Research Paper Volume 12, Issue 20 pp 20047—20068
CUEDC1 inhibits epithelial-mesenchymal transition via the TβRI/Smad signaling pathway and suppresses tumor progression in non-small cell lung cancer
- 1 The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- 2 Department of Orthopedic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
Received: December 30, 2019 Accepted: August 15, 2020 Published: October 25, 2020
https://doi.org/10.18632/aging.103329How to Cite
Copyright: © 2020 Cui et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Lung cancer remains the most lethal cancer worldwide because of its high metastasis potential. Epithelial-mesenchymal transition (EMT) is known as the first step of the metastasis cascade, but the potential regulatory mechanisms of EMT have not been clearly established. In this study, we first found that low CUEDC1 expression correlated with lymph node metastasis in non-small cell lung cancer (NSCLC) patients using immunohistochemistry (IHC). CUEDC1 knockdown promoted the metastasis of NSCLC cells and EMT process and activated TβRI/Smad signaling pathway. Overexpression of CUEDC1 decreased the metastatic potential of lung cancer cells and inhibited the EMT process and inactivated TβRI/Smad signaling pathway. Immunoprecipitation (IP) assays showed that Smurf2 is a novel CUEDC1-interacting protein. Furthermore, CUEDC1 could regulate Smurf2 expression through the degradation of Smurf2. Overexpression of Smurf2 abolished CUEDC1 knockdown induced-EMT and the activation of TβRI/Smad signaling pathway, while siRNA Smurf2 reversed CUEDC1 overexpression-mediated regulation of EMT and TβRI/Smad signaling pathway. Additionally, CUEDC1 inhibited proliferation and promoted apoptosis of NSCLC cells. In vivo, CUEDC1-knockdown cells promoted metastasis and tumor growth compared with control cells. In conclusion, our findings indicate that the crucial role of CUEDC1 in NSCLC progression and provide support for its clinical investigation for therapeutic approaches.
Abbreviations
NSCLC: non-small cell lung cancer; ADC: adenocarcinoma; SCC: squamous cell carcinoma; EMT: epithelial-mesenchymal transition; CUEDC1: CUE domain-containing protein 1; CUEDC2: CUE domain-containing protein 2; TGF-β1: transforming growth factor-β1; TβRI: TGF-β type I receptor; Smurf2: Smad ubiquitin regulatory factors 2; ERα: estrogen receptor-α; PR: progesterone receptor; IHC: immunohistochemistry; LNR: lymph node ratio; OS: overall survival; PPS: post progression survival; ELISA: enzyme-linked immunosorbent assay; IP: immunoprecipitation; TUNEL: transferase-mediated dUTP nick end-labelling.