Journal
CANCER RESEARCH
Volume 72, Issue 21, Pages 5494-5504Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-3993
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Funding
- Intramural Research Program, CCR, NCI
- NIH [K99CA151746]
- Norwegian Cancer Society and Health Region of South-Eastern Norway
- NCI, NIH [HSN261200800001E]
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Inhibitor of I kappa B kinases (IKK) are key regulators of NF-kappa B signaling. Three IKK isoforms-alpha, beta, and epsilon-have been linked to oncogenesis, yet the precise components of NF-kappa B signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-epsilon expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (P=0.03). Therefore, we hypothesized that IKK-epsilon drives ovarian cancer metastasis. IKK-epsilon was identified previously as a breast cancer oncogene and was associated with poor clinical outcome in ovarian cancer. We now define an ovarian cancer-specific IKK-epsilon-regulated gene expression signature using stably expressed short hairpin RNA targeting IKK-epsilon. Pathway analysis of the signature indicated that IKK-epsilon regulates expression of genes involved in cell motility and inflammation. We further showed that IKK-epsilon depletion in metastatic ovarian cancer cell lines decreased growth, adhesion, and invasion. Consistently, human xenografts depleted of IKK-epsilon in mice showed decreased aggressiveness, whereas overexpression of IKK-epsilon in a less invasive ovarian cancer cell line increased metastasis in vivo. Taken together, these data provide evidence that IKK-epsilon is a key coordinator of invasion and metastasis programs in ovarian cancer. Inhibition of IKK-epsilon signaling thus emerges as a viable therapeutic strategy in women whose ovarian cancer shows aberrant activation of this pathway. Cancer Res; 72(21); 5494-504. (C)2012 AACR.
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