MicroRNA let-7f inhibits tumor invasion and metastasis by targeting MYH9 in human gastric cancer.
MicroRNA let-7f inhibits tumor invasion and metastasis by targeting MYH9 in human gastric cancer.
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MicroRNA Let-7f 通过靶向 MYH9 抑制人胃癌肿瘤侵袭和转移
DOI：
10.1371/journal.pone.0018409
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发表时间：
2011-04-18
期刊：
影响因子：
3.7
通讯作者：
Fan D
中科院分区：
文献类型：
--
作者：
Liang S;He L;Zhao X;Miao Y;Gu Y;Guo C;Xue Z;Dou W;Hu F;Wu K;Nie Y;Fan D
背景：microRNAs(MiRNAs)是重要的调控因子，在肿瘤的发生和发展中起着关键作用。之前的一份报告显示，let-7家族成员可以在许多癌症中发挥肿瘤抑制因子的作用。通过miRNA阵列，我们发现LET-7f在高转移潜能的胃癌细胞系GC9811-P和SGC7901-M中表达下调，与其亲本细胞系GC9811和SGC7901-NM相比，但其机制尚不清楚。在本研究中，我们研究了let-7f是否作为一种肿瘤抑制因子来抑制胃癌的侵袭和转移。方法/主要实时聚合酶链式反应显示，在转移性胃癌组织和潜在高转移性细胞系中，let-7f的表达水平降低。LET-7f模拟物转染GC9811-P和SGC7901-M细胞后，细胞侵袭和迁移能力明显减弱。裸鼠移植瘤模型证实，慢病毒pGCsil-GFP-let-7f转染后，let-7f可抑制胃癌的体内转移。荧光素酶分析表明，let-7f直接与Myh9编码肌球蛋白IIA的3‘端非编码区结合，实时定量PCR和Western blotting进一步表明let-7f在mRNA和蛋白水平下调了肌球蛋白IIA的表达。结论/意义本研究证实LET-7f在胃癌中的过表达可通过直接靶向肿瘤转移相关基因Myh9来抑制胃癌细胞的侵袭和迁移。这些数据表明，鉴于let-7f具有减少细胞侵袭和转移的能力，它可能是一种新的胃癌治疗候选药物。
Background MicroRNAs (miRNAs) are important regulators that play key roles in tumorigenesis and tumor progression. A previous report has shown that let-7 family members can act as tumor suppressors in many cancers. Through miRNA array, we found that let-7f was downregulated in the highly metastatic potential gastric cancer cell lines GC9811-P and SGC7901-M, when compared with their parental cell lines, GC9811 and SGC7901-NM; however, the mechanism was not clear. In this study, we investigate whether let-7f acts as a tumor suppressor to inhibit invasion and metastasis in gastric cancers. Methodology/Principal Real-time PCR showed decreased levels of let-7f expression in metastatic gastric cancer tissues and cell lines that are potentially highly metastatic. Cell invasion and migration were significantly impaired in GC9811-P and SGC7901-M cell lines after transfection with let-7f-mimics. Nude mice with xenograft models of gastric cancer confirmed that let-7f could inhibit gastric cancer metastasis in vivo after transfection by the lentivirus pGCsil-GFP- let-7f. Luciferase reporter assays demonstrated that let-7f directly binds to the 3′UTR of MYH9, which codes for myosin IIA, and real-time PCR and Western blotting further indicated that let-7f downregulated the expression of myosin IIA at the mRNA and protein levels. Conclusions/Significance Our study demonstrated that overexpression of let-7f in gastric cancer could inhibit invasion and migration of gastric cancer cells through directly targeting the tumor metastasis-associated gene MYH9. These data suggest that let-7f may be a novel therapeutic candidate for gastric cancer, given its ability to reduce cell invasion and metastasis.
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