Down-Regulation of GRIM-19 Expression Is Associated With Hyperactivation of STAT3-Induced Gene Expression and Tumor Growth in Human Cervical Cancers
- 1 October 2009
- journal article
- research article
- Published by Mary Ann Liebert Inc in Journal of Interferon & Cytokine Research
- Vol. 29 (10), 695-704
- https://doi.org/10.1089/jir.2009.0003
Abstract
Cervical cancer is the most common malignant disease responsible for the deaths of a large number of women in the developing world. Although certain strains of human papillomavirus (HPV) have been identified as the cause of this disease, events that lead to formation of malignant tumors are not fully clear. STAT3 is a major oncogenic transcription factor involved in the development and progression of a number of human tumors. However, the mechanisms that result in loss of control over STAT3 activity are not understood. Gene associated with Retinoid-Interferon-induced Mortality-19 (GRIM-19) is a tumor-suppressive protein identified using a genetic technique in the interferon/retinoid-induced cell death pathway. Here, we show that reduction in GRIM-19 protein levels occur in a number of primary human cervical cancers. Consequently, these tumors tend to express a high basal level of STAT3 and its downstream target genes. More importantly, using a surrogate model, we show that restoration of GRIM-19 levels reestablishes the control over STAT3-dependent gene expression and tumor growth in vivo. GRIM-19 suppressed the expression of tumor invasion- and angiogenesis-associated factors to limit tumor growth. This study identifies another major novel molecular pathway inactivated during the development of human cervical cancer.Keywords
This publication has 50 references indexed in Scilit:
- Interferon-inducible protein, P56, inhibits HPV DNA replication by binding to the viral protein E1The EMBO Journal, 2008
- Human papillomavirus infection and the primary and secondary prevention of cervical cancerCancer, 2008
- GRIM-19 Is Essential for Maintenance of Mitochondrial Membrane PotentialMolecular Biology of the Cell, 2008
- Induction of MMP-9 release from human dermal fibroblasts by thrombin: involvement of JAK/STAT3 signaling pathway in MMP-9 releaseBMC Cell Biology, 2007
- Stat3 activation in human endometrial and cervical cancersBritish Journal of Cancer, 2007
- STAT3 as a central mediator of neoplastic cellular transformationCancer Letters, 2006
- Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasisOncogene, 2004
- The GRIMs: a new interface between cell death regulation and interferon/retinoid induced growth suppressionCytokine & Growth Factor Reviews, 2004
- 13-cis-Retinoic Acid Plus Interferon -2a: Highly Active Systemic Theraphy for Squamous Cell Carcinoma of the CervixJNCI Journal of the National Cancer Institute, 1992
- Microvascular Injury in Pathogenesis of Interferon-Induced Necrosis of Subcutaneous Tumors in MiceJNCI Journal of the National Cancer Institute, 1989