LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit.
LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit.
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LncRNA MIR17HG通过介导糖酵解相关正反馈回路促进结直肠癌肝转移
DOI：
10.1038/s41388-021-01859-6
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发表时间：
2021-07
期刊：
影响因子：
8
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
Zhao S;Guan B;Mi Y;Shi D;Wei P;Gu Y;Cai S;Xu Y;Li X;Yan D;Huang M;Li D
糖酵解在转移性肿瘤微环境的重编程中起着至关重要的作用。已经鉴定出一系列lncRNA作为致癌分子通过调节糖酵解发挥作用。然而，糖酵解相关lncRNA在调节结直肠癌肝转移（CRLM）中的作用仍然知之甚少。在本研究中，糖酵解相关lncRNA MIR 17 HG的表达从癌旁正常组织到癌旁肝转移组织逐渐增加，MIR 17 HG高表达预示着生存率低，特别是在肝转移患者中。在功能上，MIR 17 HG促进CRC细胞中的糖酵解，并在体外和体内增强其侵袭和肝转移。在机制上，MIR 17 HG作为ceRNA通过海绵状miR-138- 5 p调节HK 1表达，导致CRC细胞中的糖酵解并导致其侵袭和肝转移。更有趣的是，通过糖酵解积累的乳酸激活p38/Elk-1信号通路，促进CRC细胞中MIR 17 HG的转录表达，形成正反馈回路，最终导致持续糖酵解以及CRC细胞的侵袭和肝转移。总之，本研究表明，乳酸响应lncRNA MIR 17 HG，作为一种ceRNA，通过糖酵解介导的正反馈回路促进CRLM，可能是CRLM的一种新的生物标志物和治疗靶点。
Glycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by regulating glycolysis. However, the roles of glycolysis-related lncRNAs in regulating colorectal cancer liver metastasis (CRLM) remain poorly understood. In the present study, the expression of the glycolysis-related lncRNA MIR17HG gradually increased from adjacent normal to CRC to the paired liver metastatic tissues, and high MIR17HG expression predicted poor survival, especially in patients with liver metastasis. Functionally, MIR17HG promoted glycolysis in CRC cells and enhanced their invasion and liver metastasis in vitro and in vivo. Mechanistically, MIR17HG functioned as a ceRNA to regulate HK1 expression by sponging miR-138-5p, resulting in glycolysis in CRC cells and leading to their invasion and liver metastasis. More interestingly, lactate accumulated via glycolysis activated the p38/Elk-1 signaling pathway to promote the transcriptional expression of MIR17HG in CRC cells, forming a positive feedback loop, which eventually resulted in persistent glycolysis and the invasion and liver metastasis of CRC cells. In conclusion, the present study indicates that the lactate-responsive lncRNA MIR17HG, acting as a ceRNA, promotes CRLM through a glycolysis-mediated positive feedback circuit and might be a novel biomarker and therapeutic target for CRLM.
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