The long noncoding RNA TUG1 is required for TGF-β/TWIST1/EMT-mediated metastasis in colorectal cancer cells
The long noncoding RNA TUG1 is required for TGF-β/TWIST1/EMT-mediated metastasis in colorectal cancer cells
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长非编码 RNA TUG1 是 TGF-β/TWIST1/EMT 介导的结直肠癌细胞转移所必需的
DOI：
10.1038/s41419-020-2254-1
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发表时间：
2020-01-27
影响因子：
9
通讯作者：
Chen, Wei
中科院分区：
文献类型：
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作者：
Shen, Xuning;Hu, Xiu;Chen, Wei
结直肠癌（Colorectal cancer，CRC）是世界范围内癌症死亡的主要原因之一，而转移是CRC相关死亡的主要原因。转化生长因子-β（TGF-β）不仅在正常结肠的调节中而且在CRC的发展和转移中具有中心作用。然而，TGF-β并不被认为是理想的治疗靶点，因为它根据肿瘤阶段显示出促肿瘤发生和抗肿瘤发生活性。因此，重要的是找到TGF-β的下游信号传导组分，其可以靶向损害CRC转移。在这里，我们发现TGF-β促进CRC迁移，并上调长非编码RNA牛磺酸上调基因1（TUG 1）的表达。TUG 1基因敲低可抑制大肠癌细胞的迁移、侵袭和上皮-间质转化（EMT），并减少大肠癌在体内的肺转移。TGF-β诱导转移，TUG 1敲低抑制这些作用。此外，TGF-β不能逆转TUG 1敲低的抗转移作用。这些数据表明TUG 1是TGF-β的下游分子。此外，TWIST 1表达随着TGF-β处理而增加，并且TUG 1敲低降低了CRC细胞中TWIST 1的表达。TWIST 1敲低抑制CRC细胞的侵袭和EMT;这些效应不受同时TUG 1敲低的影响，表明TWIST 1是TUG 1的下游介质。此外，TUG 1在CRC患者中显著过表达。总之，TGF-β通过TUG 1/TWIST 1/EMT信号通路促进CRC的转移。TUG 1可能是一个很有前途的药物靶点，以抑制TGF-β通路的激活，在CRC的治疗。
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, and metastasis is the major cause of CRC-related mortality. Transforming growth factor-beta (TGF-beta) has a central role not only in the regulation of the normal colon but also in the development and metastasis of CRC. However, TGF-beta is not considered an ideal therapeutic target because it shows both pro-tumorigenic and anti-tumorigenic activity, depending on the tumor stage. Therefore, it is important to find a downstream signaling component of TGF-beta that can be targeted to impair CRC metastasis. Here, we show that TGF-beta promotes CRC migration and upregulates the expression of long-noncoding RNA Taurine Upregulated Gene 1 (TUG1). TUG1 knockdown inhibited migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells in vitro, and reduced CRC lung metastasis in vivo. TGF-beta induced metastasis, and TUG1 knockdown inhibited these effects. In addition, TGF-beta could not reverse the anti-metastasis effects of TUG1 knockdown. These data demonstrate that TUG1 is a downstream molecular of TGF-beta. Moreover, TWIST1 expression was increased with TGF-beta treatment, and TUG1 knockdown decreased TWIST1 expression in CRC cells. TWIST1 knockdown inhibited invasion and EMT in CRC cells; these effects were not changed by simultaneous TUG1 knockdown, indicating that TWIST1 is a downstream mediator of TUG1. Moreover, TUG1 was significantly overexpressed in CRC patients. In conclusion, TGF-beta promotes metastasis of CRC via a TUG1/TWIST1/EMT signaling pathway. TUG1 may be a promising drug target to inhibit TGF-beta pathway activation in the treatment of CRC.