KLF9 suppresses gastric cancer cell invasion and metastasis through transcriptional inhibition of MMP28
KLF9 suppresses gastric cancer cell invasion and metastasis through transcriptional inhibition of MMP28
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KLF9通过抑制MMP28转录抑制胃癌细胞侵袭和转移
DOI：
10.1096/fj.201802531r
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发表时间：
2019-07-01
期刊：
影响因子：
4.8
通讯作者：
Zhuo, Wei
中科院分区：
文献类型：
--
作者：
Li, Yang;Sun, Qiang;Zhuo, Wei
胃癌（GC）是人类最致命的恶性肿瘤之一，其死亡的主要原因是转移。然而，胃癌转移的确切机制仍不清楚。为了筛选参与GC转移的关键转录因子（TF），我们对癌症基因组图谱数据库进行了生物信息学分析，发现Krüppel样因子9（KLF 9）是GC转移相关的TF。KLF 9在有远处转移的胃癌患者中表达明显低于无远处转移的胃癌患者。KLF 9的异位表达可明显抑制胃癌细胞的迁移和侵袭能力。相反，KLF 9的敲低赋予GC细胞更强的侵袭能力。此外，尾静脉注射证实KLF 9强烈抑制GC在体内的肺转移过程。从机制上讲，染色质免疫沉淀结合来自DNA元件百科全书的高通量测序数据显示，KLF 9特异性结合基质金属蛋白酶（MMP）28的启动子区域。进一步的定量真实的时间PCR和双荧光素酶分析表明KLF 9直接抑制MMP 28的转录。重要的是，通过增强MMP 28的表达，可以挽救由异位KLF 9表达引起的GC细胞侵袭和转移能力的降低。总的来说，我们的研究表明KLF 9通过抑制MMP 28转录显著抑制GC细胞的侵袭和转移。李，Y.，孙，Q.，蒋，M.，Li，S.，张杰，徐志，Guo，D.，中国植物研究所，顾，T.，Wang，B.，肖湖，周，T.，Zhuo，W. KLF 9通过抑制MMP 28的转录抑制胃癌细胞的侵袭和转移。FASEB J. 33，7915-7928（2019）。www.fasebj.org
Gastric cancer (GC) is among the most lethal human malignancies, and the leading cause of GC mortality is metastasis. However, the precise mechanism of GC metastasis remains unclear. To screen key transcriptional factors (TFs) involved in GC metastasis, we performed bioinformatics analysis of The Cancer Genome Atlas database and found that Krüppel‐like factor 9 (KLF9) is a GC metastasis‐associated TF. KLF9 is significantly decreased in patients with GC with distant metastasis compared with those patients without distant metastasis. Ectopic expression of KLF9 evidently inhibited the migration and invasion capabilities of GC cells. Conversely, knockdown of KLF9 endowed GC cells with stronger invasive capacity. Moreover, tail intravenous injection confirmed that KLF9 strongly inhibits the lung metastasis process of GC in vivo. Mechanistically, chromatin immunoprecipitation coupled with high‐throughput sequencing data from Encyclopedia of DNA Elements revealed that KLF9 specifically binds to the promoter region of matrix metalloproteinase (MMP)28. Further quantitative real‐time PCR and dual‐luciferase assay indicated that KLF9 directly inhibited MMP28 transcription. Importantly, decreased invasion and metastasis capability of GC cells caused by ectopic KLF9 expression could be rescued via reinforcing MMP28 expression in vivo. Collectively, our study indicates that KLF9 significantly suppresses GC cell invasion and metastasis through inhibiting MMP28 transcription.—Li, Y., Sun, Q., Jiang, M., Li, S., Zhang, J., Xu, Z., Guo, D., Gu, T., Wang, B., Xiao, L., Zhou, T., Zhuo, W. KLF9 suppresses gastric cancer cell invasion and metastasis through transcriptional inhibition of MMP28. FASEB J. 33, 7915–7928 (2019). www.fasebj.org