Abstract
S100A4 belongs to the S100 subfamily of calcium-binding proteins and has been suggested to be directly involved in invasion and metastasis of rodent and human tumour cells. The present study demonstrates that interferon gamma (IFN-γ), but not IFN-α and IFN-β, down-regulates the S100A4 mRNA level in colon adenocarcinoma WiDr cells in time- and dose-dependent manners. The effect was not associated with any cytotoxicity and was specific for the S100A4 mRNA, since the levels of the S100A6 and GAPDH mRNAs were not significantly affected by the treatment. IFN-γ also strongly suppressed the S100A4 mRNA expression in HT-29 cells, but weakly in Colo201 cells. Flow cytometric analysis revealed that the level of the IFN-γ receptor expression in Colo201 cells was lower than that in WiDr and HT-29 cells, suggesting that the suppression of the S100A4 expression by IFN-γ depends on the amount of cell surface IFN-γ receptor protein. IFN-γ had no effect on the transcription rate of the S100A4 gene but reduced the stability of the S100A4 mRNA. WiDr cells treated with IFN-γ showed reduced motile ability, further supporting the assumption that the S100A4 gene product is involved in controlling cell motility.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
An, Z., Wang, X., Astoul, P., Danays, T., Moossa, A. R. & Hoffman, R. M. (1996) Interferon gamma is highly effective against orthotopically-implanted human pleural adenocarcinoma in nude mice. Anticancer Res 16: 2545–2551.
Barraclough, R., Savin, J., Dube, S. K. & Rudland, P. S. (1987) Molecular cloning and sequence of the gene for p9Ka, a cultured myoepithelial cell protein with strong homology to S-100, a calcium-binding protein. J Mol Biol 198: 13–20.
Besançon, F., Prezewlocki, G., Baró, I., Hongre, A-S, Escande, D. & Edelman, A. (1994) Interferon-γ downregulates CFTR gene expression in epithelial cells. Am J Physiol 267: C1398–C1404.
Bourgeade, M-F, Silbermann, F., Kühn, U., Testa, C., Peschle, S., Memet, S., Thang, M. & Besançon, F. (1992) Post-transcriptional regulation of transferrin receptor mRNA by IFN-γ. Nucleic Acids Res 20: 2997–3003.
Celio, M. R., Pauls, T. & Schwaller, B. (1996). Guidebook to the Calcium-Binding Proteins, Sambrook and Tooze (eds). Oxford University Press: Oxford
Davies, B. R., Davies, M. P. A., Gibbs, F. E. M., Barraclough, R. & Rudland, P. S. (1993) Induction of the metastatic phenotype by transfection of a benign rat mammary epithelial cell line with the gene for p9Ka, a rat calcium-binding protein, but not with the oncogene EJ-ras-1. Oncogene 8: 999–1008.
Ebralidze, A., Tulchinsky, E., Grigorian, M., Afanasyeva, A., Senin, V., Revazova, E. & Lukanidin, E. (1989) Isolation and characterization of a gene specifically expressed in different metastatic cells and whose deduced gene product has a high degree of homology to a Ca2+-binding protein family. Genes Dev 3: 1086–1093.
Ford, H. L. & Zain, S. B. (1995) Interaction of metastasis-associated mts 1 protein with non-muscle myosin. Oncogene 10: 1597–1605.
Ford, H. L., Salim, M. M., Chakravarty, R., Aluiddin, V. & Zain, S. B. (1995) Expression of mts1, a metastasis-associated gene, increases motility but not invasion of a nonmetastatic mouse mammary adenocarcinoma cell line. Oncogene 11: 2067–2075.
Goldring, M. B., Fukuo, K., Birkhead, J. R., Dudek, E. & Sandell, L. J. (1994) Transcriptional suppression by interleukin-1 and interferon-γ of type II collagen gene expression in human chondrocytes. J Cell Biochem 54: 85–99.
Goto, K., Endo, H. & Fujiyoshi, T. (1988) Cloning of the sequences expressed abundantly in established cell lines: identification of a cDNA clone highly homologous to S-100, a calcium binding protein. J Biochem 103: 48–53.
Grigorian, M. S., Tulchinsky, E. M., Zain, S., Ebralidze, A. K., Kramerov, D. A., Kriajevska, M. V., Georgiev, G. P. & Lukanidin, E. M. (1993) The mts1 gene and control of tumor metastasis. Gene 135: 229–238.
Grigorian, M., Tulchinsky, E., Burrone, O., Tarabykina, S., Georgiev, G. & Lukanidine, E. (1994) Modulation of mts 1 expression in mouse and human normal and tumour cells. Electrophoresis 15: 463–468.
Grigorian, M., Ambartsumian, N., Lykkesfeldt, A. E., Bastholm, L., Elling, F., Georgiev, G. & Lukanidin, E. (1996) Effect of mts1 (S100A4) expression on the progression of human breast cancer cells. Int J Cancer 67: 831–841.
Groudine, M., Peretz, M. & Weintraub, H. (1981) Transcriptional regulation of hemoglobin switching on chicken embryos. Mol Cell Biol 1: 281–288.
Harel-Bellan, A., Brini, A. T. & Farrar, W. L. (1988) Interferon-gamma inhibits c-myc gene expression by impairing the splice process in a colony-stimulating factors dependent murine myeloid cell line. J Immunol 141: 1012–1017.
Hilt, D. C. & Kligman, D. (1991). The S-100 protein family: a biochemical and functional overview. In Novel Calcium-binding proteins. Fundamental and Clinical Implications, Heizman CW (ed), pp. 65–103. Springer-Verlag: Berlin
Ilg, E. C., Schäfer, B. W. & Heizmann, C. W. (1996) Expression pattern of S100 calcium-binding proteins in human tumors. Int J Cancer 68: 325–332.
Jackson-Grusby, L. L., Swiergiel, J. & Linzer, D. I. H. (1987) A growth-related mRNA in cultured mouse cells encodes a placental calcium-binding protein. Nucleic Acids Res 15: 6677–6690.
Kriajevska, M. V., Cardenas, M. N., Grigorian, M. S., Ambartsumian, N. S., Georgiev, G. P. & Lukanidin, E. M. (1994) Non-muscle myosin heavy chain as a possible target for protein encoded by metastasis-related mts-1 gene. J Biol Chem 269: 19679–19682.
McMillan, T. J., Rao, J., Everett, C. A. & Hart, I. R. (1987) Interferon-induced alterations in metastatic capacity, class-1 antigen expression and natural killer cell sensitivity of melanoma cells. Int J Cancer 40: 659–663.
Masumori, N., Tsukamoto, T. & Kumamoto, Y. (1995) Interferon-gamma and interleukin-2 suppress the experimental metastasis of mouse renal adenocarcinoma. Int J Urol 2: 6–11.
Maelandsmo, G. M., Hovig, E., Skrede, M., Engebraaten, O., Flørens, V. A., Myklebost, O., Grigorian, M., Lukanidin, E., Scanlon, K. J. & Fodstad, Ø (1996) Reversal of the in vivo metastatic phenotype of human tumor cells by anti-CAPL (mts1) ribozyme. Cancer Res 56: 5490–5498.
Nakamura, N. & Takenaga, K. (1998) Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines. Clin Exp Metastasis 16: 471–479.
Ossina, N. K., Cannas, A., Powers, V. C., Fitzpatrick, P. A., Knight, J. D., Gilbert, J. R., Shekhtman, E. M., Tomei, L. D., Umansky, S. R. & Kiefer, M. C. (1997) Interferon-gamma modulates a p53-independent apoptotic pathway and apoptosis-related gene expression. J Biol Chem 272: 16351–16357.
Parker, C., Whittaker, P. A., Usmani, B. A., Lakshmi, M. S. & Sherbet, G. V. (1994) Induction of 18A2/mts 1 gene expression and its effect on metastasis and cell cycle control. DNA Cell Biol 13: 1021–1028.
Pedrocchi, M., Schäfer, B. W., Mueller, H., Eppenberger, U. & Heinzmann, C. W. (1994) Expression of Ca2+-binding proteins of the S100 family in malignant human breast-cancer cell lines and biopsy samples. Int J Cancer 57: 684–690.
Radzich, D. & Varesio, L. (1991) c-fos mRNA expression in macrophages is down-regulated by interferon-γ at the post-transcriptional level. Mol Cell Biol 11: 2718–2722.
Radinsky, R. (1995) Modulation of tumor cell gene expression and phenotype by the organ-specific metastatic environment. Cancer Metastasis Rev 14: 323–338.
Raitano, A. B. & Korc, M. (1993) Growth inhibition of a human colorectal carcinoma cell line by interleukin 1 is associated with enhanced expression of γ-interferon receptors. Cancer Res 53: 636–640.
Ramani, P. & Balkwill, F. R. (1987) Enhanced metastasis of a mouse carcinoma after in vitro treatment with murine interferon gamma. Int J Cancer 40: 830–834.
Sambrook, J., Fritsch, E. F. & Maniatis, T. (1989). Molecular Cloning: A Laboratory Manual, 2nd Edn. Cold Spring Harbor Laboratory: New York
Schäfer, B. W. & Heizmann, C. W. (1996) The S100 family of EF-hand calcium-binding proteins: functions and pathology. Trends Biochem Sci 21: 134–140.
Sen, G. C. & Lengyel, P. (1992) The interferon system. J Biol Chem 267: 5017–5020.
Strutz, F., Okada, H., Lo, C. W., Danoff, T., Carone, R. L., Tomaszewski, J. E. & Neilson, E. G. (1995) Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 130: 393–405.
Takenaga, K., Nakamura, Y., Endo, H. & Sakiyama, S. (1994a) Involvement of S100-related calcium-binding protein pEL98 (or mts 1) in cell motility and tumor cell invasion. Jpn J Cancer Res 85: 831–839.
Takenaga, K., Nakamura, Y. & Sakiyama, S. (1994b) Expression of a calcium binding protein pEL98 (mts1) during differentiation of human promyelocytic leukemia HL-60 cells. Biochem Biophys Res Commun 202: 94–101.
Takenaga, K., Nakamura, Y. & Sakiyama, S. (1994c) Cellular localization of pEL98 protein, an S100-related calcium binding protein, in fibroblasts and its tissue distribution analyzed by monoclonal antibodies. Cell Struct Funct 19: 133–141.
Takenaga, K., Nakamura, Y., Sakiyama, S., Hasegawa, Y., Sato, K. & Endo, H. (1994d) Binding of pEL98 protein, an S100-related calcium-binding protein, to nonmuscle tropomyosin. J Cell Biol 124: 757–768.
Takenaga, K., Nakamura, Y. & Sakiyama, S. (1997a) Expression of antisense RNA to S100A4 gene encoding an S100-related calcium-binding protein suppresses metastatic potential of high-metastatic Lewis lung carcinoma cells. Oncogene 14: 331–337.
Takenaga, K., Nakanishi, H., Wada, K., Suzuki, M., Matsuzaki, O., Matuura, A. & Endo, H. (1997b) Increased expression of S100A4, a metastasis-associated gene, in human colorectal adenocarcinomas. Clin Cancer Res 3: 2309–2316.
Yanagihara, K., Seyama, T. & Watanabe, Y. (1994) Antitumor potential of interferon-γ retroviral expression of mouse interferon-γ cDNA in two kinds of highly metastatic mouse tumor lines reduces their tumorigenicity. Nat Immunol 13: 102–112.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Takenaga, K. Suppression of metastasis-associated S100A4 gene expression by gamma-interferon in human colon adenocarcinoma cells. Br J Cancer 80, 127–132 (1999). https://doi.org/10.1038/sj.bjc.6690331
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690331
Keywords
This article is cited by
-
Prognostic Impact of Modulators of G proteins in Circulating Tumor Cells from Patients with Metastatic Colorectal Cancer
Scientific Reports (2016)
-
S100A6 Expression and Function in Human Osteosarcoma
Clinical Orthopaedics and Related Research (2008)
-
Interferon-γ suppresses S100A4 transcription independently of apoptosis or cell cycle arrest
British Journal of Cancer (2003)