1. Academic Validation
  2. Circ_0020256 induces fibroblast activation to drive cholangiocarcinoma development via recruitment of EIF4A3 protein to stabilize KLF4 mRNA

Circ_0020256 induces fibroblast activation to drive cholangiocarcinoma development via recruitment of EIF4A3 protein to stabilize KLF4 mRNA

  • Cell Death Discov. 2023 May 13;9(1):161. doi: 10.1038/s41420-023-01439-5.
Zongyan Li # 1 Zuxiao Chen # 2 Shiying Li 3 Xiangjun Qian 1 Lei Zhang 1 Guojie Long 1 Jiancong Xie 1 Xiaoming Huang 1 Zheyu Zheng 1 Weidong Pan 1 Haiyan Li 4 Dawei Zhang 5
Affiliations

Affiliations

  • 1 Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China.
  • 2 Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, P.R. China.
  • 3 Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong Province, P.R. China.
  • 4 Department of Breast Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China. lihy27@mail.sysu.edu.cn.
  • 5 Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China. zhangdw27@mail.sysu.edu.cn.
  • # Contributed equally.
Abstract

Cancer-associated fibroblasts (CAFs) are a kind of stromal cells in the cholangiocarcinoma (CCA) microenvironment, playing crucial roles in Cancer development. However, the potential mechanisms of the interaction between CCA cells and CAFs remain obscure. This work investigated the role of circ_0020256 in CAFs activation. We proved circ_0020256 was up-regulated in CCA. High circ_0020256 expression facilitated TGF-β1 secretion from CCA cells, which activated CAFs via the phosphorylation of SMAD2/3. Mechanistically, circ_0020256 recruited EIF4A3 protein to stabilize KLF4 mRNA and upregulate its expression, then KLF4 bound to TGF-β1 promoter and induced its transcription in CCA cells. KLF4 overexpression abrogated the inhibition of circ_0020256 silencing in TGF-β1/SMAD2/3-induced CAFs activation. Furthermore, CCA cell growth, migration, and epithelial-mesenchymal transition were favored by CAFs-secreted IL-6 via Autophagy inhibition. We also found circ_0020256 accelerated CCA tumor growth in vivo. In conclusion, circ_0020256 promoted fibroblast activation to facilitate CCA progression via EIF4A3/KLF4 pathway, providing a potential intervention for CCA progression.

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