Abstract
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.
Highlights
Metastasis is a process whereby cancer cells spread from a primary site and form tumors at distant sites [1, 2]
MiRNA expression signature was analyzed in 10 pairs of primary gastric cancers and corresponding noncancerous gastric tissues by a stem-loop real-time PCR based miRNA expression profiling method by using the TaqMan Human miRNA Array v1.0 Early Access Kit from Applied Biosystems, which includes 365 identified human miRNAs
To identify miRNAs that regulate gastric cancer metastasis, we investigated the expression of these candidate miRNAs in a series of human gastric cells and tumor cell lines by real-time PCR (RT-PCR; data not shown)
Summary
Metastasis is a process whereby cancer cells spread from a primary site and form tumors at distant sites [1, 2]. It occurs through a specific series of steps, starting with local invasion, followed by entrance of cancer cells into the bloodstream (intravasation), survival in the circulation, exit from blood vessels (extravasation), initiation, and maintenance of micrometastases at distant sites and vascularization of the resulting tumors [3]. The incidence of gastric cancer declined from the 1940s to the 1980s, it remains the most common. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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