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E-cadherin regulation in ovarian cancer: mechanisms and potential functional roles Lau, Man Tat


E-cadherin is a cell-cell adhesion protein and tumor suppressor that is silenced in many malignancies. However, the role of E-cadherin in ovarian cancer progression is still controversial. In an attempt to define the regulation of E-cadherin in ovarian cancer, we found that local growth factors, FGF2 and IGF1, suppress E-cadherin expression in ovarian cancer cells. To elucidate the role of E-cadherin in ovarian cancer progression, we found that stable knockdown of E-cadherin significantly enhances, whereas overexpression of E-cadherin reduces tumor cell growth and invasion. Loss of E-cadherin results in constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by inhibition of PTEN transcription through downregulation of Egr1. In addition, immunofluorescence microscopy and TCF promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear beta-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear beta-catenin signaling by inactivating glycogen synthase kinase-3beta indicating cross talk between the PI3K/Akt and beta-catenin signaling pathways. Furthermore, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via beta-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. Finally, the constitutive activation of PI3K/Akt signaling activates its downstream mammalian target of rapamycin (mTOR) signaling pathway. The pharmacological inhibition of PI3K and mTOR suggests that PI3K/Akt/mTOR is required for E-cadherin-depletion-induced tumor cell motility. Moreover, loss of E-cadherin induces tumor cell invasion, in part, by activation of Rho GTPase, Cdc42 and Rac1. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling and Rho GTPase activation. Thus, the loss of E-cadherin itself may contribute to dysregulate PI3K/Akt signaling and Rho GTPase activation to promote tumor proliferation and invasion in human ovarian cancer cells.

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