식도 편평세포암 환자에서 Cyclin B1, p53의 발현과 예후

Prognostic Significance of Cyclin B1 and p53 Expression in Patient with Esophageal Squamous Cell Carcinoma

  • 김치학 (고신대학교 의과대학 흉부외과학교실) ;
  • 조봉균 (고신대학교 의과대학 흉부외과학교실) ;
  • 천봉권 (고신대학교 의과대학 병리학교실) ;
  • 조성래 (고신대학교 의과대학 흉부외과학교실)
  • 발행 : 2003.12.01

초록

p53은 cyclin Bl을 통해 세포주기 중 G2-M checkpoint 이행을 조절하는 것으로 알려져 있으며 이것은 p53이 여러 종류의 악성종양의 생성과 진행에 중요한 역할을 하는 것을 암시한다. 본 연구의 목적은 식도 편평세포암 환자에서 세포주기 조절인자인 cyclin Bl과 p53의 역할을 규명하는 데 있다. 대상 및 방법: 46예의 식도 편평세포암 환자에서 채취한 정상 편평상피, 이형성 조직과 암조직에서 면역조직화학검사를 이용하여 cyclin Bl과 p53의 발현을 조사하고 임상병리학적인 인자 및 생존율과의 상관관계를 분석하였다. 결과: 정상상피의 기저층에 있는 몇 개의 세포들에서 cyclin Bl이 발현되었다. Cyclin Bl 양성세포의 범위는 이형성증의 정도가 심해질수록 증가하였다. Cyclin Bl의 양성율은 41.3% (19예/46예)였고 p53의 양성 발현율은 58.7% (27예/46예)였다. 임상병리학적 인자들 중 병기(p<0.05), 식도 주위 림프절 전이(p=0.05), 림프혈관 침범(p<0.05)만이 cyclin Bl의 발현과 관련이 있었고 단변량분석과 다변량분석에서 cyclin Bl의 발현은 예후불량과 관련이 있었다. p53의 발현은 cyclin Bl의 발현과는 상관관계가 있었으나, 임상병리학적 인자들과 예후와는 무관하였다. 결론: 이상의 결과로 cyclin Bl은 식도암의 생성에 관여함을 알 수 있었고 식도 편평세포암 환자에서 cyclin Bl의 발현은 불량한 예후를 나타내며 술 후 보강 항암요법을 시행함으로써 생존율의 향상에 기여할 수 있을 것으로 생각된다.

It has been reported that p53 regulates the G2-M checkpoint transition through cyclin Bl, and it has been suggested that p53 plays an important role in the development and progression of various malignancies. The aim of this study is to clarify the role of the cell cycle regulators, cyclin B1 and p53 in patients with esophageal squamous cell carcinoma (ESCC). Material and Method: Tissue samples from 46 patients with ESCC were included in this study. Expression levels of cyclin Bl and p53 in samples of normal squamous epithelium, dysplasia, and tumor cells from patients with ESCC were analyzed by immunohistochemical study Result: Several cells in the basement layer of normal epithelium expressed cyclin B1. The number of cyclin B1 positive cells tended to increase as the degree of dysplasia increased from low grade to high grade. More than 10% of tumor cells were cyclin B1 positive in 19 patients (41.3%). Several clinicopathologic parameters, including tumor stage (p<0.05), pathologic Iymph node status (p<0.05) and invasion of Iymphatic vessels (p<0.05), were correlated with the overexpression of cyclin B1. Elevated expression levels of cyclin B1 also correlated with a poor prognosis in patient with ESCC in univariate analysis (p<0.05) and multivariate analysis (p<0.05), In contrast, p53 expression exhibited significant correlation with the level of cyclin B1 expression, but was not associated with prognostic parameters in patients with ESCC. Conclusion: These findings suggest that cyclin B1 is involved in the pathogenesis of carcinoma of the esophagus and that elevated levels of cyclin B1 expression, but not p53 expression, may indicate a poor prognosis for patients with ESCC.

키워드

참고문헌

  1. Int J Cancer v.83 Estimates of the world-wide mortality from 25 cancers in 1990 Pisani,P.;Parkin,D.M.;Bray,F.;Ferlay,J.
  2. Cancer v.83 p53 sequence analysis predicts treatment response and outcome of patients with esophageal carcinoma Ribeiro,U.Jr.;Finkelstein,S.D.;SafatleRibeiro,A.V.(et al.) https://doi.org/10.1002/(SICI)1097-0142(19980701)83:1<7::AID-CNCR2>3.0.CO;2-R
  3. Cancer v.86 Prognostic significance of biologic factors in squamous cell carcinoma of esophagus Ikeda,G.;Isaji,S.;Chandra,B.;Watanabe,M.;Kawarada,Y. https://doi.org/10.1002/(SICI)1097-0142(19991015)86:8<1396::AID-CNCR3>3.0.CO;2-H
  4. Int J Cancer v.74 prevalance and predictive value of p53 mutation in patients with esophageal squamous cell carcinoma; a prospective clinicopathplogical study and survival analysis of 70 partients Lam,K.Y.;Tsao,S.W.;Zhang,D.(et al.) https://doi.org/10.1002/(SICI)1097-0215(19970422)74:2<212::AID-IJC13>3.0.CO;2-F
  5. Cancer v.79 p53 protein accumulation and p53 gene mutation in esophageal carcinoma. A molecular and immunohistochemical study with clinicopathological correlations Coggi,G.;Bosari,S.;Roncalli,M.(et al.) https://doi.org/10.1002/(SICI)1097-0142(19970201)79:3<425::AID-CNCR1>3.0.CO;2-H
  6. J Surg Oncol v.72 No prognostic significance of p53 expression in esophageal squamous cell carcinoma Kanamoto,A.;Kato,H.;Tachimori,Y.(et al.) https://doi.org/10.1002/(SICI)1096-9098(199910)72:2<94::AID-JSO10>3.0.CO;2-9
  7. Oncogene v.18 Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45 Zhan,Q.;Antinore,M.J.;Wang,X.W.(et al.) https://doi.org/10.1038/sj.onc.1202667
  8. Proc Natl Acad Sci USA v.96 GADD45 induciton of a G2/M cell cycle checkpoint Wang,W.;Zhan,Q.;Coursen(et al.) https://doi.org/10.1073/pnas.96.7.3706
  9. Proc Natl Acad Sci USA v.96 p53 regulates a G2 checkpoint through cyclin B1 Innocente,S.A.;Abrahamson,J.L.;Cogswell,J.P.;Lee,J.M. https://doi.org/10.1073/pnas.96.5.2147
  10. Br J Cancer v.82 p53-dependent G2 arrest associated with a decrease in cyclin A2 and B1 levels in a human carcinoma cell line Badie,C.;Bourhis,J.;SobczakThepot,J.(et al.) https://doi.org/10.1054/bjoc.1999.0976
  11. Cancer Res v.60 Constitutive activation of cyclin B1-associated cdc2 kinase overrides p53-mediated G2-M arrest Park,M.;Chae,H.D.;Yun,J.(et al.)
  12. Am J Pathol v.150 Expression of the G2-M checkpoint regulators cyclin B1 and cdc2 in nonmalignant and malignant human breastlesions, immunocytochemical and quantitative image analyses Kamamoto,H.;Kozumi,H.;Uchikoshi,T.
  13. Cancer Res v.60 Overexpression of cyclin B1 in carly-stage non-small cell lung cancer and itsclinical implication Soria,J.C.;Jang,S.J.;Khuri,F.R.(et al.)
  14. Arch pathol Lab Med v.124 Overexpression of cyclin A and cyclin B1 proteins in astrocytomas Allan,K.;Jordan,R.C.;Ang,L.C.;Taylor,M.;Young,B.
  15. Mod Pathol v.11 Prognostic factors in gastric cancer Brien,T.P.;Depowski,P.L.;Sheehan,C.E.;Ross J.S.;McKenna,B.J.
  16. Cancer v.85 The prognostic significance of proliferation-associated nucleolar protein p120 expression in prostate adenocarcinoma; a comparison with cyclins A and B1, ki-67, proliferating cell nuclear antigen, and p34cdc2 Kallakury,B.V.;Sheehan,C.E.;Rhee,S.J.(et al.) https://doi.org/10.1002/(SICI)1097-0142(19990401)85:7<1569::AID-CNCR19>3.0.CO;2-M
  17. Virchows Arch v.434 Determination of the prognostic significance of cyclin b1 overexpression in patients with esophageal squamous cell carcinoma Murakami,H.;Furihata,M.;Ohtsuki,Y.;Ogoshi,S. https://doi.org/10.1007/s004280050319
  18. Cnacer v.94 Prognostic value of cyclin B1 in patient with esophageal squamous cell carcinoma Takeno,S.;Noguchi,T.;Kikuchi,R.;Uchida,Y.;Yokoyama,S.;Muller,W. https://doi.org/10.1002/cncr.10542
  19. Int J Cancer v.77 Cellular kinetic differences beween Hodgkin's and anaplastic large cell lymphomas; relatin to the expression of p34cdc2 and cyclin B1 Leoncini,L.;Megha,T.;Lazzi,S.(et al.) https://doi.org/10.1002/(SICI)1097-0215(19980729)77:3<408::AID-IJC17>3.0.CO;2-3
  20. AnticancerRes v.19 Expression of the G2-M checkpoint regulators cyclin B1 and P34CDC2 in breast cancer; a correlation with cellular kinetics Megha,T.;Lazzi,S.;Ferrari,F.(et al.)
  21. UICC TNM classification of malignant tumours (5th ed) Sobin,L.H.;Wittekind,C.(ed.)
  22. Surg Today v.27 Expression of PCNA and p53 in esophageal dysplasia and esophageal carcinoma Murakami,S.;Uchida,Y.;Takeno,S.;Noguchi,T.;Matsumoto,K.;Shimoda,H. https://doi.org/10.1007/BF02388213
  23. Hepatology v.25 immune response to cyclin B1 in hepatocellualr carcinoma Covini,G.;Chan,E.K.;Nisshioka,M.;Morshed,S.A.;Reed,S.I.;Tan,E.M. https://doi.org/10.1002/hep.510250114