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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

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IKK-ε coordinates invasion and metastasis of ovarian cancer.

Hsu Sarah S Kim Marianne M Hernandez Lidia L Grajales Valentina V Noonan Anne A Anver Miriam M Davidson Ben B Annunziata Christina M CM

Cancer research 20120831 21

Inhibitor of IκB kinases (IKK) are key regulators of NF-κB signaling. Three IKK isoforms-α, β, and ε-have been linked to oncogenesis, yet the precise components of NF-κB signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-ε expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (P = 0.03). Therefore, we hypothesized that IKK-ε drives ovarian cancer metastasis. IKK-ε was identified previously ...[more]

PMID: 22942254

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Project description:Aim:The aim of this study was to explore the expression of peroxiredoxin1 (PRDX1) in epithelial ovarian cancer, analyze the relationship between PRDX1 and clinicopathologic parameters of patients with ovarian cancer, including their prognosis, and describe changes and the mechanisms involved in malignant biologic behavior of ovarian cancer cells when PRDX1 expression is inhibited. Methods:The expression of PRDX1 was detected immunohistochemically in 15 samples of normal ovarian tissue, 21 benign, 11 borderline, and 101 malignant epithelial ovarian tumors. Changes in ovarian cancer cell proliferation, invasion, and metastasis before and after inhibiting PRDX1 expression were assessed by cell function assay. Additionally, gene set enrichment analysis (GSEA) of PRDX1 was performed by the Cancer Genome Atlas database. A protein- protein interaction network was then constructed and a pathway function analysis of the genes in the network was conducted. Results:PRDX1 expression was mainly localized to the cytoplasm, as well as the nucleus of cells. The expression rate of PRDX1 in epithelial ovarian malignant tissues (96.04%) was significantly higher than that in borderline (72.72%) and benign (57.14%) epithelial ovarian tumors, and normal ovarian tissue (20%; all P<0.05). Cox multivariate regression analysis indicated that advanced clinical stage, low tissue differentiation, and high expression of PRDX1 were independent risk factors affecting the prognosis of epithelial ovarian cancer (all P<0.05). Cell function assay verified that the decreased expression of PRDX1 inhibited ovarian cancer cell proliferation, invasion, and metastasis. GSEA analysis indicated that PRDX1 was significantly related to the Wnt signaling pathway. Western blot analysis confirmed that PRDX1 could regulate the expression of ?-catenin in the Wnt pathway. Conclusion:Decreased expression of PRDX1 can attenuate cell proliferation, invasion, and metastasis of ovarian cancer cells. The expression of PRDX1 is related to the prognosis of patients with ovarian cancer and can therefore be used as a biomarker.

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IKK-? coordinates invasion and metastasis of ovarian cancer.

Publications

IKK-ε coordinates invasion and metastasis of ovarian cancer.

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