CXCL12 promotes human ovarian cancer cell invasion through suppressing ARHGAP10 expression
CXCL12 promotes human ovarian cancer cell invasion through suppressing ARHGAP10 expression
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CXCL12通过抑制ARHGAP10表达促进人卵巢癌细胞侵袭
DOI：
10.1016/j.bbrc.2019.07.098
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发表时间：
2019-10-20
影响因子：
3.1
通讯作者：
Cheng, Zhong-ping
中科院分区：
文献类型：
--
作者：
Luo, Ning;Chen, Dan-dan;Cheng, Zhong-ping
CXCL12/CXCR4轴与卵巢癌的侵袭和转移密切相关。然而，CXCL12/CXCR4轴潜在的下游信号与卵巢癌细胞的侵袭和转移有关的信息知之甚少。ARHGAP10是Rho GTPase激活蛋白家族中的一员，是卵巢癌潜在的抑癌基因。本研究发现CXCL12、CXCR4、血管内皮生长因子(VEGF)、血管内皮生长因子受体-2(VEGFR2)和ARHGAP10在卵巢癌组织和癌旁组织中的表达水平呈负相关。CXCL12刺激可降低ARHGAP10的表达。此外，CXCR4抑制剂(AMD3100)或血管内皮生长因子受体-2(VEGFR2)抑制剂(SU1498)可抑制CXCL12诱导的ARHGAP10的表达。最后，体外功能分析表明，当ARHGAPIO过表达时，或者当卵巢癌细胞被AMD3100或SU1498预处理时，CXCL12不会刺激卵巢癌细胞的侵袭。敲除ARHGAPIO可显著抑制SU1498对卵巢癌细胞侵袭和肺转移的抑制作用。综上所述，这些发现表明CXCL12/CXCR4通过抑制ARHGAP10的表达而促进卵巢癌细胞的侵袭，而ARHGAP10的表达是由VEGF/VEGFR2信号介导的。(C)2019 Elsevier Inc.保留所有权利。
The CXCL12/CXCR4 axis is strongly implicated as key determinant of tumor invasion and metastasis in ovarian cancer. However, little is known about the potential downstream signals of the CXCL12/CXCR4 axis that contribute to ovarian cancer cell invasion and metastasis. ARHGAP10, a member of Rho GTPase activating proteins is a potential tumor suppressor gene in ovarian cancer. In this study, a negative correlation between the protein levels of CXCL12, CXCR4, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR2) and ARHGAP10 was uncovered in ovarian cancer tissues and paired adjacent noncancerous tissues. CXCL12 stimulation reduced the expression of ARHGAP10. Furthermore, the pretreatment of CXCR4 inhibitor (AMD3100) or the vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor (SU1498) abrogated the CXCL12-deduced expression of ARHGAP10. Finally, an in vitro functional assay revealed that CXCL12 did not stimulate ovarian cancer cell invasion when ARHGAPIO was overexpressed or when ovarian cancer cells were pre-treated with AMD3100 or SU1498. Knockdown of ARHGAPIO significantly suppressed the inhibitory effects of SU1498 on ovarian cancer cell invasion and lung metastasis. In summary, these findings suggest that CXCL12/CXCR4 promotes ovarian cancer cell invasion by suppressing ARHGAP10 expression, which is mediated by VEGF/VEGFR2 signaling. (C) 2019 Elsevier Inc. All rights reserved.