Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China; Institute of Gynecological Minimally Invasive Medicine, Tongji University School of Medicine, Shanghai, China.
Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China; Institute of Gynecological Minimally Invasive Medicine, Tongji University School of Medicine, Shanghai, China.
Biochem Biophys Res Commun. 2019 Oct 20;518(3):416-422. doi: 10.1016/j.bbrc.2019.07.098. Epub 2019 Aug 22.
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 ARHGAP10 was overexpressed or when ovarian cancer cells were pre-treated with AMD3100 or SU1498. Knockdown of ARHGAP10 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.
CXCL12/CXCR4 轴被强烈认为是卵巢癌肿瘤侵袭和转移的关键决定因素。然而，对于该轴下游信号如何促进卵巢癌细胞侵袭和转移，人们知之甚少。ARHGAP10 是 Rho GTP 酶激活蛋白的一个成员，是卵巢癌中的一个潜在的肿瘤抑制基因。在这项研究中，在卵巢癌组织和配对的相邻非癌组织中发现了 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 的蛋白水平之间存在负相关。CXCL12 刺激降低了 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) 的预处理消除了 CXCL12 对 ARHGAP10 的表达下调作用。最后，体外功能测定表明，当 ARHGAP10 过表达或卵巢癌细胞预先用 AMD3100 或 SU1498 处理时，CXCL12 不会刺激卵巢癌细胞侵袭。ARHGAP10 的敲低显著抑制了 SU1498 对卵巢癌细胞侵袭和肺转移的抑制作用。总之，这些发现表明，CXCL12/CXCR4 通过抑制 ARHGAP10 的表达促进卵巢癌细胞侵袭，该过程由 VEGF/VEGFR2 信号介导。
