Immunohistochemical Expression of Nuclear Retinoid Receptor and CREB(cAMP Response Element Binding Protein) in Lung Cancers

폐암종에서 Nuclear Retinoid Receptor 및 CREB의 면역조직화학적 발현 양상

  • Shin, Jong Wook (Department of internal Medicine, Chung-Ang University) ;
  • Gi, Seung-Seok (Department of Pathology, Chung-Ang University) ;
  • Paik, Kwang Hyun (Department of Internal Medicine, Korea Cancer Center Hospital) ;
  • Choi, Won (Department of Internal Medicine, Korea Cancer Center Hospital) ;
  • Park, In Won (Department of internal Medicine, Chung-Ang University) ;
  • Kim, Mi Kyung (Department of Pathology, Chung-Ang University)
  • 신종욱 (중앙대학교 의과대학 내과학교실) ;
  • 기승석 (중앙대학교 의과대학 병리학교실) ;
  • 백광현 (원자력병원 내과) ;
  • 최원 (원자력병원 내과) ;
  • 박인원 (중앙대학교 의과대학 내과학교실) ;
  • 김미경 (중앙대학교 의과대학 병리학교실)
  • Received : 2005.09.13
  • Accepted : 2005.10.05
  • Published : 2005.12.30

Abstract

Background : Transcriptional factors of the CREB(cAMP Response Element Binding Protein) are involved in the regulation of gene expression in response to a variety of signaling pathways. Proteins produced by the CREB genes play key roles in many physiological processes, including memory and long-term potentiation. The retinoic acid receptor (RAR) axis mediates epithelial cell differentiation and proliferation in many tissues including the lung. Material and method : The RAR and CREB expression levels were examined in 60 adenocarcinomas and 60 squamous cell carcinomas of the lung using immunohistochemical staining. Results : 1) RAR protein expression was found in 58.3%(35/60) of adenocarcinomas and 36.7%(22/60) of squamous cell carcinomas(P<0.05). 2) RAR protein expression was found in 80%(16/20) of well differentiated adenocarcinomas, 60%(12/20) of moderately differentiated adenocarcinomas, and 35%(7/20) of poorly differentiated adenocarcinomas (P<0.01). 3) RAR protein expression was found in 45%(9/20) of well differentiated squamous cell carcinomas, 35%(7/20) of moderately differentiated squamous cell carcinomas, and 30%(6/20) of poorly differentiated squamous cell carcinomas (P>0.05). 4) CREB expression was found in 61.7%(37/60) of adenocarcinomas and 40%(24/60) of squamous cell carcinomas( P<0.05). 5) CREB expression was found in 85%(17/20) of well differentiated adenocarcinomas, 60%(12/20) of moderately differentiated adenocarcinomas, and 40%(8/20) of poorly differentiated adenocarcinomas (P<0.01). 6) CREB expression was found in 45%(9/20) of well differentiated squamous cell carcinomas, 35%(7/20) of moderately differentiated squamous cell carcinomas, and 35%(8/20) of poorly differentiated squamous cell carcinomas(P>0.05). 7) RAR and CREB expression was found in 68.5% of lung cancers, and there was a significant correlation between them(P<0.05). Conclusion : RAR and CREB expression can be used to indirectly determine the malignant potentiality of a cell.

배 경 : 폐를 포함한 인체내 여러 조직에서 상피세포의 분화 및 증식에 중요한 역할을 담당한다고 알려진 Retinoid acid(RA)와 여러 유전자들에서 전사조절인자로 성장관여 유전자들의 활성화에 관여하며 세포증식 및 분화에 매우 중요한 세포내 조절인자인 cAMP response-element binding protein(CREB)의 폐암종에서의 발현정도를 알아보고 조직학적 차이에 따른 발현도를 비교분석하여 발암과정에서의 관여여부와 역할을 파악하고자 하였다. 방 법 : 중앙대학교 의과대학 부속병원에서 최근 10년간 시행한 기관지내시경 및 흉부외과적 적출을 통해 얻어진 폐암종 조직중 파라핀 포매의 보관상태가 양호한 120예(선암종 60예, 편평세포암종 60예)를 연구대상으로 면역조직화학적 염색을 시행하였다. 결 과 : RAR과 CREB 모두 편평세포암종에 비해 선암종에서 발현이 의의있게 높았고(P<0.05) 선암종에서는 조직학적으로 분화도가 좋을수록 높은 발현율을 보였다(P<0.01). 총 120예의 폐암종에서 RAR과 CREB의 발현을 비교하면 65.8%의 동시발현율을 나타냈다(P<0.05) 결 론 : RAR과 CREB은 폐조직에서 점액상피세포의 분화와 상관관계가 있으며 편평세포암종보다는 선암종의 발암과정에서 일부 의미있는 역할을 수행하리라 생각되었다. 또한 RAR과 CREB의 발현부위도 통계적으로 의미 있는 일치양상을 나타내어 이들은 서로 상호작용에 의해 발암과정 중 일부 역할을 수행하리라 생각된다.

Keywords

References

  1. Westra WH, Offerhaus JG, Goodman SN, Slebos RJ, Polak M, Baas IO, et al. Overexpression of p53 tumor suppressor gene product in lung adenocarcinoma is associated with cigaretted smoking. Am J Surg Pathol 1993;17:213-20 https://doi.org/10.1097/00000478-199303000-00001
  2. Weiberg RA. Molecular biology of carcinogenesis:a multistep process. In: Broder S, editors. Molecular foundation of oncology. Baltimore: Williams; 1991. p. 27-39
  3. Bogue CW, Jacobs HC, Dynia DW, Wilson CM, Gross I. Retinoic acid increases surfactant protein mRAN in fetal rat lung in culture. Am J Physiol 1996;271:L862-8
  4. Zou L, Lim L, Costa RH, Whitsett JA. Thyroid transcription factor-1, hepatocyte nuclear factor-3beta, surfactant protein B, C, and Clara cell secretory protein in developing mouse lung. J Histochem Cytochem 1996;44:1183-93 https://doi.org/10.1177/44.10.8813084
  5. Yan C, Ghaffari M, Whitsett JA, Zeng X, Sever Z, Lin S. Retinoic acid-receptors activation of SP-B gene transcription in respiratory epithelial cells. Am J Physiol 1998;275:L239-46 https://doi.org/10.1152/ajpcell.1998.275.1.C239
  6. Shenai JP, Chytil F, Stahlman MT. Vitamin A status of neonates with bronchopulmonary dysplasia. Pediatr Res 1985;19:185-8 https://doi.org/10.1203/00006450-198502000-00007
  7. Shenai JP, Kennedy KA, Chyti F, Stahlman MT. Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia. J Pediatr 1987;111:269-77 https://doi.org/10.1016/S0022-3476(87)80086-0
  8. Metzler MD, Snyder JM. Retinoic acid differentially regulates expression of surfactant-associated proteins in human fetal lung. Endocrinology 1993;133:1990-8 https://doi.org/10.1210/en.133.5.1990
  9. Mendelsohn C, Lohnes D, Decimo D, Lufkin T, Chambon P, Mark M. Function of the retinoic acid receptors(RARs) during development(II): mltiple abnormalities at various stages of organogenesis in RAR double mutants. Development 1994;120:2749-71
  10. Naltner A, Ghaffari M, Whitsett JA, Yan C. Retinoic acid stimulation of surfactant-associated protein B promoter is thyroid transcription factor 1 site-dependent. J Biol Chem 2000;275:56-62 https://doi.org/10.1074/jbc.275.1.56
  11. de Cesare D, Jacquot S, Hanauer A, Sassone-Corsi P. Rsk-2 activity is necessary for epidermal growth factor- induced phosphorylation of CREB protein and transcription of c-fos gene. Proc Natl Acad Sci U S A 1998;95:12202-7
  12. Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell 1995;83:841-50 https://doi.org/10.1016/0092-8674(95)90200-7
  13. George TN, Snyder JM. Regulation of surfactant protein gene expression by retinoic acid metabolites. Pediatr Res 1997;41:692-701 https://doi.org/10.1203/00006450-199705000-00015
  14. George TN, Miakotina OL, Gross KL, Snyder JM. Mechanism of all trans-retinoic acid and glucocorticoid regulation of surfactant protein mRNA. Am J Physiol 1998;274:L560-6
  15. Atochina EN, Beers MF, Scanlon ST, Preston AM, Beck JM. P. carinii induces selective alterations in component expression and biophysical activity of lung surfactant. Am J Physiol 2000;278;L599-609
  16. Benbrook DM, Jones NC. Heterodimer formation between CREB and JUN proteins. Oncogene 1990;5:295-302
  17. Desdouets C, Matesic G, Molina CA, Foulkes NS, Sassone- Corsi P, Brechot C, Sobczak-Thepot. Cell cycle regulation of cyclin A gene expression by the cyclic AMP-responsive transcription factors CREB and CREM. Mol Cell Biol 1995;15:3301-9 https://doi.org/10.1128/MCB.15.6.3301
  18. Hai T, Curran T. Cross-family dimerization of transcription factors Fos/Jun and AFT/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A 1991; 88:3720-4
  19. Montminy M. Transcriptional regulation by cyclic AMP. Annu Rev Biochem 1997;66:807-22 https://doi.org/10.1146/annurev.biochem.66.1.807
  20. Kari 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
  21. Naltner A, Wert S, Whitsett JA, Yan C. Temporal/spatial expression of nuclear receptor coactivators in the mouse lung. Am J Physiol Lung Cell Mol Physiol 2000;279:L1066-74 https://doi.org/10.1152/ajplung.2000.279.6.L1066
  22. Kruyt F, Folkers G, van den Brink CE, van den Saag PT. A cyclic AMP response element is involved in retinoic acid-dependent RAR $\beta$2 promoter activation. Nucleic Acids Res 1992;20:6393-9 https://doi.org/10.1093/nar/20.23.6393
  23. Naltner A, Ghaffari M, Whitsett JA, Yan C. Retinoid acid stimulation of the human surfactant protein B promoter is thyroid transcription factor 1 site-dependent. J Biol Chem 2000;275:56-62 https://doi.org/10.1074/jbc.275.1.56
  24. Dietze EC, Caldwell LE, Marcom K, Collins SJ, Yee L, Swisshelm K, et al. Retinoids and retinoic acid receptors regulate growth arrest and apoptosis in human mammary epithelial cells and modulate expression of CBP/p300. Microsc Res Tech 2002;59:23-40 https://doi.org/10.1002/jemt.10174
  25. Vienonen A, Miettinen S, Manninen T, Altucci L, Wilhelm E, Ylikomi T. Regulation of nuclear receptor and cofactor expression in breast cancer cell lines. Eur J Endocrinol 2003;148:469-79 https://doi.org/10.1530/eje.0.1480469
  26. Kyakumoto S, Kito N, Sato N. Expression of cAMP response element binding protein (CREB)-binding protein (CBP) and the implication in retinoic acid-inducible transcription activation in human salivary gland adenocarcinoma cell line HSG. Endocr Res 2003;29:277-89 https://doi.org/10.1081/ERC-120025035