Abstract Ovarian cancer is a cancer of high mortality in women malignancies. Little is known with its property of tumor progression and no effective molecule could monitor the tumor growth or therapeutic responses of this disease. In our previous studies, we first identified that mesothelin, a secreted protein, over-expressed in ovarian cancer tissues with a poor clinical outcome in chemotherapeutic response of ovarian cancer patients. Besides, mesothelin activated PI3K/Akt signaling to inhibit paclitaxel-induced apoptosis. Here, we investigated the mechanism of mesothelin enhancing the invasion of ovarian cancer and the correlation between mesothelin and metastatic diseases. The expression of mesothelin correlated well with expression of MMP-7 in human ovarian cancer tissues. Mesothelin over-expressed or mesothelin-treated ovarian cancer cells could enhance the migration and invasion of cancer cells through the activation of MMP-7. Mesothelin could regulate the expression of MMP-7 through ERK (extracellular-signal-regulated kinase) 1/2, Akt (phosphoinositide 3-kinase), and JNK (c-jun-N-terminal kinase) pathways. The MMP-7 expression and the migrating ability of mesothelin-treated ovarian cancer cells can be suppressed by the ERK1/2 or JNK specific inhibitor, or decoy AP-1 oligonucleotide in in vitro experiments. The in vivo animal experiments also demonstrated that mice treated with MAPK/ERK or JNK- specific inhibitor could decrease the itnratumoral MMP-7 expression and delay the tumor growth. We concluded that mesothelin enhances ovarian cancer invasion by MMP-7 expression through the MAPK/ERK and JNK signal transduction pathways. And blocking these two pathways can be a potential strategy to inhibit the tumor growth of ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1405. doi:10.1158/1538-7445.AM2011-1405