4.7 Article

Cancer-associated fibroblast-derived SDF-1 induces epithelial-mesenchymal transition of lung adenocarcinoma via CXCR4/β-catenin/PPARδ signalling

Journal

CELL DEATH & DISEASE
Volume 12, Issue 2, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41419-021-03509-x

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Funding

  1. Natural Science Foundation of China [81972916, 81903185, 81502702]
  2. Liaoning Provincial Doctoral Scientific Research Initiation Fund Project [2020-BS-198]
  3. science and technology innovation foundation of Dalian [2019J11CY019]
  4. National High Technology Research and Development Program (863 Research Projects) of China [2015AA020409]

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CAFs promote EMT in lung ADC through SDF-1, which enhances invasiveness and EMT by regulating CXCR4, beta-catenin, and PPAR delta. High expression of these proteins correlated with poor prognosis, suggesting targeting the SDF-1-mediated CXCR4 beta-catenin/PPAR delta cascade may be an effective approach for lung cancer treatment.
Cancer-associated fibroblasts (CAFs) contribute to tumour epithelial-mesenchymal transition (EMT) via interaction with cancer cells. However, the molecular mechanisms underlying tumour-promoting EMT of CAFs in lung adenocarcinoma (ADC) remain unclear. Here, we observed that CAFs isolated from lung ADC promoted EMT via production of stromal cell-derived factor-1 (SDF-1) in conditioned medium (CM). CAF-derived SDF-1 enhanced invasiveness and EMT by upregulating CXCR4, beta -catenin, and PPAR delta, while downregulating these proteins reversed the effect. Furthermore, RNAi-mediated CXCR4 knockdown suppressed beta -catenin and PPAR delta expression, while beta -catenin inhibition effectively downregulated PPAR delta without affecting CXCR4; however, treatment with a PPAR delta inhibitor did not inhibit CXCR4 or beta -catenin expression. Additionally, pairwise analysis revealed that high expression of CXCR4, beta -catenin, and PPAR delta correlated positively with 75 human lung adenocarcinoma tissues, which was predictive of poor prognosis. Thus, targeting the CAF-derived, SDF-1-mediated CXCR4 beta -catenin/ PPAR delta cascade may serve as an effective targeted approach for lung cancer treatment.

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