Sema3A通过调控上皮-间质转化/基质金属蛋白酶-2参与上皮性卵巢癌转移

doi:10.19401/j.cnki.1007-3639.2020.06.004

中国癌症杂志 ›› 2020, Vol. 30 ›› Issue (6): 428-434.doi: 10.19401/j.cnki.1007-3639.2020.06.004

Sema3A通过调控上皮-间质转化/基质金属蛋白酶-2参与上皮性卵巢癌转移

王晓琴，傅鑫蕾，马如越，杨丽娜，陈亚萍，张丽文

复旦大学附属上海市第五人民医院妇产科，上海 200240

出版日期:2020-06-30 发布日期:2020-07-15
通信作者: 张丽文 E-mail: 13321837079@163.com
基金资助:
复旦大学附属上海市第五人民医院院内科研课题孵育项目（2018WYFY04）；国家自然科学基金（81602259）。

Sema3A regulates metastasis through epithelial-mesenchymal transition/matrix metalloproteinase-2 in epithelial ovarian cancer

WANG Xiaoqin, FU Xinlei, MA Ruyue, YANG Lina, CHEN Yaping, ZHANG Liwen

Department of Obstetrics and Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China

Published:2020-06-30 Online:2020-07-15
Contact: ZHANG Liwen E-mail: 13321837079@163.com

摘要/Abstract

摘要： 背景与目的：Semaphorin 3A（Sema3A）最初被认为在神经轴突导向中起重要作用，近期也被认为是一种候选的肿瘤抑制因子，参与肿瘤发生。探讨Sema3A与上皮性卵巢癌（epithelial ovarian cancer，EOC）转移的关系及其潜在机制。方法：选取2018年3月—12月于复旦大学附属上海市第五人民医院妇产科住院初治的20例腹腔转移的EOC患者（转移组）和20例无腹腔转移的EOC患者（非转移组）的卵巢组织蜡块标本，采用免疫组织化学法检测两组EOC患者卵巢组织标本中Sema3A的表达，并分析Sema3A与各组临床病理学特征的关系。蛋白质印迹法（Western blot）和实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction，RTFQ-PCR）检测5种卵巢癌细胞系中Sema3A 的表达水平；构建Sema3A过表达和沉默细胞株；transwell法和划痕实验检测Sema3A对细胞侵袭和迁移能力的影响；Western blot检测细胞上皮-间质转化（epithelial-mesenchymal transition，EMT）相关标志物和基质金属蛋白酶（matrix metalloproteinase，MMP）-2蛋白的表达情况。结果：转移组较非转移组的Sema3A表达显著降低；转移组中，Sema3A表达与患者年龄、组织分化程度、肿瘤大小无关，而与病理学类型、国际妇产科联盟（International Federation of Gynecology and Obstetrics，FIGO）分期、有无淋巴结转移有关。5种卵巢癌细胞系中，A2780细胞Sema3A表达水平较低，Sk-OV-3细胞Sema3A表达水平较高。Sema3A过表达，细胞的侵袭和迁移能力下降，钙黏蛋白E（E-cadherin）、紧密连接蛋白-1（ZO-1）表达上调，钙黏蛋白N（N-cadherin）、锌指转录因子（Slug）和MMP-2表达下调；而Sema3A沉默后，细胞的侵袭和迁移能力增强，E-cadherin、ZO-1表达下调，N-cadherin、Slug和MMP-2表达上调。结论：Sema3A通过调控EMT/MMP-2途径参与EOC转移，可能作为预测EOC转移和预后的生物学指标。

关键词: 上皮性卵巢癌, Sema3A, 腹腔转移, 上皮-间充质转化, 基质金属蛋白酶

Abstract: Background and purpose: Semaphorin 3A (Sema3A) is initially considered to play an important role in axonal orientation. Recently, Sema3A has also been considered as a candidate tumor suppressor involved in the tumorigenesis. The purpose of this study was to investigate the relationship between Sema3A and metastasis of epithelial ovarian cancer (EOC) and its underlying mechanism. Methods: We selected 20 ovarian tissue samples of EOC patients with peritoneal metastasis (the metastatic group) and 20 ovarian tissue samples of EOC patients without peritoneal metastasis (the non-metastatic group) treated initially in the Department of Gynecology of Shanghai Fifth People’s Hospital, Fudan University from Mar. 2018 to Dec. 2018, and the expression of Sema3A in ovarian tissue samples of two groups was detected by immunohistochemistry. The relationship between Sema3A and the clinical pathological features of each group was analyzed. The expression levels of Sema3A in five ovarian cancer cell lines were detected by Western blot and real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR). Establishment of stable ovarian cancer cell lines harboring Sema3A cDNA or shRNA was conducted by lentilviral infection. Transwell method and scratch test were employed to determine the invasion and migration abilities in two cell lines. The expressions of epithelial-mesenchymal transition (EMT) markers and matrix metalloproteinase (MMP)-2 protein in two cell lines were detected by Western blot. Results: The expression level of Sema3A in the metastatic group was significantly lower than that in the non-metastatic group. In the metastatic group, the expression of Sema3A was not related to the patient's age, degree of tissue differentiation or tumor size, but related to pathological type, International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. Among the five ovarian cancer cell lines, the expression level of Sema3A was lower in A2780 cells, but higher in Skov3 cells. Overexpression of Sema3A inhibited the migration and invasion abilities in A2780. Meanwhile, levels of E-cadherin and ZO-1 were significantly up-regulated, and levels of N-cadherin, Slug and MMP-2 were significantly down-regulated. Knockdown of Sema3A promoted the migration and invasion abilities in SK-OV-3. Meanwhile, levels of E-cadherin and ZO-1 were significantly down-regulated whereas levels of N-cadherin, Slug and MMP-2 were significantly up-regulated. Conclusion: Sema3A participates in the metastasis of EOC by regulating EMT/MMP-2, and may be used as a biological indicator to predict metastasis and prognosis of EOC.

Key words: Epithelial ovarian cancer, Sema3A, Peritoneal metastasis, Epithelial-mesenchymal transition, Matrix metalloproteinase

王晓琴, 傅鑫蕾, 马如越, 杨丽娜, 陈亚萍, 张丽文. Sema3A通过调控上皮-间质转化/基质金属蛋白酶-2参与上皮性卵巢癌转移[J]. 中国癌症杂志, 2020, 30(6): 428-434.

WANG Xiaoqin, FU Xinlei, MA Ruyue, YANG Lina, CHEN Yaping, ZHANG Liwen. Sema3A regulates metastasis through epithelial-mesenchymal transition/matrix metalloproteinase-2 in epithelial ovarian cancer[J]. China Oncology, 2020, 30(6): 428-434.

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Sema3A通过调控上皮-间质转化/基质金属蛋白酶-2参与上皮性卵巢癌转移

Sema3A regulates metastasis through epithelial-mesenchymal transition/matrix metalloproteinase-2 in epithelial ovarian cancer

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