Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway
Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway
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DOI：
10.1038/s41388-018-0222-3
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发表时间：
2018-06-01
期刊：
影响因子：
8
通讯作者：
Chen, Ching-Shih
中科院分区：
文献类型：
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作者：
Chu, Po-Chen;Lin, Peng-Chan;Chen, Ching-Shih
虽然胰岛素样生长因子-I受体（IGF-IR）在促进结直肠癌肝转移中的作用是已知的，但IGF-IR在结直肠癌（CRC）中上调的机制尚未确定。在这项研究中，我们获得的证据表明，突变KRAS转录激活IGF-IR基因的表达，通过Y盒结合蛋白（YB）-1上调通过一种新的MEK-Sp1-DNMT 1-miR-137途径在CRC细胞。肿瘤抑制性miR-137与YB-1翻译调节之间的机制联系很有趣，因为miR-137的表观遗传沉默代表了由于启动子超甲基化而导致的结直肠癌发生的早期事件。通过对46例KRAS突变型CRC患者的肝转移进行免疫组化评估，进一步验证了这一信号传导轴，结果显示Sp1、miR-137、YB-1和IGF-1 R的表达水平显著相关。此外，在我们的动物模型研究中，通过基因敲低或药理学抑制MEK抑制YB-1和IGF-IR的表达阻碍了KRAS驱动的结直肠肝转移。从翻译的角度来看，这种KRAS驱动的途径的鉴定可能为使用MEK抑制剂作为佐剂，与标准治疗组合，以预防接受肝切除术后KRAS突变CRC患者的结直肠肝转移复发提供了机制依据，这需要进一步研究。
Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation. This proposed signaling axis was further verified by the immunohistochemical evaluations of liver metastases from a cohort of 46 KRAS mutant CRC patients, which showed a significant correlation in the expression levels among Sp1, miR-137, YB-1, and IGF-1R. Moreover, suppression of the expression of YB-1 and IGF-IR via genetic knockdown or the pharmacological inhibition of MEK hampers KRAS-driven colorectal liver metastasis in our animal model studies. From a translational perspective, the identification of this KRAS-driven pathway might provide a mechanistic rationale for the use of a MEK inhibitor as an adjuvant, in combination with standard of care, to prevent the recurrence of colorectal liver metastasis in KRAS mutant CRC patients after receiving liver resection, which warrants further investigation.