MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis.
MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis.
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DOI：
10.1038/cddis.2017.60
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发表时间：
2017-05-04
影响因子：
9
通讯作者：
Gong S
中科院分区：
文献类型：
--
作者：
Xu W;Zhang Z;Zou K;Cheng Y;Yang M;Chen H;Wang H;Zhao J;Chen P;He L;Chen X;Geng L;Gong S
microRNA（miR）-1的异常表达已在许多人类恶性肿瘤中观察到。然而，miR-1的功能和潜在机制仍然是难以捉摸的。通过功能获得或丧失研究，阐明miR-1在肿瘤糖酵解中的特定作用。在体外和体内进行代谢研究结合基因表达分析。我们证明了miR-1在有氧糖酵解中的异常表达，即癌细胞中的瓦尔堡效应。MiR-1通过抑制Smad 3和靶向HIF-1α抑制有氧糖酵解和肿瘤细胞增殖，导致HK 2和MCT 4的表达降低，这为肿瘤细胞有氧糖酵解提供了一条新的途径。miR-1模拟物的过表达显著降低了肿瘤糖酵解，包括乳酸产生和葡萄糖摄取，以及细胞增殖，并且这些作用被Smad 3的异位表达逆转。重要的是，内源性Smad 3调节并与HIF-1α相互作用，导致Smad 3的活性增加，并且这种相互作用通过添加miR-1而显著消除。我们进一步证明Smad 3是miR-1在结直肠癌细胞中作用的核心，建立了一种以前未被认识到的机制，通过该机制，miR-1/Smad 3/HIF-1α轴促进了瓦尔堡效应，从而在体外和体内促进癌症进展。结果表明，miR-1可能具有作为肿瘤抑制因子的重要作用，提示其在晚期结直肠癌患者的分子治疗中的潜在作用。
Aberrant expression of microRNA (miR)-1 has been observed in many human malignancies. However, the function and underlying mechanism of miR-1 remains elusive. To address the specific role of miR-1 in tumor glycolysis using the gain- or loss-of-function studies. Metabolic studies combined with gene expression analysis were performed in vitro and in vivo. We demonstrated aberrant expression of miR-1 in aerobic glycolysis, the Warburg effect, in cancer cells. MiR-1 suppressed aerobic glycolysis and tumor cell proliferation via inactivation of Smad3 and targeting HIF-1α, leading to reduce HK2 and MCT4 expression, which illustrated a novel pathway to mediate aerobic glycolysis in cancer cells. Overexpression of miR-1 mimics significantly decreased tumor glycolysis, including lactate production and glucose uptake, and cell proliferation, and these effects were reversed by ectopic expression of Smad3. Importantly, endogenous Smad3 regulated and interacted with HIF-1α, resulting in increasing activity of Smad3, and this interaction was dramatically abolished by addition of miR-1. We further demonstrated that Smad3 was central to the effects of miR-1 in colorectal cancer cells, establishing a previously unappreciated mechanism by which the miR-1/Smad3/HIF-1α axis facilitates the Warburg effect to promote cancer progression in vitro and in vivo. The results indicate that miR-1 may have an essential role as a tumor suppressor, suggesting its potential role in molecular therapy of patients with advanced colorectal cancer.
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siRNA 筛选将宿主己糖激酶 2 (HK2) 基因鉴定为弓形虫感染细胞中重要的缺氧诱导转录因子 1 (HIF-1) 靶基因。
影响因子：
6.4
作者：
Menendez MT;Teygong C;Wade K;Florimond C;Blader IJ
通讯作者：
Blader IJ
影响因子：
8.8
作者：
Kojima, S.;Chiyomaru, T.;Kawakami, K.;Yoshino, H.;Enokida, H.;Nohata, N.;Fuse, M.;Ichikawa, T.;Naya, Y.;Nakagawa, M.;Seki, N.
通讯作者：
Seki, N.
影响因子：
5.2
作者：
Chu, Kaili;Gao, Guanghui;Zhou, Caicun
通讯作者：
Zhou, Caicun
影响因子：
4.8
作者：
Engel, ME;McDonnell, MA;Moses, HL
通讯作者：
Moses, HL
影响因子：
8
作者：
Kretschmer, A;Moepert, K;Klippel, A
通讯作者：
Klippel, A