跳至主要内容

Protein Expression of STAT3, pSTAT3, MMP-7 and VEGF in Colorectal Adenocarcinoma: An Immunohistochemical Study

Read full paper at:
http://www.scirp.org/journal/PaperInformation.aspx?PaperID=51251#.VGAcqWfHRK0

Background: The purpose of the present study is to investigate the expression levels of STAT3, pSTAT3, MMP-7 and VEGF in colorectal adenocarcinoma, and also to determine association with the clinico-pathological parameters and co-expression of these genes. Methods: An immunohistochemical method was used to evaluate the expression of MMP-7 and VEGF genes in 93 archival tissues whereas STAT3 and pSTAT3 expression was determined in 75 cases. Results: Overexpression of STAT3 was detected in 26.7% (20/75), pSTAT3 in 13.4% (10/75), MMP-7 in 38.8% (36/93) and VEGF in 59.2% (55/93) of the colorectal carcinomas. STAT3, MMP-7 and VEGF immunopositivity were significantly correlated with poorly-differentiated tumors (P = 0.004; P = 0.03; P = 0.002, respectively) but not with other parameters. However, pSTAT3 immunostaining was not significantly associated with the clinico-pathological characteristics. Significant relationship was noted between overexpression of pSTAT3 and STAT3 (P < 0.001), pSTAT3 and VEGF (P = 0.044), pSTAT3 and MMP-7 (P = 0.003), and STAT3 and VEGF (P = 0.037) but marginal association was detected between STAT3 and MMP-7 (P = 0.057), and MMP-7 and VEGF (P = 0.052). Conclusion: Our data suggest that expression of these genes may have an important role in tumor dedifferentiation and may be useful as indicators of biologic aggressiveness. Co-expression of the biomarkers by cancer cells may have important implications in colorectal cancer biology and could be useful biological markers of the malignant phenotype.
Cite this paper
Naidu, R. , Nee, L. , Wah, M. , Moissinac, K. , Jamal, A. , Rose, I. , Gul, Y. , Chooi, P. and San, G. (2014) Protein Expression of STAT3, pSTAT3, MMP-7 and VEGF in Colorectal Adenocarcinoma: An Immunohistochemical Study. Journal of Cancer Therapy, 5, 1175-1185. doi: 10.4236/jct.2014.513119
 

[1] Levy, D.E. and Darnell Jr., J.E. (2002) Stats: Transcriptional Control and Biological Impact. Nature Reviews Molecular Cell Biology, 3, 651-662. http://dx.doi.org/10.1038/nrm909
[2] Bromberg, J. (2002) Stat Proteins and Oncogenesis. Journal of Clinical Investigation, 109, 1139-1142. http://dx.doi.org/10.1172/JCI0215617
[3] Tsareva, S.A., Moriggl, R., Corvinus, F.M., Wiederanders, B., Schütz, A., Kovacic, B. and Friedrich, K. (2007) Signal Transducer and Activator of Transcription 3 Activation Promotes Invasive Growth of Colon Carcinomas through Matrix Metalloproteinase Induction. Neoplasia, 9, 279-291.
http://dx.doi.org/10.1593/neo.06820
[4] Ma, X.T., Wang, S., Ye, Y.J., Du, R.Y., Cui, Z.R. and Somsouk, M. (2004) Constitutive Activation of Stat3 Signaling Pathway in Human Colorectal Carcinoma. World Journal of Gastroenterology, 10, 1569-1573.
[5] Bowman, T., Garcia, R., Turkson, J. and Jove, R. (2000) STATs in Oncogenesis. Oncogene, 19, 2474-2488. http://dx.doi.org/10.1038/sj.onc.1203527
[6] Niu, G., Wright, K.L., Huang, M., Song, L., Haura, E., Turkson, J., Zhang, S., Wang, T., Sinibaldi, D., Loppola, D., Heller, R., Ellis, L.M., Karras, J., Bromberg, J., Pardoll, D., Jove, R. and Yu, H. (2002) Constitutive Stat3 Activity Up-Regulates VEGF Expression and Tumor Angiogenesis. Oncogene, 21, 2000-2008. http://dx.doi.org/10.1038/sj.onc.1205260
[7] Real, P.J., Sierra, A., De Juan, A., Segovia, J.C., Lopez-Vega, J.M. and Fernandez-Luna, J.L. (2002) Resistance to Chemotherapy via Stat3-Dependent Overexpression of Bcl-2 in Metastatic Breast Cancer Cells. Oncogene, 21, 7611-7668. http://dx.doi.org/10.1038/sj.onc.1206004
[8] Kusaba, T., Nakayama, T., Yamazumi, K., Yakata, Y., Yoshizaki, A., Inoue, K., Nagayasu, T. and Sekine, I. (2006) Activation of STAT3 Is a Marker of Poor Prognosis in Human Colorectal Cancer. Oncology Reports, 15, 1445-1451.
[9] Park, J.K., Hong, R., Kim, K.J., Lee, T.B. and Lim, S.C. (2008) Significance of p-STAT3 Expression in Human Colorectal Adenocarcinoma. Oncology Reports, 20, 597-604.
[10] Curran, S. and Murray, G.I. (2000) Matrix Metalloproteinases: Molecular Aspects of Their Roles in Tumour Invasion and Metastasis. European Journal of Cancer, 36, 1621-1630.
http://dx.doi.org/10.1016/S0959-8049(00)00156-8
[11] Stetler-Stevenson, W.G., Hewitt, R. and Corcoran, M. (1996) Matrix Metalloproteinases and Tumour Invasion: From Correlation and Causality to the Clinic. Seminar Cancer Biology, 7, 147-154.
http://dx.doi.org/10.1006/scbi.1996.0020
[12] Wilson, C.L. and Matrisian, L.M. (1996) Matrilysin: An Epithelial Matrix Metalloproteinase with Potentially Novel Functions. International Journal of Biochemistry and Cell Biology, 28, 123-136.
http://dx.doi.org/10.1016/1357-2725(95)00121-2
[13] Newell, K.J., Witty, J.P., Rodgers, W.H. and Matrisian, L.M. (1994) Expression and Localization of Matrix-Degrading Metalloproteinases during Colorectal Tumorigenesis. Molecular Carcinogenesis, 10, 199-206. http://dx.doi.org/10.1002/mc.2940100404
[14] Ishikawa, T., Ichikawa, Y., Mitsuhashi, M., Momiyama, N., Chishima, T., Tanaka, K., Yamaoka, H., Miyazakic, K., Nagashima, Y., Akitaya, T. and Shimada, H. (1996) Matrilysin Is Associated with Progression of Colorectal Tumor. Cancer Letters, 107, 5-10. http://dx.doi.org/10.1016/0304-3835(96)04336-4
[15] Adachi, Y., Yamamoto, H., Itoh, F., Arimura, Y., Nishi, M., Endo, T. and Imai, K. (2001) Clinicopathologic and Prognostic Significance of Matrilysin Expression at the Invasive Front in Human Colorectal Cancers. International Journal of Cancer, 95, 290-294.
[16] Masaki, T., Sugiyama, M., Matsuoka, H., Abe, N., Izumisato, Y., Sakamoto, A. and Atomi, Y. (2003) Matrix Metalloproteinases May Contribute Compensationally to Tumor Invasion in T1 Colorectal Carcinomas. Anticancer Research, 23, 4169-4173.
[17] Masaki, T., Matsuoka, H., Sugiyama, M., Abe, N., Goto, A., Sakamoto, A. and Atomi, Y. (2001) Matrilysin (MMP-7) as a Significant Determinant of Malignant Potential of Early Invasive Colorectal Carcinomas. British Journal of Cancer, 84, 1317-1321. http://dx.doi.org/10.1054/bjoc.2001.1790
[18] Hanahan, D. and Folkman, J. (1996) Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis. Cell, 86, 353-364. http://dx.doi.org/10.1016/S0092-8674(00)80108-7
[19] Dvorak, H.F., Detmar, M., Claffey, K.P., Nagy, J.A., van de Water, L. and Senger, D.R. (1995) Vascular Permeability Factor/Vascular Endothelial Growth Factor: An Important Mediator of Angiogenesis in Malignancy and Inflammation. International Archives of Allergy and Immunology, 107, 233-235. http://dx.doi.org/10.1159/000236988
[20] Guba, M., Seeliger, H., Kleespies, A., Jauch, K.W. and Bruns, C. (2004) Vascular Endothelial Growth Factor in Colorectal Cancer. International Journal of Colorectal Disease, 19, 510-517.
http://dx.doi.org/10.1007/s00384-003-0576-y
[21] Zafirellis, K., Agrogiannis, G., Zachaki, A., Gravani, K., Karameris, A. and Kombouras, C. (2008) Prognostic Significance of VEGF Expression Evaluated by Quantitative Immunohistochemical Analysis in Colorectal Cancer. Journal of Surgical Research, 147, 99-107.
http://dx.doi.org/10.1016/j.jss.2007.05.041
[22] Altomare, D.F., Rotelli, M.T., Pentimone, A., Rossiello, M.R., Martinelli, E., Guglielmi, A., De Fazio, M., Marino, F., Memeo, V., Colucci, M. and Semeraro, N. (2007) Tissue Factor and Vascular Endothelial Growth Factor Expression in Colorectal Cancer: Relation with Cancer Recurrence. Colorectal Disease, 9, 133-138. http://dx.doi.org/10.1111/j.1463-1318.2006.01158.x
[23] Lim, G.C.C. and Halimah, Y. (2004) Second Report of the National Cancer Registry. Cancer Incidence in Malaysia 2003. National Cancer Registry, Lumpur.
[24] Madbouly, K.M., Senagore, A.J., Mukerjee, A., Delaney, C.P., Connor, J. and Fazio, V.W. (2007) Does Immunostaining Effectively Upstage Colorectal Cancer by Identifying Micrometastatic Nodal Disease? International Journal of Colorectal Disease, 22, 39-48. http://dx.doi.org/10.1007/s00384-006-0098-5
[25] Hbibi, A.T., Lagorce, C., Wind, P., Spano, J.P., Guetz, G., Milano, G., Benamouzig, R., Rixe, O., Morere, J.F., Breau, J.L., Martin, A. and Fagard, R. (2008) Identification of a Functional EGF-R/p60c-src/STAT3 Pathway in Colorectal Carcinoma: Analysis of Its Long-Term Prognostic Value. Cancer Biomarkers, 4, 83-91.
[26] Kawada, M., Seno, H., Uenoyama, Y., Sawabu, T., Kanda, N., Fukui, H., Shimahara, Y. and Chiba, T. (2006) Signal Transducers and Activators of Transcription 3 Activation Is Involved in Nuclear Accumulation of Beta-Catenin in Colorectal Cancer. Cancer Research, 66, 2913-2917.
http://dx.doi.org/10.1158/0008-5472.CAN-05-3460
[27] Kusaba, T., Nakayama, T., Yamazumi, K., Yakata, Y., Yoshizaki, A., Nagayasu, T. and Sekine, I. (2005) Expression of p-STAT3 in Human Colorectal Adenocarcinoma and Adenoma; Correlation with Clinicopathological Factors. Journal of Clinical Pathology, 58, 833-838.
http://dx.doi.org/10.1136/jcp.2004.023416
[28] Xiong, H., Zhang, Z.G., Tian, X.Q., Sun, D.F., Liang, Q.C., Zhang, Y.J., Lu, R., Chen, Y.X. and Fang, J.Y. (2008) Inhibition of JAK1, 2/STAT3 Signaling Induces Apoptosis, Cell Cycle Arrest, and Reduces Tumor Cell Invasion in Colorectal Cancer Cells. Neoplasia, 10, 287-297.
[29] Lassmann, S., Schuster, I., Walch, A., Gobel, H., Jütting, U., Makowiec, F., Hopt, U. and Werner, M. (2007) STAT3 mRNA and Protein Expression in Colorectal Cancer: Effects on STAT3-Inducible Targets Linked to Cell Survival and Proliferation. Journal of Clinical Pathology, 60, 173-179.
http://dx.doi.org/10.1136/jcp.2005.035113
[30] Adachi, Y., Yamamoto, H., Itoh, F., Hinoda, Y., Okada, Y. and Imai, K. (1999) Contribution of Matrilysin (MMP-7) to the Metastatic Pathway of Human Colorectal Cancers. Gut, 45, 252-258.
http://dx.doi.org/10.1136/gut.45.2.252
[31] Remy, L., Trespeuch, C., Bachy, S., Scoazec, J.Y. and Rousselle, P. (2006) Matrilysin 1 Influences Colon Carcinoma Cell Migration by Cleavage of the Laminin-5 β3 Chain. Cancer Research, 66, 11228-11237. http://dx.doi.org/10.1158/0008-5472.CAN-06-1187
[32] Jeffery, N., McLean, M.H., El-Omar, E.M. and Murray, G.I. (2009) The Matrix Metalloproteinase/Tissue Inhibitor of Matrix Metalloproteinase Profile in Colorectal Polyp Cancers. Histopathology, 4, 820-828. http://dx.doi.org/10.1111/j.1365-2559.2009.03301.x
[33] Fang, Y.J., Lu, Z.H., Wang, G.Q., Pan, Z.Z., Zhou, Z.W., Yun, J.P., Zhang, M.F. and Wan, D.S. (2009) Elevated Expressions of MMP7, TROP2, and Survivin Are Associated with Survival, Disease Recurrence, and Liver Metastasis of Colon Cancer. International Journal of Colorectal Disease, 24, 875-884. http://dx.doi.org/10.1007/s00384-009-0725-z
[34] Roca, F., Mauro, L.V., Morandi, A., Bonadeo, F., Vaccaro, C., Quintana, G.O., Specterman, S., Joffé, E.B.K., Pallotta, M.Q., Puricelli, L.I. and Lastiri, J. (2006) Prognostic Value of E-Cadherin, β-Catenin, MMPs (7 and 9), and TIMPs (1 and 2) in Patients with Colorectal Carcinoma. Journal of Surgical Oncology, 93, 151-160. http://dx.doi.org/10.1002/jso.20413
[35] Barresi, V., Di Gregorio, C., Regiani-Bonetti, L., Leon, M., Barresi, G. and Vitarelli, E. (2010) Stage I Colorectal Carcinoma: VEGF Immunohistochemical Expression, Microvessel Density, and Their Correlation with Clinical Outcome. Virchows Archiv, 457, 11-19. http://dx.doi.org/10.1007/s00428-010-0933-5
[36] Yin, Y., Cao, L.Y., Wu, W.Q., Li, H., Jiang, Y. and Zhang, H.F. (2010) Blocking Effects of siRNA on VEGF Expression in Human Colorectal Cancer Cells. World Journal of Gastroenterology, 16, 1086-1092. http://dx.doi.org/10.3748/wjg.v16.i9.1086
[37] Kwon, H.C., Kim, S.H., Oh, S.Y., Lee, S., Kwon, K.A., Lee, J.H., Choi, H.J., Park, K.J., Lee, H.S., Roh, M.S. and Kim, H.J. (2010) Clinicopathological Significance of Nuclear Factor-κB, HIF-1α, and Vascular Endothelial Growth Factor Expression in Stage III Colorectal Cancer. Cancer Science, 10, 1557-1561. http://dx.doi.org/10.1111/j.1349-7006.2010.01553.x
[38] Ljujic, B., Radosavljevic, G., Jovanovic, I., Pavlovic, S., Zdravkovic, N., Milovanovic, M., Acimovic, L., Knezevic, M., Bankovic, D., Zdravkovic, D. and Arsenijevic, N. (2010) Elevated Serum Level of IL-23 Correlates with Expression of VEGF in Human Colorectal Carcinoma. Archive of Medical Research, 41, 182-189. http://dx.doi.org/10.1016/j.arcmed.2010.02.009
[39] Cao, D., Hou, M., Guan, Y.S., Jiang, M., Yang, Y. and Gou, H.F. (2009) Expression of HIF-1α and VEGF in Colorectal Cancer: Association with Clinical Outcomes and Prognostic Implications. BMC Cancer, 9, 432. http://dx.doi.org/10.1186/1471-2407-9-432
[40] Doger, F.K., Meteoglu, I., Tuncyurek, P., Okyay, P. and Cevikel, H. (2006) Does the EGFR and VEGF Expression Predict the Prognosis in Colon Cancer? European Surgical Research, 38, 540-544. http://dx.doi.org/10.1159/000096774
[41] Noike, T., Miwa, S., Soeda, J., Kobayashi, A. and Miyagawa, S. (2008) Increased Expression of Thioredoxin-1, Vascular Endothelial Growth Factor, and Redox Factor-1 Is Associated with Poor Prognosis in Patients with Liver Metastasis from Colorectal Cancer. Human Pathology, 39, 201-208.
http://dx.doi.org/10.1016/j.humpath.2007.04.024
[42] Zhang, C., Hao, L., Wang, L., Xiao, Y., Ge, H., Zhu, Z., Luo, Y. and Zhang, Y. (2010) Elevated IGFIR Expression Regulating VEGF and VEGF-C Predicts Lymph Node Metastasis in Human Colorectal Cancer. BMC Cancer, 10, 184. http://dx.doi.org/10.1186/1471-2407-10-184
[43] Khorana, A.A., Ryan, C.K., Cox, C., Eberly, S. and Sahasrabudhe, D.M. (2003) Vascular Endothelial Growth Factor, CD68, and Epidermal Growth Factor Receptor Expression and Survival in Patients with Stage II and Stage III Colon Carcinoma: A Role for the Host Response in Prognosis. Cancer, 97, 960-968. http://dx.doi.org/10.1002/cncr.11152
[44] Uner, A., Ebinc, F.A., Akyurek, N., Unsal, D., Mentes, B.B. and Dursun, A. (2005) Vascular Endothelial Growth Factor, c-erbB-2 and c-erbB-3 Expression in Colorectal Adenoma and Adenocarcinoma. Experimental Oncology, 27, 225-228.
[45] Ottaiano, A., Franco, R., Talamanca, A., Liguori, G., Tatangelo, F., Delrio, P., Nasti, G., Barletta, E., Facchini, G., Daniele, B., Di Blasi, A., Napolitano, M., Ieranò, C., Calemma, R., Leonardi, E., Albino, V., De Angelis, V., Falanga, M., Boccia, V., Capuozzo, M., Parisi, V., Botti, G., Castello, G., Iaffaioli, V.R. and Scala, S. (2006) Overexpression of both CXC Chemokine Receptor 4 and Vascular Endothelial Growth Factor Proteins Predicts Early Distant Relapse in Stage II-III Colorectal Cancer Patients. Clinical Cancer Research, 12, 2795-2803. http://dx.doi.org/10.1158/1078-0432.CCR-05-2142
[46] Dassoulas, K., Gazouli, M., Theodoropoulos, G., Christoni, Z., Rizos, S., Zisi-Serbetzoglou, A., et al. (2010) Vascular Endothelial Growth Factor and Endoglin Expression in Colorectal Cancer. Journal of Cancer Research Clinical Oncology, 136, 703-708. http://dx.doi.org/10.1007/s00432-009-0709-y
[47] Cascio, S., Ferla, R., D’Andrea, A., Gerbino, A., Bazan, V., Surmacz, E. and Russo, A. (2009) Expression of Angiogenic Regulators, VEGF and Leptin, Is Regulated by the EGF/PI3K/STAT3 Pathway in Colorectal Cancer Cells. Journal of Cell Physiology, 221, 189-194.
http://dx.doi.org/10.1002/jcp.21843
[48] Overall, C.M. and Kleifeld, O. (2006) Validating Matrix Metalloproteinases as Drug Targets and Anti-Targets for Cancer Therapy. Nature Review Cancer, 6, 227-239. http://dx.doi.org/10.1038/nrc1821
[49] Roy, R., Zhan, B. and Moses, M.A. (2006) Making the Cut: Protease-Mediated Regulation of Angiogenesis. Experimental Cell Research, 312, 608-622.
http://dx.doi.org/10.1016/j.yexcr.2005.11.022
[50] Ito, T.K., Ishii, G., Chiba, H. and Ochiai, A. (2007) The VEGF Angiogenic Switch of Fibroblasts Is Regulated by MMP-7 from Cancer Cells. Oncogene, 26, 7194-7203.
http://dx.doi.org/10.1038/sj.onc.1210535                  eww141110lx

评论

此博客中的热门博文

Does Immigration Promote the Investment of the Monopolistic Firm?

In the present paper, we examine the effect of increasing uncertainty of immigrants’ growth on the optimal timing of investment of a firm that has a monopolistic power over the labor market. It is revealed that when the uncertainty of immigrants’ growth is more than a threshold level, increasing uncertainty of immigrants’ growth accelerates the optimal timing of firms’ investment and enhances the economic growth, even if the uncertainty of immigrants’ growth is formulated by the geometric Brownian motion, which is in sharp contrast to the standard result that an increase in the uncertainty postpones the optimal timing. With an increase in the immigrants over the past ten years, workforces in the host countries have been growing significantly to the extent that the immigrants represent 70% of the increase in the workforce in Europe, and 47% in the United States as OECD indicates. In the present paper, we attempted to investigate the effect of increased uncertainty caused by the growi...

Education Policy Implementation: A Mechanism for Enhancing Primary Education Development in Zanzibar

Education is one of the fundamental rights of individuals; therefore, the government of a country needs to develop and strengthen educational policy and quality as well as to ensure that everyone has equal access to basic education. The improvement of access and quality of education in the world is becoming as an essential factor in development, whereas the basic education (primary school), is acknowledged as a foundation of the higher educational development for every country. To fulfill this goal, governments introduce several policies and procedures; however, it requires some reforms and participation from the politician, policymakers, and other stakeholders to re-examine educational policy so that it can lead to multiplication and betterment of the reforms. Educational reforms actually focus on accountability. A positive educational development and reform is very challenging and needs more effort and strategy on how to use and utilize the resources effectively as such it can achie...