miR-103/107 Promote Metastasis of Colorectal Cancer by Targeting the Metastasis Suppressors DAPK and KLF4
miR-103/107 Promote Metastasis of Colorectal Cancer by Targeting the Metastasis Suppressors DAPK and KLF4
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DOI：
10.1158/0008-5472.can-12-0667
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发表时间：
2012-07-15
期刊：
影响因子：
11.2
通讯作者：
Chen, Ruey-Hwa
中科院分区：
文献类型：
--
作者：
Chen, Hsin-Yi;Lin, Yu-Min;Chen, Ruey-Hwa
转移是结直肠癌（CRC）预后不良的主要原因，越来越多的证据支持miRNA对癌症进展的贡献。在此，我们发现miR-103和miR-107（miR-103/107）的高表达与CRC细胞系的转移潜力和CRC患者的不良预后相关。我们发现，miR-103/107靶向CRC细胞中已知的转移抑制因子死亡相关蛋白激酶（DAPK）和Kruppel样因子4（KLF 4），导致细胞运动性和细胞-基质粘附增加，细胞-细胞粘附和上皮标志物表达降低。miR-103/107的表达在缺氧的情况下增加，从而增强DAPK和KLF 4的下调以及缺氧诱导的运动性和侵袭性。在CRC小鼠模型中，miR-103/107过表达增强了局部侵袭和肝转移效应，这被DAPK或KLF 4的再表达抑制。miR-103/107介导的DAPK和KLF 4的下调也使得CRC细胞能够在转移部位定殖。临床上，miR-103/107高、DAPK低和KLF 4低表达谱的特征与CRC患者的淋巴结和远处转移的程度相关，并作为转移复发和生存率差的预后标志物。因此，我们的研究结果表明，miR-103/107介导的DAPK和KLF 4的抑制促进了CRC的转移，并且这种调节回路可能在一定程度上促进了缺氧刺激的肿瘤转移。破坏这种调节的策略可能被开发来阻断CRC转移。Cancer Res; 72（14）; 3631-41. (c)2012年AACR。
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.