title: miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3.
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.
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Liu
authors.forename: Taiqian
authors.initials: T
authors.lastname: Gong
authors.forename: Mengbin
authors.initials: M
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Gang
authors.initials: G
authors.lastname: Ji
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Shi
authors.forename: Zheyi
authors.initials: Z
authors.lastname: Han
authors.forename: Shuang
authors.initials: S
authors.lastname: Han
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Nie
authors.forename: Xiong
authors.initials: X
authors.lastname: Chen
authors.forename: Qinchuan
authors.initials: Q
authors.lastname: Zhao
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.forename: Fan
authors.initials: F
authors.lastname: Daiming
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D051879:Twist-Related Protein 1; C116887:EPB41L3 protein, human; C525067:MIR223, human; C103173:TWIST1 protein, human