State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China.
Mol Cancer Res. 2011 Jul;9(7):824-33. doi: 10.1158/1541-7786.MCR-10-0529. Epub 2011 May 31.
Traditional research modes aim to find cancer-specific single therapeutic target. Recently, emerging evidence suggested that some micro-RNAs (miRNA) can function as oncogenes or tumor suppressors. miRNAs are single-stranded, small noncoding RNA genes that can regulate hundreds of downstream target genes. In this study, we evaluated the miRNA expression patterns in gastric carcinoma and the specific role of miR-223 in gastric cancer metastasis. miRNA expression signature was first analyzed by real-time PCR on 10 paired gastric carcinomas and confirmed in another 20 paired gastric carcinoma tissues. With the 2-fold expression difference as a cutoff level, we identified 22 differential expressed mature miRNAs. Sixteen miRNAs were upregulated in gastric carcinoma, including miR-223, miR-21, miR-23b, miR-222, miR-25, miR-23a, miR-221, miR-107, miR-103, miR-99a, miR-100, miR-125b, miR-92, miR-146a, miR-214 and miR-191, and six miRNAs were downregulated in gastric carcinoma, including let-7a, miR-126, miR-210, miR-181b, miR-197, and miR-30aa-5p. After examining these miRNAs in several human gastric originated cell lines, we found that miR-223 is overexpressed only in metastatic gastric cancer cells and stimulated nonmetastatic gastric cancer cells migration and invasion. Mechanistically, miR-223, induced by the transcription factor Twist, posttranscriptionally downregulates EPB41L3 expression by directly targeting its 3'-untranslated regions. Significantly, overexpression of miR-223 in primary gastric carcinomas is associated with poor metastasis-free survival. These findings indicate a new regulatory mode, namely, specific miRNA, which is activated by its upstream transcription factor, could suppress its direct targets and lead to tumor invasion and metastasis.
传统的研究模式旨在寻找癌症特异性的单一治疗靶点。最近，新出现的证据表明，一些 microRNA（miRNA）可以作为癌基因或肿瘤抑制因子发挥作用。miRNA 是单链、小的非编码 RNA 基因，可以调节数百个下游靶基因。在这项研究中，我们评估了胃癌中的 miRNA 表达模式以及 miR-223 在胃癌转移中的特定作用。首先通过实时 PCR 分析了 10 对配对胃癌中的 miRNA 表达谱，并在另外 20 对配对胃癌组织中进行了验证。以 2 倍差异表达作为截断水平，我们鉴定了 22 个差异表达的成熟 miRNA。在胃癌中上调了 16 个 miRNA，包括 miR-223、miR-21、miR-23b、miR-222、miR-25、miR-23a、miR-221、miR-107、miR-103、miR-99a、miR-100、miR-125b、miR-92、miR-146a、miR-214 和 miR-191，而下调了 6 个 miRNA，包括 let-7a、miR-126、miR-210、miR-181b、miR-197 和 miR-30aa-5p。在检查了几种人胃来源的细胞系中的这些 miRNA 后，我们发现 miR-223 仅在转移性胃癌细胞中过表达，并刺激非转移性胃癌细胞的迁移和侵袭。从机制上讲，miR-223 由转录因子 Twist 诱导，通过直接靶向其 3'非翻译区，转录后下调 EPB41L3 的表达。重要的是，原发性胃癌中 miR-223 的过表达与较差的无转移生存相关。这些发现表明了一种新的调节模式，即特定的 miRNA，由其上游转录因子激活，可抑制其直接靶基因，导致肿瘤侵袭和转移。
