KOLOREKTAL ADENOMLAR VE ADENOKARSİNOMLARDA HÜCRE SİKLUSUNU DÜZENLEYEN PROTEİNLERİN VE APOPİTOZLA İLGİLİ BELİRTEÇLERİN EKSPRESYONU
AMAÇ:Tümör gelişimi proliferasyon, büyümede durma ve hücre ölümü arasındaki denge ile düzenlenir. Buçalışmada, kolon karsinomunun gelişimindeki rollerinin değerlendirilmesinde p27, siklin D1, bcl-2 ve bcl-xexpresyonunu inceledik.GEREÇ ve YÖNTEM:p27, siklin D1, bcl-2 ve bcl-x expresyonunun düzeyleri, adenomlara komşu normalmukozada (n=30), adenomlarda (n=30), adenokarsinomlara komşu normal mukozada (n=63),adenokarsinomlarda (n=63) ve metastazlarda (n=16) immünohistokimyasal olarak incelendi. İmmün boyamaiçin standart streptavidin-biotin immünperoksidaz metodu kullanıldı ve boyanan slaytlar yarı kantitatif kriterlerkullanarak mikroskopik olarak incelendi.BULGULAR:Normal mukozada p27 protein ekspresyonu saptandı, adenokarsinomlar ise bu proteinekspresyonunda azalma gösterdi. p27 ekspresyonunda azalma tümör progresyonu ile ilişkili idi (p=0,026). SiklinD1 boyaması adenokarsinom ve metastazların çoğunda belirgindi (p=0,042). Bu arada, p27 ve siklin D1ekspresyonu arasında herhangi bir ilişki saptamadık. Bcl-2 ve bcl-x ekspresyonu da tümör progresyonundaistatistiksel olarak belirgin anlamlılık göstermedi.SONUÇ:Bu çalışmanın sonucu p27 ve siklin D1 protein düzeylerinin kolon kanserinin progresyonunundaönemli rolü olduğunu göstermektedir. Bcl-2 ve bcl-x ekspresyonunun ise rolü saptanmamıştır
Kolorektal Adenomlar ve Adenokarsinomlarda Hücre Siklusunu Düzenleyen Proteinlerin ve Apopitozla Ilgili Belirteçlerin Ekspresyonu
OBJECTIVE: Tumor growth is regulated by a balance between proliferation, growth arrest and cell death. In this study, we have examined the expression of p27, cyclin D1, bcl-2, and bcl-x for evaluation of their roles in colon carcinoma progression. MATERIALS and METHODS: The levels of p27, cyclin D1, bcl-2, and bcl-x expression were examined by immunohistochemistry in transitional normal mucosa adjacent to adenomas (n=30), adenomas (n=30), transitional normal mucosa adjacent to adenocarcinomas (n=63), adenocarcinomas (n=63) and metastasis (n=16). Standard streptavidin-biotin immunperoxidase method was used for immunostaining and the stained slides were examined microscopically using semiquantitative criteria. RESULTS: Normal mucosa expressed p27 protein and adenocarcinomas displayed a decrease in the expression of this protein. Decreased expression of p27 was associated with tumor progression (p=0.026). Cyclin D1 staining was prominent in most of the adenocarcinomas and metastasis (p=0.042). Meanwhile, we could not find any relation between p27 and cyclin D1 expression. Bcl-2 and bcl-x expression also did not show any statistically significant correlation in tumor progression. CONCLUSION: The results of this study indicate that reduced p27 and cyclin D1 protein levels play an important role in progression of colon cancer. Bcl-2, and bcl-x expression were of no role.
___
- 1. Rosai J. Rosai and Ackerman's Surgical Pathology, Vol
1, 9th ed. Mosby, Elsevier, Philadelphia, USA,
2004;776-855.
- 2. Michalides RJAM. Cell cycle regulators: mechanisms
and their role in aetiology, prognosis, and treatment of
cancer. J Clin Pathol 1999;52:555-68.
- 3. Fredersdorf S, Burns J, Milne AM, Packham G, Fallis
L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby
AM, Barnes DM, Shousha S, O'Hare MJ, Lu X. High
level expression of p27kip1 and cyclin D1 in some
human breast cancer cells: inverse correlation between
the expression of p27/kip1 and degree of malignancy in
human breast and colorectal cancers. Proc Natl Acad
Sci 1997;94:6380-5.
- 4. Holland TA, Elder J, McCloud JM, et al. Subcellular
localisation of cyclin D1 protein in colorectal tumors is
associated with p21 WAF1/CIP1 expression and
correlates with patient survival. Int J Cancer
2001;95:302-6.
- 5. Arber N, Hibshoosh H, YasuiW, NeugutAI, Hibshoosh
A, Yao Y, Sgambato A, Yamamato H, Shapira I,
Rosenman D, Fabian I, Weinstein IB, Tahara E, Hult
PR. Abnormalities in the expression of cell cyclerelated
proteins in tumors of the small bowel. Cancer
Epidemiol Biomarkers Prev 1999;8:1101-5.
- 6. Mineta H, Miura K, Suzuki I, et al. Low p27 expression
correlates with poor prognosis for patients with oral
tongue squamous cell carcinoma. Cancer
1999;85:1011-7.
- 7. Culhaci N, Sagol O, Karademir S, Astarcioglu H,
Astarcioglu I, Soyturk M, Oztop I, Obuz F. Expression
of transforming growth factor-beta-1 and p27 in
pancreatic adenocarcinomas: relation with cell-cycleassociated
proteins and clinicopathologic
characteristics. BMC Cancer 2005;5:98.
- 8. Yang RM, Naitoh J, Murphy M, et al. Low p27
expression predicts poor disease-free survival in
patients with prostate cancer. J Urol 1998;159:941-5.
- 9. Belluco C, Esposito G, Bertorelle R, Mistro A, Fassina
A Vieceli G, Chieco-Bianchi L, Nitti D, Lise M.
Absence of the cell cycle inhibitor p27Kip1 protein
predicts poor outcome in patients with stage I-III
colorectal cancer.Ann Surg Oncol 1999;6:19-25.
- 10. Tornillo L, Lugli A, Zlobec I, Willi N, Glatz K,
Lehmann F, Spichtin HP, Maurer R, Stoios D, Sauter G,
Terracciano L. Prognostic value of cell cycle and
apoptosis regulatory proteins in mismatch repairproficient
colorectal cancer: a tissue microarray-based
approach.Am J Clin Pathol 2007;127:114-23.
- 11. Thomas GV, Szigeti K, Murphy M, Draetta G, Pagano
M, Loda M. Down-regulation of p27 is associated with
development of colorectal adenocarcinoma metastases.
Am J Pathol 1998;153:681-7.
- 12. Hershko DD, Shapira M. Prognostic role of p27/Kip1
deregulation in colorectal cancer. Cancer
2006;107:668-75.
- 13. Chetty R. p27 protein and cancers of the
gastrointestinal tract and liver: an overview. J Clin
Gastroenterolog 2003;37:23-7.
- 14. Palmqvist R, Stenling R, Oberg A, Landberg G.
Expression of cyclin D1 and retinoblastoma protein in
colorectal cancer. Eur J Cancer 1998;34:1575-81.
- 15. Sheyn I, Noffsinger AE, Heffelfinger S, Davis B,
Miller MA, Fenoglio-Preiser CM. Amplification and
expression of the cyclin D1 gene in anal and esophageal
squamous cell carcinomas. Hum Pathol 1997;28:270-
6.
- 16. Bondi J, Bukholm G, Nesland JM, Bukholm IR.
Expression of non-membranous beta-catenin and
gamma-catenin, c-Myc and cyclin D1 in relation to
patient outcome in human colon adenocarcinomas.
APMIS 2004;112:49-56.
- 17. Cheah PY, Choo PH, Yao J, Eu KW, Seow-Choen F. A
survival-stratification mo
. Cancer
2002;95:2479-86.
- 18. Bukholm IK, Nesland JM. Protein expression of p53,
p21(WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in
human colon carcinomas. Virchows Arch
2000;436:224-8.
- 19. Kristt D, Turner I, Koren R, Ramadan E, Gal R.
Overexpression of cyclin D1 mRNA in colorectal
carcinomas and relationship to clinicopathological
features: an in situ hybridization analysis. Pathol Oncol
Res 2000;6:65-70.
- 20. Hur K, Kim JR, Yoon BI, Lee JK, Choi JH, Oh GT, Kim
DY. Overexpression of cyclin D1 and cyclin E in 1,2-
dimethylhydrazine dihydrochloride-induced rat colon
carcinogenesis. J Vet Sci 2000;1:121-6.
- 21. McKay JA, Douglas JJ, Ross VG, Curran S,Ahmed FY,
Loane JF, Murray GI, McLeod HL. Expression of cell
cycle control proteins in primary colorectal tumorsdoes not always predict expression in lymph node
metastases. Clin Cancer Res 2000;6:1113-8.
- 22. McKay JA, Douglas JJ, Ross VG, Curran S, Murray GI,
Cassidy J, McLeod HL. Cyclin D1 protein expression
and gene polymorphism in colorectal cancer. Int J
Cancer 2000;88:77-81.
- 23. Otori K, Sugiyama K, Fukushima S, Esumi H.
Expression of cyclin D1 gene in rat colorectal aberrant
crypt foci and tumors induced by azoxymethane.
Cancer Lett 1999;140:99-104.
- 24. Kim WB, Han HJ, Lee HJ, Park SS, Song TJ, Kim HK,
Suh SO, Kim YC, Choi SY. Expression and clinical
significance of cell cycle regulatory proteins in
gallbladder and extrahepatic bile duct cancer. Ann Surg
Oncol 2009;16:23-34.
- 25. Del Pizzo JJ, Borkowski A, Jacobs SC, et al. Loss of
cell cycle regulators p27 and cyclin E in transitional
cell carcinoma of the bladder correlates with tumor
grade and patient survival. Am J Pathol
1999;155:1129-36.
- 26. Armengol C, Boix L, Bachs O, et al. p27 is an
independent predictor of recurrence after surgical
resection in patients with small hepatocellular
carcinoma. J Hepatol 2003;38:591-7.
- 27. Biroccio A, Benassi B, D'Agnano I, D'Angelo C,
Buglioni S, Mottolese M, Ricciotti A, Citro G,
Cosimelli M, Ramsay RG, Calabretta B, Zupi G. c-Myc
and bcl-x overexpression predicts poor prognosis in
colorectal cancer.Am J Pathol 2001;158:1289-99.
- 28. Palazzo JP, Kafka NJ, Grasso L, Chakrani F, Hanau C,
Cuesta KH, Mercer WE. The role of p53, p21
WAF1/CIPI, and bcl-2 in radioresistantcolorectal
carcinoma. Hum Pathol 1997;28:1189-95.
- 29. Grizzle WE, Manne U, Weiss HL, Jhala N, Talley L.
Molecular staging of colorectal cancer in AfricanAmerican
and Caucasian patients using phenotypic
expression of p53, Bcl-2, MUC-1 AND p27(kip-1). Int
J Cancer 2002;97:403-9.
- 30. De Angelis PM, Stokke T, Thorstensen L, Lothe RA,
Clausen OPF. Apoptosis and expression of Bax, Bcl-x,
and Bcl-2 apoptotic regulatory proteins in colorectal
carcinomas, and associations with p53
genotype/phenotype. J Clin Pathol 1998;51:254-61.
- 31. Kanczuga-Koda L, Sulkowski S, Koda M,
Skrzydlewska E, Sulkowska M. Connexin 26
correlates with Bcl-xL and Bax proteins expression in
colorectal cancer. World J Gastroenterol
2005;11:1544-8.
- 32. Paradiso A, Simone G, Lena MD, et al. Expression of
apoptosis-related markers and clinical outcome in
patients with advanced colorectal cancer. British J
Cancer 2001;84:651-8.