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circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis

Authors
  • Hu, Chonghui1, 1
  • Xia, Renpeng1, 2, 3
  • Zhang, Xiang4, 5
  • Li, Tingting6
  • Ye, Yuancheng1, 2
  • Li, Guolin7
  • He, Rihua1
  • Li, Zhihua5, 4
  • Lin, Qing1
  • Zheng, Shangyou1
  • Chen, Rufu1, 2, 6
  • 1 Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, People’s Republic of China , Guangzhou (China)
  • 2 Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China , Guangzhou (China)
  • 3 Hunan Children’s Hospital, Changsha, Hunan, 410007, People’s Republic of China , Changsha (China)
  • 4 Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, People’s Republic of China , Guangzhou (China)
  • 5 Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China , Guangzhou (China)
  • 6 South China University of Technology, Guangzhou, Guangdong Province, 510006, People’s Republic of China , Guangzhou (China)
  • 7 The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China , Guangzhou (China)
Type
Published Article
Journal
Molecular Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Jan 19, 2022
Volume
21
Issue
1
Identifiers
DOI: 10.1186/s12943-022-01501-3
Source
Springer Nature
Keywords
Disciplines
  • Research
License
Green

Abstract

BackgroundCancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which CAFs promote chemotherapy resistance remains unexplored. Here, we explored the role of circRNAs in CAF-induced GEM resistance in PDAC.MethodscircRNA sequencing and quantitative real-time PCR (qRT–PCR) were utilized to screen CAF-specific circRNAs. The effects of CAF circFARP1 expression on GEM resistance in tumor cells were assessed in vitro and in vivo. RNA-seq, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were used to screen the downstream target and underlying mechanism of circFARP1.ResultscircFARP1 (hsa_circ_0002557), a CAF-specific circRNA, was positively correlated with GEM chemoresistance and poor survival in an advanced PDAC cohort. Silencing or overexpressing circFARP1 in CAFs altered the ability of CAFs to induce tumor cell stemness and GEM resistance via leukemia inhibitory factor (LIF). Mechanistically, we found that circFARP1 directly binds with caveolin 1 (CAV1) and blocks the interaction of CAV1 and the E3 ubiquitin-protein ligase zinc and ring finger 1 (ZNRF1) to inhibit CAV1 degradation, which enhances LIF secretion. In addition, circFARP1 upregulated LIF expression by sponging miR-660-3p. Moreover, high circFARP1 levels were positively correlated with elevated serum LIF levels in PDAC and poor patient survival. Decreasing circFARP1 levels and neutralizing LIF significantly suppressed PDAC growth and GEM resistance in patient-derived xenograft models.ConclusionsThe circFARP1/CAV1/miR-660-3p/LIF axis is critical for CAF-induced GEM resistance in PDAC. Hence, circFARP1 may be a potential therapeutic target for PDAC.

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