Park Sang Ho, Chung Youn Jee, Song Jae Yen, Kim Sang Il, Pépin David, MacLaughlin David T, Donahoe Patricia K, Kim Jang Heub
Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul 137-140, Republic of Korea.
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Int J Oncol. 2017 Mar;50(3):1022-1028. doi: 10.3892/ijo.2017.3874. Epub 2017 Feb 13.
Müllerian inhibiting substance/anti-Müllerian hormone (MIS/AMH) has been suggested as a biotherapeutic agent in gynecological cancers that highly express the MIS/AMH type II receptors (MISRII/AMHRII) but the anticancer mechanisms by which MIS/AMH acts are not fully understood. Our experiments show that MIS/AMH inhibits ovarian cancer by deregulating the Wnt signal pathway via the β-catenin interacting protein (ICAT). MIS/AMH inhibition of ICAT by small interfering RNAs (siRNA) decreased ICAT driven ovarian cancer cell viability as measured by the methylthiazoltetrazolium assay, reversed cell cycle arrest and annexin V expression and diminished migration by scratch wound assay. Changes in expression of regulatory proteins were shown by western blotting. We determined that MIS/AMH upregulated ICAT in ovarian cancer cell line which caused decreased cell viability, cell cycle arrest and apoptosis. This effect, however, was blocked when ICAT was downregulated by siRNA. The present study demonstrates a role for ICAT in MIS/AMH mediated inhibition of the Wnt signaling pathway in ovarian cancer.
苗勒管抑制物质/抗苗勒管激素（MIS/AMH）已被提议作为一种生物治疗剂用于高表达MIS/AMH II型受体（MISRII/AMHRII）的妇科癌症，但MIS/AMH发挥作用的抗癌机制尚未完全明确。我们的实验表明，MIS/AMH通过β-连环蛋白相互作用蛋白（ICAT）失调Wnt信号通路来抑制卵巢癌。通过小干扰RNA（siRNA）抑制MIS/AMH对ICAT的作用，可降低ICAT驱动的卵巢癌细胞活力（通过噻唑蓝比色法测定），逆转细胞周期阻滞和膜联蛋白V表达，并通过划痕试验减少细胞迁移。通过蛋白质印迹法显示调节蛋白表达的变化。我们确定MIS/AMH在卵巢癌细胞系中上调ICAT，这导致细胞活力降低、细胞周期阻滞和凋亡。然而，当通过siRNA下调ICAT时，这种作用被阻断。本研究证明了ICAT在MIS/AMH介导的卵巢癌Wnt信号通路抑制中的作用。
