NFATc 1 regulates cell proliferation , migration , and invasion of ovarian cancer skov 3 cells in vitro and in vivo

NFATc1 (nuclear factor of activated T-cells c1) is associated with malignancy in several cancer models. However, the expression and function of NFATc1 in ovarian cancer remain elusive. In the present study, we investigated the role of NFATc1 in human epithelial ovarian cancer (EOC) using human ovarian adenocarcinoma SKOV3 cells and patient characteristics. NFATc1 expression was silenced by siRNA in the SKOV3 ovarian cancer cell line and in human ovarian cancer nude mouse xenografts. Real-time PCR, western blotting, immunohistochemical staining, MTT, flow cytometry, Transwell, erasion trace and mouse assays were used to detect NFATc1 expression, cell proliferation, apoptosis, cell invasion and migration, tumor growth and angiogenesis. Survival analysis was performed to assess the correlation between NFATc1 expression and survival. NFATc1 was overexpressed in the SKOV3 ovarian cancer cell line and in human serous/mucinous ovarian cancer tissues. The silencing of NFATc1 expression by siRNA reduced cell proliferation and migration and promoted apoptosis in vitro and decreased the ovarian cancer cell tumorigenesis in vivo in nude mice. NFATc1 overexpression in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival and of early relapse (P<0.01) in a univariate analysis. Our present data provide evidence that NFATc1 is overexpressed in human serous/mucinous ovarian cancer and is associated with a poor prognosis. NFATc1 silencing regulates the cell cycle, apoptosis, invasion and migration. NFATc1 thus has the potential to be a therapeutic target and to be used in EOC diagnosis and prognosis. Introduction The nuclear factor of activated T-cell (NFAT) family is a multigene family of Ca2+/calcineurin-dependent transcription factors that were initially identified in T‐lymphocytes (1) and is composed of four classical calcium-responsive members, NFATc1, NFATc2, NFATc3 and NFATc4, and the new recently cloned member calcium insensitive NFAT5 (2). Each of these proteins appears to be expressed as several isoforms by alternative splicing. NFAT proteins are confined to the cytoplasm of unstimulated cells in a highly phosphorylated form under basal conditions. After an increase in intracellular calcium, NFAT proteins are dephosphorylated by the serine/threonine phosphatase calcineurin and translocate to the nucleus. Once in the nucleus, they bind to consensus DNA sequences, activating the transcription of NFAT-dependent genes (3), and its expression is associated with other essential transcription factors, such as AP-1 (4), GATA-4, EGR, MEF2 and the important oncogene FOXP (5). In addition to the immune system, NFAT is functionally important in osteoclast differentiation (6), endothelial cell differentiation in cardiac valve morphogenesis (7) and in preventing organ transplant rejection (8). Over the past 20 years, evidence supports a role for NFAT signaling in cell growth and development, and it is expressed not only in lymphocytes but also in other histocytes (including epithelial cells) (9-11). Some researchers have further found that NFAT is also closely related to tumorigenicity (12). The subtypes of the NFAT family have unique functions; among them, NFATc1 (nuclear factor of activated T-cells c1) (also referred to as NFAT2) has been demonstrated to be associated with tumorigenesis (13-15). Studies have found that NFATc1 plays an essential role in the regulation of fibroblast NIH 3T3 cells through the induction of the tumoral phenotype, which indicates that NFATc1 is a potential oncogene (16). In addition, as previously mentioned, NFATc1 proteins are dephosphorylated by calcineurin, and calcineurin plays an essential role in the development of malignant lymphomas (17). Recent evidence also has confirmed that NFATc1 is overexpressed in other malignancies and is a key factor in their development, such as prostate (18) and pancreatic cancers (19). NFATc1 is overexpressed in human solid tumors and hematological malignancies (20) and is also functionally important in NFATc1 regulates cell proliferation, migration, and invasion of ovarian cancer skov3 cells in vitro and in vivo LONG LI1, ZHAONING DuAN2, JIHuI Yu1 and HONG-XING DANG3 Departments of 1Physical Examination and 2Gynecology, The First Affiliated Hospital of Chongqing Medical University; 3Department of PICu, Children's Hospital of Chongqing Medical university, Ministry of Education Key Laboratory of Child Development and Disorders; China International Science and Technology Cooperation base of Child Development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400016, P.R. China Received January 14, 2016; Accepted February 20, 2016 DOI: 10.3892/or.2016. 4904 Correspondence to: Dr Hong-Xing Dang, Department of PICu, Children's Hospital of Chongqing Medical university, Chongqing