Wnt信号通路
癌症研究
转化生长因子
上皮-间质转换
转移
细胞生物学
SMAD公司
信号转导
生物
癌症
医学
内科学
作者
Teppei Sugano,Mari Masuda,Fumitaka Takeshita,Noriko Motoi,Toru Hirozane,Naoko Goto,Shigeki Kashimoto,Yutaka Uno,Hideki Moriyama,Masaaki Sawa,Yuichi Nagakawa,Akihiko Tsuchida,Masahiro Seike,Akihiko Gemma,Tesshi Yamada
标识
DOI:10.1038/s41416-020-01162-3
摘要
Abstract Background Metastasis is the primary cause of death in cancer patients, and its management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been implicated in the process of cancer metastasis, and its pharmacological interference holds therapeutic promise. Methods Traf2- and Nck-interacting kinase (TNIK) functions as a transcriptional coregulator of Wnt target genes. Given the convergence of Wnt and transforming growth factor-β (TGFβ) signalling, we examined the effects of a small-molecule TNIK inhibitor (named NCB-0846) on the TGFβ1-induced EMT of lung cancer cells. Results NCB-0846 inhibited the TGFβ1-induced EMT of A549 cells. This inhibition was associated with inhibition of Sma- and Mad-Related Protein-2/3 (SMAD2/3) phosphorylation and nuclear translocation. NCB-0846 abolished the lung metastasis of TGFβ1-treated A549 cells injected into the tail veins of immunodeficient mice. The inhibition of EMT was mediated by suppression of the TGFβ receptor type-I ( TGFBR1 ) gene, at least partly through the induction of microRNAs targeting the TGFBR1 transcript [miR-320 (a, b and d) and miR-186]. Conclusions NCB-0846 pharmacologically blocks the TGFβ/SMAD signalling and EMT induction of lung cancer cells by transcriptionally downregulating TGFBRI expression, representing a potentially promising approach for prevention of metastasis in lung cancer patients.
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