4571
  25. Mohamedein A, Yousif-Kadaru AG, Ahmed SA, Saida H, Zaki ZA, Eldin , et al. Acarboxy prothrombin (PIVKA II) as a tumour marker for hepatocellular carcinoma and other liver diseases. East Afr. Med. J. 1995;72:584–587
  26. Morrison AA, Venables JP, Dellaire G, Ladomery MR. The Wilms tumour suppressor protein WT1 (+KTS isoform) binds alpha-actinin 1 mRNA via its zinc-finger domain. Biochem. Cell Biol. 2006;84:789–798
  27. Okuda H, Obata H, Nakanishi T, Furukawa R, Hashimoto E. Production of abnormal prothrombin (des-gamma-carboxy prothrombin) by hepatocellular carcinoma. A clinical and experimental study. J. Hepatol. 1987;4:357–363
  28. Okuda H, Nakanishi T, Takatsu K, Saito A, Hayashi N, Watanabe K, et al. Measurement of serum levels of des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma by a revised enzyme immunoassay kit with increased sensitivity. Cancer. 1999;85:812–818
  29. Okuda H, Nakanishi T, Takatsu K, Saito A, Hayashi N, Takasaki K, et al. Serum levels of des-gamma-carboxy prothrombin measured using the revised enzyme immunoassay kit with increased sensitivity in relation to clinicopathologic features of solitary hepatocellular carcinoma. Cancer. 2000;88:544–549
  30. Ono M, Ohta H, Ohhira M, Sekiya C, Namiki M. Measurement of immunoreactive prothrombin precursor and vitamin-K-dependent gamma-carboxylation in human hepatocellular carcinoma tissues: decreased carboxylation of prothrombin precursor as a cause of des-gamma-carboxyprothrombin synthesis. Tumour Biol. 1990;11:319–326
  31. Otsuka M, et al. Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation. Hepatology. 2004;40:243–251
  32. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin. 1999;49:33–641
  33. Price PA, Williamson MK. Substrate recognition by the vitamin K-dependent gamma-glutamyl carboxylase: identification of a sequence homology between the carboxylase and the carboxylase recognition site in the substrate. Protein Sci. 1993;2:1987–1988
  34. Pudota BN, Hommema EL, Hallgren KW, McNally BA, Lee S, Berkner KL. Identification of sequences within the gamma-carboxylase that represent a novel contact site with vitamin K-dependent proteins and that are required for activity. J. Biol. Chem. 2001;276:46878–46886
  35. Romero EE, Deo R, Velazquez-Estades LJ, Roth DA. Cloning, structural organization, and transcriptional activity of the rat vitamin K-dependent gamma-glutamyl carboxylase gene. Biochem. Biophys. Res. Commun. 1998;248:783–788
  36. Rost S, Fregin A, Koch D, Compes M, Muller CR, Oldenburg J. Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. Br. J. Haematol. 2004;126:546–549
  37. Sakon M, Monden M, Gotoh M, Kanai T, Umeshita K, Nakano Y, et al. Relationship between pathologic prognostic factors and abnormal levels of des-gamma-carboxy prothrombin and alpha-fetoprotein in hepatocellular carcinoma. Am. J. Surg. 1992;163:251–256
  38. Shimada M, Takenaka K, Fujiwara Y, Gion T, Kajiyama K, Maeda T, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein positive status as a new prognostic indicator after hepatic resection for hepatocellular carcinoma. Cancer. 1996;78:2094–2100
  39. Spronk HM, Farah RA, Buchanan GR, Vermeer C, Soute BA. Novel mutation in the gamma-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K-dependent blood coagulation factors. Blood. 2000;96:3650–3652
  40. Stickeler E, Kittrell F, Medina D, Berget SM. Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis. Oncogene. 1999;18:3574–3582
  41. Suehiro T, Matsumata T, Itasaka H, Taketomi A, Yamamoto K, Sugimachi K. Des-gamma-carboxy prothrombin and proliferative activity of hepatocellular carcinoma. Surgery. 1995;117:682–691
  42. Suzuki M, Shiraha H, Fujikawa T, Takaoka N, Ueda N, Nakanishi Y, et al. Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma. J. Biol. Chem. 2005;280:6409–6415
  43. Tagawa M, Omata M, Ohto M. Nucleotide sequence of prothrombin gene in abnormal prothrombin-producing hepatocellular carcinoma cell lines. Cancer. 1992;69:643–647
  44. Tamano M, et al. Serum and tissue PIVKA-II expression reflect the biological malignant potential of small hepatocellular carcinoma. Hepatol. Res. 2002;22:261–269
  45. Thakur S, et al. Localization of BRCA1 and a splice variant identifies the nuclear localization signal. Mol. Cell. Biol. 1997;17:444–452
  46. Thornton JK, Dalgleish C, Venables JP, Sergeant KA, Ehrmann IE, Lu X, et al. The tumour-suppressor protein ASPP1 is nuclear in human germ cells and can modulate ratios of CD44 exon V5 spliced isoforms in vivo. Oncogene. 2006;25:3104–3112
  47. Tie J, Wu SM, Jin D, Nicchitta CV, Stafford DW. A topological study of the human gamma-glutamyl carboxylase. Blood. 2000;96:973–978
  48. Toyoda H, et al. Prognostic significance of simultaneous measurement of three tumor markers in patients with hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 2006;4:111–117
  49. Uehara S, Gotoh K, Handa H, Honjo K, Hirayama A. Process of carboxylation of glutamic acid residues in the gla domain of human des-gamma-carboxyprothrombin. Clin. Chim. Acta. 1999;289:33–44
  50. Weitz IC, Liebman HA. Des-gamma-carboxy (abnormal) prothrombin and hepatocellular carcinoma: a critical review. Hepatology. 1993;18:990–997
  51. Wu SM, Cheung WF, Frazier D, Stafford DW. Cloning and expression of the cDNA for human gamma-glutamyl carboxylase. Science. 1991;254:1634–1636
  52. Wu SM, Morris DP, Stafford DW. Identification and purification to near homogeneity of the vitamin K-dependent carboxylase. Proc. Natl. Acad. Sci. U.S.A. 1991;88:2236–2240
  53. Wu SM, Stafford DW, Frazier LD, Fu YY, High KA, Chu K, et al. Genomic sequence and transcription start site for the human gamma-glutamyl carboxylase. Blood. 1997;89:4058–4062
  54. Wu JY, Tang H, Havlioglu N. Alternative pre-mRNA splicing and regulation of programmed cell death. Prog. Mol. Subcell. Biol. 2003;31:153–185
  55. Zhu X, Daffada AA, Chan CM, Dowsett M. Identification of an exon 3 deletion splice variant androgen receptor mRNA in human breast cancer. Int. J. Cancer. 1997;72:574–580

PII: S1574-7891(08)00074-4

doi: 10.1016/j.molonc.2008.06.004

Molecular Oncology
Volume 2, Issue 3 , Pages 241-249 , October 2008