RasGRF2 promotes migration and invasion of colorectal cancer cells by modulating expression of MMP9 through Src/Akt/NF-κB pathway
RasGRF2 promotes migration and invasion of colorectal cancer cells by modulating expression of MMP9 through Src/Akt/NF-κB pathway
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DOI：
10.1080/15384047.2018.1529117
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发表时间：
2019-04-03
影响因子：
3.6
通讯作者：
Yang, Tao
中科院分区：
文献类型：
--
作者：
Lu, Peifen;Chen, Junjun;Yang, Tao
Ras 特异性鸟嘌呤核苷酸释放因子 2 (RasGRF2) 是鸟嘌呤核苷酸交换因子家族的成员，在多种组织和癌症中表达。然而，RasGRF2在癌症中的作用报道较少，尤其是在结直肠癌（CRC）中。因此，本研究旨在研究 RasGRF2 的功能及其影响 CRC 样本和细胞系中肿瘤进展的方式。我们首先测量了结肠癌手术切除后26对肿瘤和非肿瘤结肠组织中RasGRF2 mRNA水平，并测定了97对石蜡包埋结肠癌组织中RasGRF2蛋白水平，发现与邻近非肿瘤组织相比，结直肠肿瘤组织中RasGRF2 mRNA和蛋白水平升高。然后，我们检查了 RasGRF2 敲低对 CRC 细胞（SW480、HCT116 和 LS174T）增殖、迁移和侵袭的影响。将RasGRF2敲低的HCT116细胞注射到裸鼠尾静脉中以产生转移模型，并测量肿瘤转移情况。我们发现，CRC 细胞中 RasGRF2 的敲低会减少其体外迁移和侵袭以及小鼠体内的转移。此外，我们还探讨了 RasGRF2 介导的 CRC 迁移和侵袭的潜在分子机制。结果表明，CRC 细胞中 RasGRF2 的敲低会损害 MMP9 的表达并抑制 Src/Akt 和 NF-kappa B 信号传导的激活。我们得出结论，RasGRF2 在控制 CRC 的迁移和侵袭中发挥作用，并通过 Src/PI 3-激酶和 NF-kappa B 途径调节 MMP9 的表达。
Ras-specific guanine nucleotide-releasing factor 2 (RasGRF2) is a member of the guanine nucleotide exchange factors family which is expressed in a variety of tissues and cancer. However, the role of RasGRF2 in cancer is less reported, especially in colorectal cancer(CRC). Hence, the present study aimed to investigated the function of RasGRF2 and ways in which it affects tumor progression in CRC samples and cell lines. We first measured RasGRF2 mRNA level in 26 paired tumor and nontumor colon tissues after colon cancer surgical resection, and determined RasGRF2 protein level in 97 paired paraffin-embedded colon cancer tissues, and found that levels of RasGRF2 mRNA and protein were increased in colorectal tumor tissues, compared with adjacent non-tumor tissues. We then examined the effects of RasGRF2 knockdown on proliferation, migration and invasion were analyzed in CRC cells (SW480, HCT116 and LS174T). HCT116 cells with RasGRF2 knockdown were injected into the tail vein in nude mice to yield metastatic model, and tumor metastasis was measured as well. We found that knockdown of RasGRF2 in CRC cells reduced their migration and invasion in vitro and metastasis in mice. Furthermore, we explored the underlying molecular mechanism for RasGRF2-mediated CRC migration and invasion. The results showed that knockdown of RasGRF2 in CRC cells impairing the expression of MMP9 and inhibiting the activation of Src/Akt and NF-kappa B signaling. We conclude that RasGRF2 plays a role in controlling migration and invasion of CRC and modulates the expression of MMP9 through Src/PI 3-kinase and the NF-kappa B pathways.