Annals of Surgical Treatment and Research

The Korean Surgical Society (대한외과학회)
권호 표지

Expression of Proteins Related Cell Cycle and Apoptosis during Diethylnitrosamine (DEN)-induced Hepatocarcinogenesis in Rats

Diethylnitrosamine으로 유도된 쥐의 간암화 과정에서 세포주기 및 세포자멸사 관련 단백 발현

Sim, Woo-Jung;Kim, Yong-Seok;Choi, Yoo-Shin;Kim, Beom-Gyu;Cha, Seong-Jae;Lim, Hyun-Muck;Park, Eon-Sub
심우정;김용석;최유신;김범규;차성재;임현묵;박언섭

  • Published : 20081200
⟨ Previous Next ⟩

Abstract

Purpose: To explore the role of cell cycle and apoptosis regulators during hepatocarcinogenesis, the expression of cell cycle-related proteins (cyclin D1 and p27kip1) and apoptosis-related proteins (p53, survivin, caspase 3). Methods: Sprague-Dawley rats were given 120 ppm diethylnitrosamine (DEN) as a carcinogen and sequentially sacrificed. The expression of cell cycle and apoptotic related proteins were examined by light microscopy and immunohistochemistry. Results: During the DEN-induced hepatocarcinogenesis, sequential histologic changes from preneoplastic lesions (altered hepatic cellular foci, hyperplastic nodules, and hepatocellular adenomas) and ultimately overt hepatocellular carcinomas and metastatic lesions were noted. The cyclin D1 were progressively increased from preneoplastic lesions to hepatocellular carcinomas. However, the p27kip1 and the survivine proteins did not show any other difference with the increasing degree of carcinogenesis. The p53 and caspase 3 proteins were more significantly increased in hepatocellular carcinomas than preneoplastic lesions. The cyclin D1 protein expression did not show any correlation with the expression of p27Kip1 protein, but the p53 expression was related to the expression of survivin and caspase 3. Conclusion: From the above results, over-expression of cyclin D1 plays a role in the early and late stages of hepatocarcinogenesis. In addition p53 and caspase 3 might be useful markers for evaluating the risk of malignant transformation. (J Korean Surg Soc 2008;75:359-367)

Keywords

References

  1. Scherer E, Emmelot P. Kinetics of induction and growth of precancerous liver-cell foci, and liver tumor formation by diethylnitrosamine in the rat. Eur J Cancer 1975;11:689-96. https://doi.org/10.1016/0014-2964(75)90042-0
  2. Hartwell LH, Kastan MB. Cell cycle control and cancer. Science 1994;266:1821-8. https://doi.org/10.1126/science.7997877
  3. Wu MS, Shun CT, Sheu JC, Wang HP, Wang JT, Lee WJ, et al. Overexpression of mutant p53 and c-erbB-2 proteins and mutations of the p15 and p16 genes in human gastric carcinoma: with respect to histological subtypes and stages. J Gastroenterol Hepatol 1998;13:305-10. https://doi.org/10.1111/j.1440-1746.1998.01560.x
  4. Kamb A. Cell-cycle regulators and cancer. Trends Genet 1995;11:136-40. https://doi.org/10.1016/S0168-9525(00)89027-7
  5. Guo Y, Sklar GN, Borkowski A, Kyprianou N. Loss of the cyclin-dependent kinase inhibitor p27 (Kip1) protein in human prostate cancer correlates with tumor grade. Clin Cancer Res 1997;3:2269-74.
  6. Grossman D, McNiff JM, Li F, Altieri DC. Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol 1999;113:1076-81. https://doi.org/10.1046/j.1523-1747.1999.00776.x
  7. Li F, Ambrosini G, Chu EY, Plesicia J, Tognin S, Marchisio PC, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396:580-4. https://doi.org/10.1038/25141
  8. Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 2002;21:2613-22. https://doi.org/10.1038/sj.onc.1205353
  9. Maronpot RR, Montgomery CA Jr, Boorman GA, McConnell EE. National Toxicology Program nomenclature for hepatoproliferative lesions of rats. Toxicol Pathol 1986;14:263-73. https://doi.org/10.1177/019262338601400217
  10. Miyagawa S, Okada N, Takasaki Y, Iida T, Kitano Y, Yoshigawa K, et al. Expression of proliferating cell nuclear antigen/cyclin in human keratinocytes. J Invest Dermatol 1989;93:678-81. https://doi.org/10.1111/1523-1747.ep12319857
  11. Cox LS. Multiple pathways control cell growth and transformation: overlapping and independent activities of p53 and p21Cip1/WAF1/Sdi1. J Pathol 1997;183:134-40. https://doi.org/10.1002/(SICI)1096-9896(199710)183:2<134::AID-PATH960>3.0.CO;2-D
  12. Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 1992;119:493-501. https://doi.org/10.1083/jcb.119.3.493
  13. Grasl-Kraupp B, Ruttkay-Nedecky B, Műllauer L, Taper H, Huber W, Bursch W, et al. Inherent increase of apoptosis in liver tumors: implications for carcinogenesis and tumor regression. Hepatology 1997;25:906-12. https://doi.org/10.1002/hep.510250420
  14. Meki AR, Abdel-Ghaffar SK, El-Gibaly I. Aflatoxin B1 induces apoptosis in rat liver: protective effect of melatonin. Neuro Endocrinol Lett 2001;22:417-26.
  15. Sherr CJ. Cancer cell cycle. Science 1996;274:1672-7. https://doi.org/10.1126/science.274.5293.1672
  16. Pines J, Hunter T. Cyclins and cancer. II: cyclin D and cyclin dependant kinase inhibitors come of age. Cell 1994;79:573-82. https://doi.org/10.1016/0092-8674(94)90543-6
  17. Nishida N, Fukuda Y, Ishizaki K, Nakao K. Alteration of cell cycle-related genes in hepatocarcinogenesis. Histol Histopathol 1997;12:1019-25.
  18. Lloyd RV, Jin L, Qian X, Kulig E. Aberrenr p27kip1 expression in endocrine and other tumors. Am J Pathol 1997;150:401-7.
  19. Lane DP. Cancer. p53, guardian of genome. Nature 1992;358: 15-6. https://doi.org/10.1038/358015a0
  20. Sela B. Survivin: anti-apoptosis protein and a prognostic marker for tumor progression and recurrence. Harefuah 2002;141: 103-7, 123.
  21. Ito T, Shiraki K, Sugimoto K, Yamanaka T, Fujikawa K, Ito M, et al. Survivin promotes cell proliferation in human hepatocellular carcinoma. Hepatology 2000;31:1080-5. https://doi.org/10.1053/he.2000.6496
  22. Kumar S. Interleukin-1$\beta$-converting enzyme (ICE)-like protease in apoptosis. Trends Biochem Sci 1995;20:198-202. https://doi.org/10.1016/S0968-0004(00)89007-6
  23. Cryns V, Yuan J. Proteases to die for. Genes Dev 1998;12: 1551-70. https://doi.org/10.1101/gad.12.11.1551
  24. Tewari M, Quan LT, O`Rourke K, Desnoyers S, Zeng Z, Beidler DR, et al. Yama/CPP32beta, a mammalian homolog of CED-3, is a Crma-inhibitable protease that cleaves the death substrate poly (ADP-ribose) polymerase. Cell 1995;81:801-9. https://doi.org/10.1016/0092-8674(95)90541-3
  25. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatus A, Nagata S. A caspase-activated deoxyribonuclease (DNase) that degrades DNA during apoptosis, and its inhibitor ICAD (inhibitor of caspase-activated deoxyribonuclease). Nature 1998;391:43-50. https://doi.org/10.1038/34112
  26. Kothakota S, Azuma T, Reinhard C, Kippel A, Tang J, Chu K, et al. Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 1997;278:294-8. https://doi.org/10.1126/science.278.5336.294
  27. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995;80: 293-9. https://doi.org/10.1016/0092-8674(95)90412-3