The Immunohistochemical Expression of STAT3, Bcl-xL, and MMP-2 Proteins in Colon Adenoma and Adenocarcinoma
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Background/Aims: Signal transducers and activators of transcription (STATs) are a family of transcription factors that are activated in response to cytokines and growth factors. STAT3 activation has been implicated in modulating the activity of downstream mediators, such as Bcl-xL and matrix metalloproteinase-2 (MMP-2). The aim of this study was to investigate the immunohistochemical expression of STAT3, B-cell lymphoma-extra large (Bcl-xL), and MMP-2proteins according to histopathological parameters in colon adenocarcinomas, including lymph node metastasis, tumor differentiation, the TNM stage and the tumor size. Methods:Immunohistochemical staining with monoclonal STAT3,Bcl-xL, and MMP-2 antibodies was performed on paraffinembedded specimens from 20 colon adenomas and 39adenocarcinomas. Results: The expression of STAT3, Bcl-xL,and MMP-2 was increased in the adenocarcinomas as compared with the adenomas (p<0.001). STAT3 expression was stronger in tumors with a distant metastasis than in tumors without a distant metastasis (p=0.012). A larger tumor size was related to an increase in STAT3 expression (p=0.035). Conclusions: STAT3, Bcl-xL, and MMP-2 may play important roles in the tumorigenesis of colorectal carcinoma. STAT3may be indicative of a poor prognosis due to its correlation with distant metastases and a larger tumor size.
Abstract
Background/Aims: Signal transducers and activators of transcription (STATs) are a family of transcription factors that are activated in response to cytokines and growth factors. STAT3 activation has been implicated in modulating the activity of downstream mediators, such as Bcl-xL and matrix metalloproteinase-2 (MMP-2). The aim of this study was to investigate the immunohistochemical expression of STAT3, B-cell lymphoma-extra large (Bcl-xL), and MMP-2proteins according to histopathological parameters in colon adenocarcinomas, including lymph node metastasis, tumor differentiation, the TNM stage and the tumor size. Methods:Immunohistochemical staining with monoclonal STAT3,Bcl-xL, and MMP-2 antibodies was performed on paraffinembedded specimens from 20 colon adenomas and 39adenocarcinomas. Results: The expression of STAT3, Bcl-xL,and MMP-2 was increased in the adenocarcinomas as compared with the adenomas (p<0.001). STAT3 expression was stronger in tumors with a distant metastasis than in tumors without a distant metastasis (p=0.012). A larger tumor size was related to an increase in STAT3 expression (p=0.035). Conclusions: STAT3, Bcl-xL, and MMP-2 may play important roles in the tumorigenesis of colorectal carcinoma. STAT3may be indicative of a poor prognosis due to its correlation with distant metastases and a larger tumor size.
참고문헌 (45)
- Shike M, "Primary prevention of colorectal cancer. The WHO Collaborating Centre for the Prevention of Colorectal Cancer", Bull World Health Organ, 68, pp.377~385 (1990)
- Jackman RJ, "The adenoma-carcinoma sequence in cancer of the colon", Surg Gynecol Obstet, 93, pp.327~330 (1951)
- Bromberg J, "Stat proteins and oncogenesis", J Clin Invest, 109, pp.1139~1142 (2002)
- Darnell JE Jr, "STATs and gene regulation", Science, 277, pp.1630~1635 (1997)
- Huang S, "Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications", Clin Cancer Res, 13, pp.1362~1366 (2007)
- Levy DE, "Stats: transcriptional control and biological impact", Nat Rev Mol Cell Biol, 3, pp.651~662 (2002)
- Mora LB, "Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells", Cancer Res, 62, pp.6659~6666 (2002)
- Smithgall TE, "Control of myeloid differentiation and survival by Stats", Oncogene, 19, pp.2612~2618 (2000)
- Huang M, "Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells", Gynecol Oncol, 79, pp.67~73 (2000)
- 강신혁, "Activation of Stat3 in human melanoma promotes brain metastasis", CANCER RESEARCH, 66(6), pp.3188~3196, AMER ASSOC CANCER RESEARCH
- Boise LH, "bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death", Cell, 74, pp.597~608 (1993)
- Tsujimoto Y, "Bcl-2 family: life-or-death switch", FEBS Lett, 466, pp.6~10 (2000)
- Vander Heiden MG, "Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria", Cell, 91, pp.627~637 (1997)
- Gottlieb E, "Bcl-x(L) prevents the initial decrease in mitochondrial membrane potential and subsequent reactive oxygen species production during tumor necrosis factor alpha-induced apoptosis", Mol Cell Biol, 20, pp.5680~5689 (2000)
- Lynch CC, "Matrix metalloproteinases in tumor-host cell communication", Differentiation, 70, pp.561~573 (2002)
- Poulsom R, "Stromal expression of 72 kda type IV collagenase (MMP-2) and TIMP-2 mRNAs in colorectal neoplasia", Am J Pathol, 141, pp.389~396 (1992)
- Zucker S, "Role of matrix metalloproteinases (MMPs) in colorectal cancer", Cancer Metastasis Rev, 23, pp.101~117 (2004)
- Jass JR, "Histological typing of intestinal tumours" (1989), Springer-Verlag
- Greene FL, "AJCC cancer staging handbook: TNM classification of malignant tumors" (2002), Springer
- Wegenka UM, "Acute-phase response factor, a nuclear factor binding to acutephase response elements, is rapidly activated by interleukin-6 at the posttranslational level", Mol Cell Biol, 13, pp.276~288 (1993)
- Yu H, "The STATs of cancer: new molecular targets come of age", Nat Rev Cancer, 4, pp.97~105 (2004)
- Spiekermann K, "Constitutive activation of STAT transcription factors in acute myelogenous leukemia", Eur J Haematol, 67, pp.63~71 (2001)
- Garcia R, "Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells", Oncogene, 20, pp.2499~2513 (2001)
- Dhir R, "Stat3 activation in prostatic carcinomas", Prostate, 51, pp.241~246 (2002)
- Catlett-Falcone R, "Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells", Immunity, 10, pp.105~115 (1999)
- Ma XT, "Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma", World J Gastroenterol, 10, pp.1569~1573 (2004)
- Kusaba T, "Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma: correlation with clinicopathological factors", J Clin Pathol, 58, pp.833~838 (2005)
- Liu L, "STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importinalpha3", Proc Natl Acad Sci U S A, 102, pp.8150~8155 (2005)
- Yang J, "Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation", Cancer Res, 65, pp.939~947 (2005)
- Liddle FJ, "Tyrosine phosphorylation is required for functional activation of disulfide-containing constitutively active STAT mutants", Biochemistry, 45, pp.5599~5605 (2006)
- Bromberg JF, "Stat3 as an oncogene", Cell, 98, pp.295~303 (1999)
- Xie TX, "Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis", Oncogene, 23, pp.3550~3560 (2004)
- Horiguchi A, "Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: a study of incidence and its association with pathological features and clinical outcome", J Urol, 168, pp.762~765 (2002)
- Reed JC, "BCL-2 family proteins: regulators of cell death involved in the pathogenesis of cancer and resistance to therapy", J Cell Biochem, 60, pp.23~32 (1996)
- McDonnell TJ, "Importance of the Bcl-2 family in cell death regulation", Experientia, 52, pp.1008~1017 (1996)
- 이동수, "위선종, 위선암에서 Bcl-2, Bcl-xL, Bax, p53 단백의 면역조직화학 발현", 대한소화기학회지, 45(6), pp.394~400 (2005), 대한소화기학회
- Krajewska M, "Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas", Cancer Res, 56, pp.2422~2427 (1996)
- Friess H, "Moderate activation of the apoptosis inhibitor bcl-xL worsens the prognosis in pancreatic cancer", Ann Surg, 228, pp.780~787 (1998)
- Zhang YL, "Significance of Bcl-xL in human colon carcinoma", World J Gastroenterol, 14, pp.3069~3073 (2008)
- Kusaba T, "Activation of STAT3 is a marker of poor prognosis in human colorectal cancer", Oncol Rep, 15, pp.1445~1451 (2006)
- Tsareva SA, "Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction", Neoplasia, 9, pp.279~291 (2007)
- Tomita T, "Matrix metalloproteinases and tissue inhibitors of metalloproteinases in colonic adenomas-adenocarcinomas", Dis Colon Rectum, 39, pp.1255~1264 (1996)
- Parsons SL, "Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy", Br J Cancer, 78, pp.1495~1502 (1998)
- 신정은, "대장 선종과 대장암에서 MMP-2, HIF-1α 및 VEGF의 발현", 대한소화기학회지, 50(1), pp.9~18 (2007), 대한소화기학회
- Mysliwiec AG, "Matrix metalloproteinases in colorectal cancer", Clin Colorectal Cancer, 1, pp.208~219 (2002)
