Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Comparison of Immunohistochemical Expression of CBP(cAMP-responsive Element Binding Protein) Transcriptional Co-activator between Premalignant Lesions and Squamous Cell Carcinomas in the Lungs

전암성 폐병변 및 편평상피세포폐암 조직에서 CBP(cAMP-responsive Ele-ment Binding Protein) 전사 공동 활성인자의 면역조직화학적 발현양상의 비교

  • Shin, Jong Wook (Department of Internal Medicine, College of Medicine, Chung-Ang University) ;
  • Kim, Jin Soo (Department of Pathology, College of Medicine, Chung-Ang University) ;
  • Kim, Mi Kyung (Department of Pathology, College of Medicine, Chung-Ang University)
  • 신종욱 (중앙대학교 의과대학 내과학교실) ;
  • 김진수 (중앙대학교 의과대학 병리학교실) ;
  • 김미경 (중앙대학교 의과대학 병리학교실)
  • Received : 2007.05.03
  • Accepted : 2007.08.23
  • Published : 2007.08.30
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Abstract

Background: The pathogenesis of lung cancer includes the accumulation of multiple genetic abnormalities. The CREB-binding protein(CBP) is one of several transcriptional co-activators among various sequence-specific DNA-binding transcription factors. CBP is involved in a wide range of cellular activities, such as DNA repair, cell growth, differentiation, and apoptosis that are suspected of contributing to tumorigenesis. The goal of this study was to evaluate CBP expression in a series of human lung tissues containing normal epithelium, premalignant lesions(hyperplasia and dysplasia) and squamous cell carcinomas. Materials and Methods: Immunohistochemical staining was performed on formalin-fixed paraffin-embedded sections by use of a monoclonal anti-CBP antibody. CBP expression was compared in samples from 120 patients with premalignant and malignant histological types including 20 metaplastic specimens, 40 dysplastic specimens, and 60 squamous cell carcinomas in the lung. Results: CBP expression was seen in 35% (7/20) of the metaplastic specimens. 65% (26/40) of the dysplastic specimens, and 70% (42/60) of the squamous cell carcinomas (p<0.05). According to celluar atypism, CBP expression was 50% (10/20) of the low-grade dysplastic specimens and 80% (16/20) of the high-grade dysplastic specimens(p <0.01). By cellular differentiation, CBP expression was seen in 95% (19/20) of the well differentiated squamous cell carcinomas, 85% (17/20) of the moderately differentiated carcinomas and 30% (6/20) of the poorly differentiated lesions (p <0.05). Conclusion: These results suggest that CBP may have an important role in malignant transformation of precancerous lung lesions and may be a marker for malignancy.

폐암의 발생은 여러 많은 유전자의 변화가 축적되어 나타나는 일련의 과정에 의한다. 세포 내 전사 조절 인자의 하나인 CBP는 폐를 포함한 인체 내 여러 조직에서 상피세포의 분화 및 증식에 중요한 역할을 담당하며, 유전자들에서 전사조절인자로서 세포의 성장에 관여하며 발암 과정에서도 중요할 것으로 기대된다. 이에 아직까지 폐암에서 CBP에 대한 연구가 확정된 바가 없어, 폐의 전암성 병변(상피 화생 20예, 이형성증 40예) 및 편평상피세포폐암 60예를 대상으로 하여 CBP의 발현정도를 면역화학적 방법으로 비교 분석하여 다음과 같은 결과를 얻었다. 1) 화생성 병변(7예; 35%)에 비해 이형성 병변(26례; 65%)이나 편평세포암종(42례; 70%)에서 CBP의 발현이 유의하게 높았다(p<0.05). 2) 이형성 병변의 경우, 경도의 이형성 병변(20예 중 10예; 50%)보다 고도의 이형성 병변(20예 중 16예; 80%)에서 높은 CBP의 발현율을 보였다(p<0.01). 3) 편평세포암의 분화도별로 살펴보았을 때, 고분화암에서 95%(20예 중 19예), 중등도 분화암에서 85%(20예 중 17예), 저분화 암에서는 30%(20예 중 6예)의 발현율을 보였다(p<0.05). 이상과 같은 결과를 볼 때, CBP는 폐 조직에서 정상 기관지 상피 세포가 전암성 병변으로 변하거나 전암성 병변이 암으로 진행하는 과정에서 중요한 역할을 하는 것으로 보이며, 세포가 암으로의 발전할 수 있는 잠재성을 가늠하는 표지자가 될 수 있을 것으로 보인다.

Keywords

References

  1. Gazdar AF, Minna JD. Chapter 16, Molecular techniques of early detection of lung cancer and for studying preneoplasia. In: Pas HI, Carbone DP, Minna JD, Johnson DH, Turrisi AT III, editors. Lung cancer: principles and practice. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. p. 200-9
  2. Haber DA, Fearon ER. The promise of cancer genetics. Lancet 1998;351:SII1-8 https://doi.org/10.1016/S0140-6736(98)90326-9
  3. Harris AL Antiangiogenesis for cancer therapy. Lancet 1997;349:SII13-15
  4. Levitzki A. Targeting signal transduction for disease therapy. Curr Opin Cell Biol 1996;8:239-44 https://doi.org/10.1016/S0955-0674(96)80071-8
  5. Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science 1997;278:1043-50 https://doi.org/10.1126/science.278.5340.1043
  6. Karin M, Smeal T. Control of transcription factors by signal transduction pathways: the beginning of the end. Trends Biochem Sci 1992;17:418-22 https://doi.org/10.1016/0968-0004(92)90012-X
  7. Quinn PG. Distinct activation domains within cAMP response element-binding protein(CREB) mediate basal and cAMP-stinulated transcription. J Biol Chem 1993;268:16999-7009
  8. Sassone-Corsi P. Transcription factors responsive to cAMP. Annu Rev Cell Dev BioI 1995;11:355-77 https://doi.org/10.1146/annurev.cb.11.110195.002035
  9. Vo N, Goodman RH CREB-binding protein and p300 in transcriptional regulation. J Biol Chem 2001;276: 13505-8 https://doi.org/10.1074/jbc.R000025200
  10. Xu L, Lavinsky RM, Dasen JS, Flynn S, McInerney EM, Mullen TM, et al. Signal-specific co-activator domain requirements for Pit-1 activation. Nature 1998;395:301-6 https://doi.org/10.1038/26270
  11. Giordano A, Avantaggiati ML. p300 and CBP: partners for life and death. J Cell Physiol 1999;181:218-30 https://doi.org/10.1002/(SICI)1097-4652(199911)181:2<218::AID-JCP4>3.0.CO;2-5
  12. Grossman SR p300/CBP/p53 interaction and regulation of the p53 response. Eur J Biochem 2001;268:2773-8 https://doi.org/10.1046/j.1432-1327.2001.02226.x
  13. Ito A, Lai CH, Zhao X, Saito S, Hamilton MH, Appella E, et al. p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 2001;20:1331-40 https://doi.org/10.1093/emboj/20.6.1331
  14. Gu W, Roeder RG. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997;90:595-606 https://doi.org/10.1016/S0092-8674(00)80521-8
  15. Avantaggiati ML, Ogryzko V, Gardner K, Giordano A, Levine AS, Kelly K. Recruitment of p300/CBP in p53-dependent signal pathways. Cell 1997;80:1175-84
  16. Gu W, Shi XL, Roeder RG. Synergistic activation of transcription by CBP and p53. Nature 1997;387: 819-23 https://doi.org/10.1038/42972
  17. Lill NL, Grossman SR, Ginsberg D, DeCaprio J, Livingston DM Binding and modulation of p53 by p300/CBP coactivators. Nature 1997:387;823-7 https://doi.org/10.1038/42981
  18. Pao GM, Janknecht R, Ruffner H, Hunter T, Verma 1M CBP/p300 interact with and function as transcriptional coactivators of BRCA1. Proc Natl Acad Sci USA 2000;97:1020-5
  19. Borrow J, Stanton VP Jr, Andresen JM, Becher R, Behm FG, Chaganti RS, et al. The translocation t(8;16)(P11;p13) of acute myelogenous leukemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet 1996;14:33-41 https://doi.org/10.1038/ng0996-33
  20. Rowley JD, Reshmi S, Sobulo O, Musvee T, Anastasi J, Raimondi S, et al. All patients with the T(11;16) (q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Blood 1997;90:535-41
  21. Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B, et al. MLL is fused to CBP, a histoneacetyl transferase, intherapy-related acutemyeloid leukemia with a t(11;16)(q23;p13.3). Proc Natl Acad Sci USA 1997;94:8732-7 https://doi.org/10.1073/pnas.94.16.8732
  22. Kitabayashi I, Yokoyama A, Shimizu K, Ohki M Interaction and functional cooperation of the leukemiaassociated factors AML1 and p300 in myeloid cell differentiation. EMBO J 1998;17:2994-3004 https://doi.org/10.1093/emboj/17.11.2994
  23. Huang S, Qiu Y, Stein RW, Brandt SJ. p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein. Oncogene 1999;18:4958-67 https://doi.org/10.1038/sj.onc.1202889
  24. Arias J, Alberts AS, Brindle P, Claret FX, Smeal T, Karin M, et al. Activation of cAMP an mitogen responsive genes relies on a common nuclear factor. Nature 1994;370:226-9 https://doi.org/10.1038/370226a0
  25. Bannister AJ, Oehler T, Wilhelm D, Angel P, Kouzarides T. Stimulation of c-Jun activity by CBP: c-Jun residues Ser63/73 are required for CBP induced stimulation in vivo and CBP binding in vitro. Oncogene 1995;11:2509-14
  26. Bannister AJ, Kouzarides T. CBP-induced stimulation of c-Fos activity is abrogated by E1A. EMBO J 1995;14:4758-62
  27. Dai P, Akimaru H, Tanaka Y, Hou DX, Yasukawa T, Kanei-Ishii C, et al. CBP as a transcriptional coactivator of c-Myb. Genes Dev 1996;10:528-40 https://doi.org/10.1101/gad.10.5.528
  28. Trouche D, Cook A, Kouzarides T. The CBP coactivator stimulates E2F1/DP1 activity. Nucleic Acids Res 1996;24:4139-45 https://doi.org/10.1093/nar/24.21.4139
  29. Krecicki T, Jelen M, Zalesska-krecicka M, Szkudlarek T, Szajowski K Immunohistochemically stained markers (p53, PCNA, bcl-2) in dysplastic lesions of the larynx. Cancer Lett 1999;143:23-8 https://doi.org/10.1016/S0304-3835(99)00174-3
  30. Karamouzis MV, Papadas T, Varakis I, Sotiropoulou-Bonikou G, Papavassiliou AG. Induction of the CBP transcriptional co-activator early during laryngeal carcinogenesis. J Cancer Res Clin Oncol 2002;128:135-40 https://doi.org/10.1007/s00432-001-0317-y
  31. Goodman RH, Smolik S. CBP/p300 in cell growth, transformation and development. Genes Dev 2000;14: 1553-77
  32. Kishimoto M, Kohno T, Okudela K, Otsuka A, Sasaki H, Tanabe C, et al. Mutations and deletions of the CBP gene in human lung cancer. Clin Cancer Res 2005;11:512-9
  33. Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an important mechanism in inflammatory lung diseases. COPD 2005;2:445-55 https://doi.org/10.1080/15412550500346683
  34. Huang WC, Ju TK, Hung MC, Chen CC. Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol Cell 2007;26:75-87 https://doi.org/10.1016/j.molcel.2007.02.019
  35. Gorgoulis VG, Zacharatos P, Mariatos G, Kotsinas A, Bouda M, Kletsas D, et al. Transcription factor E2F-1 acts as a growth-promoting factor and is associated with adverse prognosis in non-small cell lung carcinomas. J Pathol 2002;198:142-56 https://doi.org/10.1002/path.1121