IKK-? coordinates invasion and metastasis of ovarian cancer.

ABSTRACT: Inhibitor of I?B kinases (IKK) are key regulators of NF-?B signaling. Three IKK isoforms-?, ?, and ?-have been linked to oncogenesis, yet the precise components of NF-?B signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-? expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (P = 0.03). Therefore, we hypothesized that IKK-? drives ovarian cancer metastasis. IKK-? 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-?-regulated gene expression signature using stably expressed short hairpin RNA targeting IKK-?. Pathway analysis of the signature indicated that IKK-? regulates expression of genes involved in cell motility and inflammation. We further showed that IKK-? depletion in metastatic ovarian cancer cell lines decreased growth, adhesion, and invasion. Consistently, human xenografts depleted of IKK-? in mice showed decreased aggressiveness, whereas overexpression of IKK-? in a less invasive ovarian cancer cell line increased metastasis in vivo. Taken together, these data provide evidence that IKK-? is a key coordinator of invasion and metastasis programs in ovarian cancer. Inhibition of IKK-? signaling thus emerges as a viable therapeutic strategy in women whose ovarian cancer shows aberrant activation of this pathway.

SUBMITTER: Hsu S 

PROVIDER: S-EPMC3488159 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature