期刊
GUT
卷 62, 期 9, 页码 1315-1326出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2011-301846
关键词
Colorectal cancer; metastasis; miR-200c; EMT; methylation; cancer; carcinogenesis; cell biology; gastric cancer; cancer genetics; cancer syndromes; chemotherapy; abdominal surgery; colorectal antral surgery; hepatic surgery; DNA microsatellite instability; juvenile polyposis; HNPCC syndrome; familial adenomatous polyposis; cancer prevention; non-steroidal; colon carcinogenesis; 5-aminosalicylic acid (5-ASA); molecular genetics
资金
- National Cancer Institute, National Institutes of Health [R01 CA72851, CA129286]
- Baylor Research Institute
- Grants-in-Aid for Scientific Research [23650615, 24591985] Funding Source: KAKEN
Objective Distant metastasis is the major cause of cancer-related death in patients with colorectal cancer (CRC). Although the microRNA-200 (miR-200) family is a crucial inhibitor of epithelial-to-mesenchymal transition (EMT) in human cancer, the role of miR-200 members in the pathogenesis of metastatic CRC has not been investigated. Design Fifty-four pairs of primary CRC and corresponding matched liver metastasis tissue specimens were analysed for expression and methylation status of the miR-200 family members. Functional analysis of miR-200c overexpression was investigated in CRC cell lines, and cells were analysed for proliferation, invasion and migration. Expression of several miR-200c target genes (ZEB1, ETS1 and FLT1) and EMT markers (E-cadherin and vimentin) in CRC cell lines and tissue specimens was validated. Results Liver metastasis tissues showed higher expression of miR-200c (primary CRC=1.31 vs. liver metastasis=1.59; p=0.0014) and miR-141 (primary CRC=0.14 vs. liver metastasis=0.17; p=0.0234) than did primary CRCs, which was significantly associated with hypomethylation of the promoter region of these miRNAs (primary CRC=61.2% vs. liver metastasis=46.7%; p<0.0001). The invasive front in primary CRC tissues revealed low miR-200c expression by in situ hybridization analysis. Transfection of miR-200c precursors resulted in enhanced cell proliferation but reduced invasion and migration behaviours in CRC cell lines. Overexpression of miR-200c in CRC cell lines caused reduced expression of putative gene targets, and resulted in increased E-cadherin and reduced vimentin expression. The associations between miR-200c, target genes and EMT markers were validated in primary CRCs and matching liver metastasis tissues. Conclusions miR-200c plays an important role in mediating EMT and metastatic behaviour in the colon. Its expression is epigenetically regulated, and miR-200c may serve as a potential diagnostic marker and therapeutic target for patients with CRC.
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