2. Academic Validation
  3. LINC00941 promotes CRC metastasis through preventing SMAD4 protein degradation and activating the TGF-β/SMAD2/3 signaling pathway

LINC00941 promotes CRC metastasis through preventing SMAD4 protein degradation and activating the TGF-β/SMAD2/3 signaling pathway

  • Cell Death Differ. 2021 Jan;28(1):219-232. doi: 10.1038/s41418-020-0596-y.
Nan Wu  # 1,  Mingzuo Jiang  # 2,  Haiming Liu  # 3,  Yi Chu  # 2,  Dan Wang 1,  Jiayi Cao 1,  Zhiyang Wang 1,  Xin Xie 1,  Yuying Han 4,  Bing Xu 5 6
Affiliations

Affiliations

  • 1 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China.
  • 2 State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, China.
  • 3 School of Software Engineering, Beijing Jiaotong University, Beijing, 100044, China.
  • 4 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China. 254046797@qq.com.
  • 5 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China. xubing@nwu.edu.cn.
  • 6 State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, China. xubing@nwu.edu.cn.
  • # Contributed equally.
PMID: 32737443 DOI: 10.1038/s41418-020-0596-y
Abstract

LINC00941 is a novel lncRNA that has been found to exhibit protumorigenic and prometastatic behaviors during tumorigenesis. However, its role in metastatic CRC remains unknown. We aimed to investigate the functions and mechanisms of LINC00941 in CRC metastasis. LINC00941 was shown to be upregulated in CRC, and upregulated LINC00941 was associated with poor prognosis. Functionally, LINC00941 promoted migratory and invasive capacities and accelerated lung metastasis in nude mice. Mechanistically, LINC00941 activated EMT in CRC cells, as indicated by the increased expression of key molecular markers of cell invasion and metastasis (Vimentin, Fibronectin, and Twist1) and simultaneous decreased expression of the main invasion suppressors E-cadherin and ZO-1. LINC00941 was found to activate EMT by directly binding the SMAD4 protein MH2 domain and competing with β-TrCP to prevent SMAD4 protein degradation, thus activating the TGF-β/SMAD2/3 signaling pathway. Our data reveal the essential role of LINC00941 in metastatic CRC via activation of the TGF-β/SMAD2/3 axis, which provides new insight into the mechanism of metastatic CRC and a novel potential therapeutic target for advanced CRC.

Figures
Products
Inhibitors & Agonists