標題: miR-103/107 Promote Metastasis of Colorectal Cancer by Targeting the Metastasis Suppressors DAPK and KLF4
作者: Chen, Hsin-Yi
Lin, Yu-Min
Chung, Hsiang-Ching
Lang, Yaw-Dong
Lin, Ching-Jung
Huang, John
Wang, Wei-Chi
Lin, Feng-Mao
Chen, Zhen
Huang, Hsien-Da
Shyy, John Y. -J.
Liang, Jin-Tung
Chen, Ruey-Hwa
生物資訊及系統生物研究所
Institude of Bioinformatics and Systems Biology
公開日期: 15-Jul-2012
摘要: Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of miRNAs to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in patients with CRC. We showed that miR-103/107 targeted the known metastasis suppressors death-associated protein kinase (DAPK) and Kruppel-like factor 4 (KLF4) in CRC cells, resulting in increased cell motility and cell-matrix adhesion and decreased cell-cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxia-induced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis effects, which were suppressed by reexpression of DAPK or KLF4. miR-103/107-mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a metastatic site. Clinically, the signature of a miR-103/107 high, DAPK low, and KLF4 low expression profile correlated with the extent of lymph node and distant metastasis in patients with CRC and served as a prognostic marker for metastasis recurrence and poor survival. Our findings therefore indicate that miR-103/107-mediated repression of DAPK and KLF4 promotes metastasis in CRC, and this regulatory circuit may contribute in part to hypoxia-stimulated tumormetastasis. Strategies that disrupt this regulation might be developed to block CRC metastasis. Cancer Res; 72(14); 3631-41. (c) 2012 AACR.
URI: http://dx.doi.org/10.1158/0008-5472.CAN-12-0667
http://hdl.handle.net/11536/16939
ISSN: 0008-5472
DOI: 10.1158/0008-5472.CAN-12-0667
期刊: CANCER RESEARCH
Volume: 72
Issue: 14
起始頁: 3631
結束頁: 3641
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