Similar articles

Abstract: Insulin-like growth factor binding-protein-7 (IGFBP7) was obtained from our previous colonic adenocarcinoma (CRC) and normal mucosa suppression subtraction hybridization (SSH) cDNA libraries. By RT-PCR and immunohistochemistry, we found that IGFBP7 was overexpressed in CRC tissue compared to normal tissue. However, our in vitro experiments performed in 10 CRC cell lines showed that IGFBP7 expressed only in SW480 and Caco2 cell lines, which implied an underlying reversible regulatory mechanism. Using methylation-specific PCR (MSP) and bisulfite sodium PCR (BSP), we found that its expression was associated with DNA hypomethylation of exon1. This was further supported by the in vitro study which showed restored IGFBP7 expression after demethylation agent 5-aza-2'-deoxycytidine treatment. Correlation analysis between IGFBP7 expression and prognosis indicated that overexpression of IGFBP7 in CRC tissue correlated with favourable survival. Investigation of the functional role of IGFBP7 through transfection studies showed that IGFBP7 protein could inhibit growth rate, decrease colony formation activity, and induce apoptosis in RKO and SW620 cells, suggesting it a potential tumor suppressor protein in colorectal carcinogenesis. In conclusion, our study clearly demonstrated that IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis and its expression is associated with DNA hypomethylation of exon 1.

[1] Adachi, Y., Itoh, F., Yamamoto, H., Arimura, Y., Kikkawa-Okabe, Y., Miyazaki, K., Carbone, D.P., Imai, K., 2001. Expression of angiomodulin (tumor-derived adhesion factor/mac25) in invading tumor cells correlates with poor prognosis in human colorectal cancer. Int. J. Cancer, 95(4):216-222.

[2] Bieche, I., Lerebours, F., Tozlu, S., Espie, M., Marty, M., Lidereau, R., 2004. Molecular profiling of inflammatory breast cancer: identification of a poor-prognosis gene expression signature. Clin. Cancer Res., 10(20):6789-6795.

[3] Degeorges, A., Wang, F., Frierson, H.F.Jr, Seth, A., Chung, L.W., Sikes, R.A., 1999. Human prostate cancer expresses the low affinity insulin-like growth factor binding protein IGFBP7. Cancer Res., 59(12):2787-2790.

[4] Herman, J.G., Graff, J.R., Myohanen, S., Nelkin, B.D., Baylin, S.B., 1996. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl. Acad. Sci. USA, 93 (18):9821-9826.

[5] How, H.K., Yeoh, A., Quah, T.C., Oh, Y., Rosenfeld, R.G., Lee, K.O., 1999. Insulin-like growth factor binding proteins (IGFBPs) and IGFBP-related protein 1-levels in cerebrospinal fluid of children with acute lymphoblastic leukemia. J. Clin. Endocrinol. Metab., 84(4):1283-1287.

[6] Kato, M.V., 2000. A secreted tumor-suppressor, mac25, with activin-binding activity. Mol. Med., 6(2):126-135.

[7] Kim, H.S., Nagalla, S.R., Oh, Y., Wilson, E., Roberts, C.T.Jr, Rosenfeld, R.G., 1997. Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc. Natl. Acad. Sci. USA, 94(24):12981-12986.

[8] Komatsu, S., Okazaki, Y., Tateno, M., Kawai, J., Konno, H., Kusakabe, M., Yoshiki, A., Muramatsu, M., Held, W.A., Hayashizaki, Y., 2000. Methylation and downregulated expression of mac25/insulin-like growth factor binding protein-7 is associated with liver tumorigenesis in SV40T/t antigen transgenic mice, screened by restriction landmark genomic scanning for methylation (RLGS-M). Biochem. Biophys. Res. Commun., 267(1):109-117.

[9] Luo, M.J., Lai, M.D., 2001. Identification of differentially expressed genes in normal mucosa, adenoma and adenocarcinoma of colon by SSH. World J. Gastroenterol., 7(5):726-731.

[10] Murphy, M., Pykett, M.J., Harnish, P., Zang, K.D., George, D.L., 1993. Identification and characterization of genes differentially expressed in meningiomas. Cell Growth Differ., 4(9):715-722.

[11] Mutaguchi, K., Yasumoto, H., Mita, K., Matsubara, A., Shiina, H., Igawa, M., Dahiya, R., Usui, T., 2003. Restoration of insulin-like growth factor binding protein-related protein 1 has a tumor-suppressive activity through induction of apoptosis in human prostate cancer. Cancer Res., 63(22):7717-7723.

[12] Seth, A., Kitching, R., Landberg, G., Xu, J., Zubovits, J., Burger, A.M., 2003. Gene expression profiling of ductal carcinomas in situ and invasive breast tumors. Anticancer Res., 23(3A):2043-2051.

[13] Shao, L.N., Huang, Q., Luo, M., Lai, M., 2004. Detection of the differentially expressed gene IGF-binding protein-related protein-1 and analysis of its relationship to fasting glucose in Chinese colorectal cancer patients. Endocr. Relat. Cancer, 11(1):141-148.

[14] Spano, J.P., Lagorce, C., Atlan, D., Milano, G., Domont, J., Benamouzig, R., Attar, A., Benichou, J., Martin, A., Morere, J.F., et al., 2005. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann. Oncol., 16(1):102-108.

[15] Sprenger, C.C., Damon, S.E., Hwa, V., Rosenfeld, R.G., Plymate, S.R., 1999. Insulin-like growth factor binding protein-related protein 1 (IGFBP7) is a potential tumor suppressor protein for prostate cancer. Cancer Res., 59(10):2370-2375.

[16] Watson, M.A., Gutmann, D.H., Peterson, K., Chicoine, M.R., Kleinschmidt-DeMasters, B.K., Brown, H.G., Perry, A., 2002. Molecular characterization of human meningiomas by gene expression profiling using high-density oligonucleotide microarrays. Am. J. Pathol., 161(2):665-672.

[17] Welsh, J.B., Sapinoso, L.M., Kern, S.G., Brown, D.A., Liu, T., Bauskin, A.R., Ward, R.L., Hawkins, N.J., Quinn, D.I., Russell, P.J., et al., 2003. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc. Natl. Acad. Sci. USA, 100(6):3410-3415.

[18] Wilson, H.M., Birnbaum, R.S., Poot, M., Quinn, L.S., Swisshelm, K., 2002. Insulin-like growth factor binding protein-related protein 1 inhibits proliferation of MCF-7 breast cancer cells via a senescence-like mechanism. Cell Growth Differ., 13(5):205-213.

[19] Zumkeller, W., 2001. IGFs and IGFBPs: surrogate markers for diagnosis and surveillance of tumour growth? Mol. Pathol., 54(5):285-288.