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  • br Introduction br Ovarian cancer is the th leading


    1. Introduction
    Ovarian cancer is the 5th leading cause of cancer death among women and causes more deaths than all other gynecologic malignancies combined in the United States, resulting in approximately 14,000 es-timated deaths in 2018. When ovarian cancer is diagnosed at early stage, patients usually have a favorable prognosis and the overall 5-year survival rate is as high as 93%. However, due to lack of early symptoms and effective screening tests, more than 70% of patients are diagnosed at advanced stages (stage III or IV) with distant metastases, at which point the 5-year survival rate falls below 30% [1]. Current treatments of ovarian cancer include radiotherapy and chemotherapy combined with debulking surgery [2], however, the high rate of relapse and che-moresistance make the management of ovarian cancer particularly challenging [3]. Therefore, understanding the molecular mechanisms underlying the development and progression of ovarian cancer is ur-gently required.
    Many growth factors, their receptors, and downstream signaling pathways are often important regulators of tumor initiation and pro-gression [4]. Of these, activin A signaling is a well-known modulator of
    many types of human cancers, including ovarian cancer [5]. Activin A belongs to the transforming growth factor-β (TGF-β) superfamily and is a homodimer of inhibin βA (INHBA) subunits [6]. Activin A signals by binding to activin type II serine/threonine kinase receptors (either ACTRIIA or ACTRIIB) on the cell surface, which recruit and phos-phorylate activin type I receptors (ACTRIB, also known as activin re-ceptor-like kinase 4 (ALK4)). Classically, phosphorylated activin type I receptors induce phosphorylation of SMAD2 and SMAD3, which then form heterotrimeric complexes with common SMAD4. These complexes then translocate to the nucleus and act as transcription factors to modulate gene K 252a [7].
    Ovarian cancer is a highly metastatic disease and tumor cell mi-gration, invasion and metastasis are important factors in ovarian cancer recurrence and treatment failure (Klymenko et al., 2017). Clinical stu-dies have reported elevated activin A levels in serum, cyst fluid, and peritoneal fluid of patients with ovarian cancer [8]. Dean et al. de-monstrated higher transcript levels of activin A receptors (ACTRIIA and ACTRIB/ALK4) in ovarian cancer compared to normal ovaries, and high expression of both INHBA and ACTRIIA was associated with shorter disease-free survival in ovarian cancer patients [9]. Immunostaining
    * Corresponding author. Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute University of British Columbia, Room 317, 950 West 28th Avenue, Vancouver, British Columbia, V5Z 4H4, Canada.
    E-mail address: (P.C.K. Leung).
    analyses have also shown that higher levels of INHBA protein are cor-related with reduced survival in ovarian cystadenocarinoma patients [5]. These studies suggest the activation of activin A signaling plays an important role in ovarian cancer development and progression.
    E-cadherin and N-cadherin are classical transmembrane glycopro-teins that mediate cell-cell adhesion. E-cadherin is typically expressed in epithelial cells whereas N-cadherin expression is largely confined to neural or mesenchymal cells [10]. The loss of E-cadherin and upregu-lation of N-cadherin is a key event that facilitates the acquisition of invasive mesenchymal cell characteristics by epithelial cells, which plays crucial roles in tumor metastatic progression [11]. Reduced levels of E-cadherin are associated with advanced tumor progression and poor prognosis in ovarian cancer [12]. We have previously demonstrated that downregulation of E-cadherin contributes to increased ovarian cancer cell migration and invasiveness [13–16]. Several transcription factors are known to repress E-cadherin expression during carcino-genesis, including the zinc finger factors SNAIL [17] and SLUG [18].