From the Cell Biology and Physiology Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India and.
J Biol Chem. 2014 Jan 17;289(3):1415-28. doi: 10.1074/jbc.M113.535427. Epub 2013 Nov 19.
Uncontrolled cell growth and tissue invasion define the characteristic features of cancer. Several growth factors regulate these processes by inducing specific signaling pathways. We show that FGF16, a novel factor, is expressed in human ovary, and its expression is markedly increased in ovarian tumors. This finding indicated possible involvement of FGF16 in ovarian cancer progression. We observed that FGF16 stimulates the proliferation of human ovarian adenocarcinoma cells, SKOV-3 and OAW-42. Furthermore, through the activation of FGF receptor-mediated intracellular MAPK pathway, FGF16 regulates the expression of MMP2, MMP9, SNAI1, and CDH1 and thus facilitates cellular invasion. Inhibition of FGFR as well as MAPK pathway reduces the proliferative and invasive behavior of ovarian cancer cells. Moreover, ovarian tumors with up-regulated PITX2 expression also showed activation of Wnt/β-catenin pathway that prompted us to investigate possible interaction among FGF16, PITX2, and Wnt pathway. We identified that PITX2 homeodomain transcription factor interacts with and regulates FGF16 expression. Furthermore, activation of the Wnt/β-catenin pathway induces FGF16 expression. Moreover, FGF16 promoter possesses the binding elements of PITX2 as well as T-cell factor (Wnt-responsive), in close proximity, where PITX2 and β-catenin binds to and synergistically activates the same. A detail study showed that both PITX2 and T-cell factor elements and the interaction with their binding partners are necessary for target gene expression. Taken together, our findings indicate that FGF16 in conjunction with Wnt pathway contributes to the cancer phenotype of ovarian cells and suggests that modulation of its expression in ovarian cells might be a promising therapeutic strategy for the treatment of invasive ovarian cancers.
不受控制的细胞生长和组织侵袭定义了癌症的特征。几种生长因子通过诱导特定的信号通路来调节这些过程。我们表明，FGF16 是一种新型因子，在人卵巢中表达，其在卵巢肿瘤中的表达明显增加。这一发现表明 FGF16 可能参与了卵巢癌的进展。我们观察到 FGF16 刺激人卵巢腺癌细胞 SKOV-3 和 OAW-42 的增殖。此外，通过激活 FGF 受体介导的细胞内 MAPK 通路，FGF16 调节 MMP2、MMP9、SNAI1 和 CDH1 的表达，从而促进细胞侵袭。抑制 FGFR 以及 MAPK 通路可降低卵巢癌细胞的增殖和侵袭行为。此外，上调 PITX2 表达的卵巢肿瘤也显示出 Wnt/β-catenin 通路的激活，促使我们研究 FGF16、PITX2 和 Wnt 通路之间可能的相互作用。我们确定了 PITX2 同源域转录因子与 FGF16 相互作用并调节其表达。此外，Wnt/β-catenin 通路的激活诱导 FGF16 表达。此外，FGF16 启动子具有 PITX2 和 T 细胞因子（Wnt 反应性）的结合元件，紧密相邻，其中 PITX2 和 β-catenin 结合并协同激活相同的元件。一项详细的研究表明，PITX2 和 T 细胞因子元件及其与结合伙伴的相互作用对于靶基因的表达都是必要的。总之，我们的研究结果表明，FGF16 与 Wnt 通路一起导致卵巢细胞的癌症表型，并表明调节其在卵巢细胞中的表达可能是治疗侵袭性卵巢癌的一种有前途的治疗策略。
