Abstract
Purpose
Constitutive activation of signal transducer and activator of transcription-5 (Stat5) was recently found to be associated with tumor progression through stimulating cell proliferation and preventing apoptosis. However, it is not clear how activated Stat5 is expressed in colon cancer. We aimed to investigate the correlation between phosphorylated Stat5 (p-Stat5) expression and cell cycle regulators (cyclin D1) expression in colonic adenocarcinoma and the relationship between expression of these two proteins and various clinicopathological parameters, including overall survival.
Methods
P-Stat5 and cyclin D1 expression were determined by immunohistochemical staining from 169 cases of resected colonic adenocarcinoma specimens.
Results
P-Stat5 expression correlated with cyclin D1 expression (r = 0.250, P = 0.001). P-Stat5-positive staining was associated with the depth of tumor invasion (P = 0.002). Univariate survival analysis showed that lymph node metastasis, distant metastasis, TNM stage (all P < 0.0001), T stage (P = 0.024), p-Stat5-positive expression (P = 0.002), and cyclin D1-positive expression (P = 0.039) were associated with shorter survival in patients with colonic adenocarcinoma. Multivariate survival analysis showed that only distant metastasis (P < 0.001; hazard ratio [HR] = 4.96), TNM stage (P < 0.001; HR = 9.80), and p-Stat5 overexpression (P = 0.020; HR = 1.84) were independent predictors of poor prognosis.
Conclusions
Our findings provide the first evidence that p-Stat5 may play an important role in cyclin D1 overexpression and contribute to colonic adenocarcinoma progression.
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References
Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249
Toyoda Y, Nakayama T, Ito Y et al (2009) Trends in colorectal cancer incidence by subsite in Osaka, Japan. Jpn J Clin Oncol 39:189–191
Jung KW, Won YJ, Park S et al (2009) Cancer statistics in Korea: incidence, mortality and survival in 2005. J Korean Med Sci 24:995–1003
Bujanda L, Sarasqueta C, Hijona E et al (2010) Colorectal cancer prognosis twenty years later. World J Gastroenterol 16:862–867
De Roock W, Biesmans B, De Schutter J et al (2009) Clinical biomarkers in oncology: focus on colorectal cancer. Mol Diagn Ther 13:103–114
Buettner R, Mora LB, Jove R (2002) Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8:945–954
Buitenhuis M, Coffer PJ, Koenderman L (2004) Signal transducer and activator of transcription 5 (STAT5). Int J Biochem Cell Biol 36:2120–2124
Nevalainen MT, Xie J, Torhorst J et al (2004) Signal transducer and activator of transcription-5 activation and breast cancer prognosis. J Clin Oncol 22:2053–2060
Lee TK, Man K, Poon RT et al (2006) Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial–mesenchymal transition. Cancer Res 66:9948–9956
Xiong H, Su WY, Liang QC et al (2009) Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells. Lab Invest 89:717–725
Xiong H, Chen ZF, Liang QC et al (2009) Inhibition of DNA methyltransferase induces G2 cell cycle arrest and apoptosis in human colorectal cancer cells via inhibition of JAK2/STAT3/STAT5 signalling. J Cell Mol Med 13:3668–3679
Nam S, Williams A, Vultur A et al (2007) Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells. Mol Cancer Ther 6:1400–1405
Chien CM, Yang SH, Lin KL et al (2008) Novel indoloquinoline derivative, IQDMA, suppresses STAT5 phosphorylation and induces apoptosis in HL-60 cells. Chem Biol Interact 176:40–47
Liang QC, Xiong H, Zhao ZW et al (2009) Inhibition of transcription factor STAT5b suppresses proliferation, induces G1 cell cycle arrest and reduces tumor cell invasion in human glioblastoma multiforme cells. Cancer Lett 273:164–171
O’Connell JB, Maggard MA, Ko CY (2004) Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 96:1420–1425
Jass JR, Sobin LH, Watanabe H (1990) The World Health Organization’s histologic classification of gastrointestinal tumors. A commentary on the second edition. Cancer 66:2162–2167
Kusaba T, Nakayama T, Yamazumi K et al (2006) Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep 15:1445–1451
Masuda M, Suzui M, Yasumatu R et al (2002) Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res 62:3351–3355
Lewis RS, Ward AC (2008) Stat5 as a diagnostic marker for leukemia. Expert Rev Mol Diagn 8:73–82
Tan SH, Nevalainen MT (2008) Signal transducer and activator of transcription 5A/B in prostate and breast cancers. Endocr Relat Cancer 15:367–390
Li H, Ahonen TJ, Alanen K et al (2004) Activation of signal transducer and activator of transcription 5 in human prostate cancer is associated with high histological grade. Cancer Res 64:4774–4782
Li H, Zhang Y, Glass A et al (2005) Activation of signal transducer and activator of transcription-5 in prostate cancer predicts early recurrence. Clin Cancer Res 11:5863–5868
de Groot RP, Raaijmakers JA, Lammers JW et al (2000) STAT5-dependent cyclin D1 and Bcl-xL expression in Bcr-Abl-transformed cells. Mol Cell Biol Res Commun 3:299–305
Nevins JR (1992) E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science 258:424–429
Huang WS, Wang JP, Wang T et al (2007) ShRNA-mediated gene silencing of beta-catenin inhibits growth of human colon cancer cells. World J Gastroenterol 13:6581–6587
Shan BE, Wang MX, Li RQ (2009) Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway. Cancer Investig 27:604–612
Itami A, Shimada Y, Watanabe G et al (1999) Prognostic value of p27(Kip1) and CyclinD1 expression in esophageal cancer. Oncology 57:311–317
Umekita Y, Ohi Y, Sagara Y et al (2002) Overexpression of cyclinD1 predicts for poor prognosis in estrogen receptor-negative breast cancer patients. Int J Cancer 98:415–418
Arici DS, Tuncer E, Ozer H et al (2009) Expression of retinoblastoma and cyclin D1 in gastric carcinoma. Neoplasma 56:63–67
Fu ZJ, Ma ZY, Wang QR et al (2008) Overexpression of CyclinD1 and underexpression of p16 correlate with lymph node metastases in laryngeal squamous cell carcinoma in Chinese patients. Clin Exp Metastasis 25:887–892
Acknowledgments
This study was supported by a grant from the Natural Science Fund of Heilongjiang Province (key projects; no. ZD 200804-02) and the Science Technological Research Funds of the Department of Education of Heilongjiang Province (no. 11551295 and no. 11541224).
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Mao, Y., Li, Z., Lou, C. et al. Expression of phosphorylated Stat5 predicts expression of cyclin D1 and correlates with poor prognosis of colonic adenocarcinoma. Int J Colorectal Dis 26, 29–35 (2011). https://doi.org/10.1007/s00384-010-1090-7
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DOI: https://doi.org/10.1007/s00384-010-1090-7