Laboratory for Reproductive Immunology, Fudan University Shanghai Medical College, Hospital and Institute of Obstetrics and Gynecology, IBS, Shanghai 200011, People's Republic of China.
J Mol Endocrinol. 2011 Aug 31;47(2):195-208. doi: 10.1530/JME-10-0165. Print 2011 Oct.
Tetraspanin CD82 is a wide-spectrum tumor metastasis suppressor that inhibits motility and invasiveness of cancer cells. Endometriosis is a benign gynecological disorder, but appears malignant behaviors including invasion, ectopic implantation and recurrence. This study is to elucidate the role of CD82 expression regulation in the pathogenesis of endometriosis. The short interfering RNA silence was established to analyze the roles of CD82, chemokine CCL2, and its receptor CCR2 in the invasiveness of endometrial stromal cells (ESCs). We have found that the mRNA and protein levels of CD82 in the primary normal ESCs from endometrium without endometriosis are significantly higher than that of the primary ESCs from eutopic endometrium and ectopic tissue. CD82 inhibits the invasiveness of ESCs by downregulating CCL2 secretion and CCR2 expression via mitogen-activated protein kinase (MAPK) and integrinβ1 signal pathway, and in turn upregulating the expression of TIMP1 and TIMP2 in an autocrine manner. The combination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with 17β-estradiol can promote the invasion of ESCs via suppressing CD82 expression and stimulating CCL2 secretion and CCR2 expression, and the enhanced interaction of CCL2-CCR2 recruits more macrophages into the ectopic milieu in a paracrine manner, which further downregulates CD82 expression in the ectopic ESCs. Our study has demonstrated for the first time that the abnormal lower CD82 expression in ESCs induced by TCDD and estrogen may be an important molecular basis of endometriosis pathogenesis through enhancing the CCL2 secretion and CCR2 expression and the invasion of ESCs via MAPK and integrinβ1 signal pathway.
四跨膜蛋白 CD82 是一种广谱肿瘤转移抑制因子，可抑制癌细胞的运动性和侵袭性。子宫内膜异位症是一种良性妇科疾病，但表现出恶性行为，包括侵袭、异位种植和复发。本研究旨在阐明 CD82 表达调控在子宫内膜异位症发病机制中的作用。利用短发夹 RNA 沉默技术分析 CD82、趋化因子 CCL2 及其受体 CCR2 在子宫内膜基质细胞（ESCs）侵袭中的作用。我们发现，无子宫内膜异位症的子宫内膜原发性正常 ESCs 的 CD82 mRNA 和蛋白水平明显高于在位和异位组织的原发性 ESCs。CD82 通过下调 MAPK 和整合素β1 信号通路下调 CCL2 分泌和 CCR2 表达，从而以自分泌方式上调 TIMP1 和 TIMP2 的表达，抑制 ESCs 的侵袭。2,3,7,8-四氯二苯并对二恶英（TCDD）与 17β-雌二醇联合作用可通过抑制 CD82 表达并刺激 CCL2 分泌和 CCR2 表达促进 ESCs 的侵袭，增强的 CCL2-CCR2 相互作用通过旁分泌方式招募更多的巨噬细胞进入异位环境，进一步下调异位 ESCs 中的 CD82 表达。本研究首次证明，TCDD 和雌激素诱导的 ESCs 中异常低表达的 CD82 通过增强 MAPK 和整合素β1 信号通路促进 CCL2 分泌和 CCR2 表达以及 ESCs 的侵袭，可能是子宫内膜异位症发病机制的重要分子基础。
