Zou Minghua, Zhang Xianquan, Xu Changhua
Department of Oncology, The Second Affiliated Hospital, Chongqing Medical University, 74 Linjiang Road, Chongqing, 400010, China.
Cell Oncol (Dordr). 2016 Feb;39(1):47-57. doi: 10.1007/s13402-015-0251-7. Epub 2015 Oct 28.
Ovarian cancer is a highly lethal gynecological malignancy for which the overall prognosis has remained poor over the past few decades. Interleukin (IL6) has been found to be a major contributor to the initiation and progression of ovarian cancer. This cytokine exerts its activity through activation of several signaling pathways, in particular the signal transducer and activator of transcription (STAT3) pathway. Here, we aimed at investigating the capacity of a natural dietary compound found in cruciferous vegetables, i.e., 3,3'-diindolylmethane (DIM), to target the metastatic phenotype of ovarian cancer cells through functional p-STAT3.
The human ovarian carcinoma-derived cell lines SKOV3 and A2780 were treated with IL6 and/or DIM and subjected to in vitro proliferation, adhesion, migration and invasion assays to assess the anti-metastatic and anti-IL6 effects of DIM, as well as to assess gene expression alterations before and after shRNA-mediated STAT3 silencing.
We found that DIM inhibits IL6-mediated increases in ovarian cancer cell adhesion, migration and invasion. These results were corroborated by shRNA-mediated STAT3 silencing. Through Western blot and ELISA analyses direct evidence was provided for the capacity of DIM to inhibit ovarian cancer cell adhesion, migration and invasion, which was found to be associated with down-regulation of the matrix metalloproteinases MMP-2 and MMP-9.
From our data we conclude that DIM exhibits an anti-IL6-like activity by inhibiting p-STAT3 enhanced ovarian cancer cell proliferation and in vitro metastasis-associated events, i.e., adhesion, migration and invasion. Most significantly, MMP-2 and MMP-9, which are known to promote and enhance metastasis, were found to act as targets of DIM. This anti-IL6-like property of DIM may pave the way for the development of novel ovarian cancer preventive and/or therapeutic strategies.
卵巢癌是一种致死率很高的妇科恶性肿瘤，在过去几十年中其总体预后一直很差。白细胞介素（IL6）已被发现是卵巢癌发生和发展的主要促成因素。这种细胞因子通过激活多种信号通路发挥其活性，特别是信号转导和转录激活因子（STAT3）通路。在此，我们旨在研究十字花科蔬菜中发现的一种天然膳食化合物，即3,3'-二吲哚甲烷（DIM），通过功能性p-STAT3靶向卵巢癌细胞转移表型的能力。
用人卵巢癌衍生的细胞系SKOV3和A2780分别用IL6和/或DIM处理，并进行体外增殖、黏附、迁移和侵袭试验，以评估DIM的抗转移和抗IL6作用，以及评估shRNA介导的STAT3沉默前后的基因表达变化。
我们发现DIM可抑制IL6介导的卵巢癌细胞黏附、迁移和侵袭增加。shRNA介导的STAT3沉默证实了这些结果。通过蛋白质印迹法和酶联免疫吸附测定分析，直接证明了DIM抑制卵巢癌细胞黏附、迁移和侵袭的能力，发现这与基质金属蛋白酶MMP-2和MMP-9的下调有关。
根据我们的数据，我们得出结论，DIM通过抑制p-STAT3增强的卵巢癌细胞增殖以及体外转移相关事件，即黏附、迁移和侵袭，表现出类似抗IL6的活性。最显著的是，已知促进和增强转移的MMP-2和MMP-9被发现是DIM的作用靶点。DIM的这种类似抗IL6的特性可能为开发新的卵巢癌预防和/或治疗策略铺平道路。
