Ratio of miR-196s to HOXC8 messenger RNA correlates with breast cancer cell migration and metastasis.
Ratio of miR-196s to HOXC8 messenger RNA correlates with breast cancer cell migration and metastasis.
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DOI：
10.1158/0008-5472.can-10-1675
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Li Y;Zhang M;Chen H;Dong Z;Ganapathy V;Thangaraju M;Huang S
表达谱分析已经鉴定了转移相关的miRNAs，但是技术限制阻碍了转移抑制miRNAs的发现。在这项研究中，我们通过功能筛选寻找抑制转移的miRNAs。将单个miRNA慢病毒导入转移性MDA-MB-231乳腺癌细胞中，并分析其对细胞迁移的影响，细胞迁移是癌症转移的关键步骤。在筛选的486种miRNA中，鉴定出14种，包括miRNA-196家族的所有成员（miR-196 a1、miR-1962和miR-196 b）。miR-196 a1/2或miR-196 b的高表达可抑制乳腺癌细胞的体外侵袭和体内自发转移，表明miR-196家族成员是有效的转移抑制因子。我们发现miR-196抑制了转录因子HOXC 8的表达。siRNA介导的HOXC 8敲低抑制了细胞迁移和转移，HOXC 8的异位表达阻止了miR-196对细胞迁移和转移的影响，这暗示了功能联系。与已描述的其他转移相关miRNA不同，miR-196 s的表达与乳腺癌细胞迁移或临床乳腺肿瘤标本的转移状态无关。相反，我们检测到miR-196与HOXC 8信息的比例与乳腺癌细胞系的迁移行为以及临床样本的转移状态之间存在良好的相关性。我们的研究结果确定了miRNA-196 s作为有效的转移抑制因子，并揭示了miR-196 s与HOXC 8 mRNA的比例可能是乳腺肿瘤转移能力的指标。
Expression profiling has identified metastasis-associated miRNAs but technical limitations hinder the discovery of metastasis-suppressing miRNAs. In this study, we sought metastasis-suppressing miRNAs by functional screening. Individual miRNAs were lentivirally introduced into metastatic MDA-MB-231 breast cancer cells and analyzed for effects on cell migration, a critical step in cancer metastasis. Among 486 miRNAs screened, 14 were identified that included all of the members of the miRNA-196 family (miR-196a1, miR-1962 and miR-196b). Enforced expression of miR-196a1/2 or miR-196b abrogated in vitro invasion and in vivo spontaneous metastasis of breast cancer cells, indicating that members of miR-196 family are potent metastasis suppressors. We found that miR-196 inhibited expression of the transcription factor HOXC8. Functional linkage was implied by siRNA-mediated knockdown of HOXC8, which suppressed cell migration and metastasis, and by ectopic expression of HOXC8, which prevented the effects of miR-196 on cell migration and metastasis. Unlike other metastasis-associated miRNAs that have been described, the expression of the miR-196s was not correlated to breast cancer cell migration or the metastatic status of clinical breast tumor specimens. Instead, we detected an excellent correlation between the ratio of miR-196 to HOXC8 messages and the migratory behavior of breast cancer cell lines as well as the metastatic status of clinical samples. Our findings identify miRNA-196s as potent metastasis suppressors and reveal that the ratio of miR-196s to HOXC8 mRNA may be an indicator of the metastatic capability of breast tumors.