溶血磷脂酸通过Rac的活化诱导卵巢癌细胞的侵袭转移  

Lysophosphatidic acid （LPA） stimulates invasion and metastatic colonization of ovarian cancer cells through Rac activation

作　　者：余雪琛[1] 张元珍[1] 陈慧君[1] 

机构地区：[1]武汉大学中南医院妇产科,430071

出　　处：《中华肿瘤杂志》2015年第2期95-100,共6页Chinese Journal of Oncology

基　　金：国家自然基金青年基金（81202071）

摘　　要：目的：探讨溶血磷脂酸（ LPA）诱导卵巢癌细胞侵袭转移的作用机制。方法采用裸鼠转移瘤模型检测卵巢癌细胞SK-OV3、HEY、OVCAR3、IGROV1的体内转移能力；Matrigel侵袭实验检测卵巢癌细胞对LPA的体外反应性；采用Rac （－）或Rac （＋）腺病毒感染相应卵巢癌细胞，检测其LPA反应性的改变；谷胱甘肽巯基转移酶融合蛋白下拉分析检测经LPA诱导后Rac、Cdc42、RhoA活化水平。结果裸鼠转移瘤实验显示，接种SK-OV3和HEY细胞的裸鼠，体内布满转移瘤，该细胞为侵袭性卵巢癌细胞；接种OVCAR3和IGROV1细胞的裸鼠，体内无明显转移瘤，该细胞为非侵袭性卵巢癌细胞。 Matrigel侵袭实验显示，LPA刺激前后，SK-OV3细胞A值分别为0．594±0．023和1．697±0．049，HEY细胞A值分别为0．804±0．070和1．851±0．095，差异均有统计学意义（均P＜0．01）；LPA刺激前后，OVCAR3细胞A值分别为0．336±0．017和0．374±0．007，IGROV1细胞A值分别为0．491±0．036和0．479±0．061，差异均无统计学意义（均P＞0．05）。 SK-OV3和HEY细胞对LPA反应性良好，OVCAR3和IGROV1细胞对LPA反应性较差。卵巢癌细胞的体内转移能力与其对LPA的反应性呈正相关（r＝0．983，P＜0．05）。 Rac（－）腺病毒感染前后，SK-OV3细胞对LPA诱导的细胞侵袭倍增能力分别为2．988±0．095和0．997±0．100，HEY细胞对LPA诱导的细胞侵袭倍增能力分别为2．404±0．059和0．901±0．072，差异均有统计学意义（均P＝0．01），Rac（－）腺病毒可阻断侵袭性卵巢癌细胞对LPA诱导的反应。 Rac（＋）腺病毒感染前后，OVCAR3细胞对LPA诱导的细胞侵袭倍增能力分别为1．072±0．080和1．898±0．078， IGROV1细胞对LPA诱导的细胞侵袭倍增能力分别为1．002±0．044和2．141±0．057，差异均有统计学意义（P＜0．01，P＜0．05），Rac（＋）腺病毒可使非侵袭性卵巢癌细胞对LPA的诱导�Objective To investigate the mechanisms of lysophosphatidic acid （ LPA ） in stimulating invasion and metastatic colonization of ovarian cancer cells. Methods The metastatic ability in vivo of ovarian cancer SK-OV3, HEY, OVCAR3, and IGROV1 cells was determined in tumor-bearing nude mouse models. Matrigel assay was used to detect the changes of response in vitro of ovarian cancer cells to LPA after Rac（ -） or Rac（ ＋） adenovirus treatment. LPA-induced Rho GTPase activation was detected by GST-fusion protein binding assay. Results The peritoneal metastatic colonization assay showed overt metastatic colonization in mice receiving SK-OV3 and HEY cell inoculation, indicating that they are invasive cells. Metastatic colonization was not detected in animals receiving OVCAR3 and IGROV1 cells, indicating that these cells are non-invasive cells. In the matrigel invasion assay, exposure to LPA led to a notably greater migratory response in metastatic SK-OV3 and HEY cells （Optical density：SK-OV3 cells：0. 594 ± 0. 023 vs. 1. 697 ± 0. 049, P〈0. 01; HEY cells：0. 804 ± 0. 070 vs. 1. 851 ± 0. 095, P〈0. 01）. But LPA did little in the non-metastatic OVCAR3 and IGROV1 cells （Optical density A：OVCAR3 cells：0. 336 ± 0. 017 vs. 0. 374 ± 0. 007, P 〉0. 05;IGROV1 cells： 0. 491 ± 0. 036 vs. 0. 479 ± 0. 061, P 〉0. 05）. LPA migratory responses of ovarian cancer cells were closely related to their metastatic colonization capabilities （r=0.983, P〈0.05）. Rac（ -） blocked the LPA response of invasive SK-OV3 and HEY cells （LPA-induced fold increase of cell migration：SK-OV3 cells：2. 988 ± 0. 095 vs. 0. 997 ± 0. 100,P=0. 01; HEY cells：2. 404 ± 0. 059 vs. 0. 901 ± 0. 072, P=0. 01）. But Rac（ ＋） confered the non-invasive cells with LPA response and invasion capability （ LPA-induced fold increase of cell migration： OVCAR3 cells：1. 072 ± 0. 080 vs. 1. 898 ± 0. 078,P 〈0. 01; IGROV1 cells： 1. 002 ± 0. 044 vs. 2. 141 ± 0. 057, P 〈0. 05）. Among Rho GTPases, only R

关 键 词：卵巢肿瘤 溶血磷脂酸 肿瘤侵袭 肿瘤转移 

分 类 号：R737.31[医药卫生—肿瘤]