Activin A promotes ovarian cancer cell migration by suppressing E-cadherin expression

The highly invasive and metastatic properties of ovarian cancer make it the leading cause of death among gynecological cancers. Elevated levels of activin A and its receptors have been found in ovarian tumors and are associated with reduced survival in ovarian cancer patients. The role of activin A in promoting ovarian cancer cell migration and invasion has been previously reported, however, the underlying molecular mechanisms remain largely unknown. Here, we show that treatment of SKOV3 and OVISE cells with activin A decreases the expression of E-cadherin. These effects are completely diminished by inhibition or knockdown of the activin type I receptor. Treatment with activin A activates SMAD2/3 signaling but does not alter MEK-ERK1/2 or PI3K/AKT signaling pathway activity. Knockdown of SMAD2, SMAD3 or SMAD4 abolishes the downregulation of E-cadherin by activin A. Moreover, activin A treatment induces the expression of transcription factors SNAIL and SLUG, which mediate the suppressive effects of activin A on E-cadherin expression. Importantly, forced-expression of E-cadherin inhibits both basal and activin A-induced cell migration. Taken together, our results suggest that activin A downregulates E-cadherin expression by upregulating SLUG and SNAIL expression via SMAD2/3-SMAD4-dependent signaling. Loss of E-cadherin contributes to activin A-induced ovarian cancer cell migration.