Cancer Cell Biology
Suppression of the TIG3 tumor suppressor gene in human ovarian carcinomas is mediated via mitogen-activated kinase-dependent and -independent mechanisms
Article first published online: 26 APR 2005
Copyright © 2005 Wiley-Liss, Inc.
International Journal of Cancer
Volume 116, Issue 6, pages 894–902, 10 October 2005
How to Cite
Lotz, K., Kellner, T., Heitmann, M., Nazarenko, I., Noske, A., Malek, A., Gontarewicz, A., Schäfer, R. and Sers, C. (2005), Suppression of the TIG3 tumor suppressor gene in human ovarian carcinomas is mediated via mitogen-activated kinase-dependent and -independent mechanisms. Int. J. Cancer, 116: 894–902. doi: 10.1002/ijc.21127
- Issue published online: 28 JUL 2005
- Article first published online: 26 APR 2005
- Manuscript Accepted: 7 FEB 2005
- Manuscript Received: 9 AUG 2004
- Berliner Krebsgesellschaft
- Charité, Berlin
- Deutsche Krebsgesellschaft. Grant Number: 10-1273-SeI.
- ovarian carcinoma;
- MEK/ERK target;
- IFN target
The TIG3 gene is a retinoic acid inducible class II tumor suppressor gene downregulated in several human tumors and malignant cell lines. Diminished TIG3 expression correlates with decreased differentiation whereas forced expression of TIG3 suppresses oncogenic signaling pathways and subsequently induces differentiation or apoptosis in tumor cells. Analysis of TIG3 mRNA expression in a large set of cDNA pools derived from matched tumor and normal human tissues showed a significant downregulation of TIG3 in 29% of the cDNA samples obtained from ovarian carcinomas. Using in situ hybridization, we demonstrated expression of TIG3 in the epithelial lining of 7 normal ovaries but loss of TIG3 expression in 15/19 of human ovarian carcinoma tissues. In SKOV-3, CAOV-3 and ES-2 ovarian carcinoma cell lines, downregulation of TIG3 mRNA was reversible and dependent on an activated MEK-ERK signaling pathway. Re-expression of TIG3 mRNA in these cells upon specific interference with the MEK-pathway was correlated with growth inhibition of the cells. In OVCAR-3 and A27/80 ovarian carcinoma cells, TIG3 suppression is MEK-ERK independent, but expression could be reconstituted upon interferon gamma (IFNγ) induction. Overexpression of TIG3 in A27/80 ovarian carcinoma cells significantly impaired cell growth and despite increased mRNA levels, TIG3 protein was hardly detectable. These results suggest that TIG3 is negatively regulated by an activated MEK-ERK signaling pathway. Further mechanisms must interfere with TIG3 expression that are independent of MEK and partially include interferon-responsive components. © 2005 Wiley-Liss, Inc.