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

• DOI: 10.1038/s41419-021-03509-x
• Publication Date: 2021-02-26T12:04:10Z
• Authors: Yingyan Wang; Wen Lan; Mingxin Xu; Jing Song; Jun Mao; Chunyan Li; Xiaohui Du; Yunling Jiang; Encheng Li; Rui Zhang; Qi Wang
• Keywords: Adult; Male; 0301 basic medicine; Receptors, CXCR4; Epithelial-Mesenchymal Transition; Lung Neoplasms; Adenocarcinoma of Lung; Article; 03 medical and health sciences; Cancer-Associated Fibroblasts; Paracrine Communication; Humans; PPAR delta; Aged; Aged, 80 and over; QH573-671; Middle Aged; Prognosis; Chemokine CXCL12; Coculture Techniques; 3. Good health; Gene Expression Regulation, Neoplastic; A549 Cells; Culture Media, Conditioned; Female; Cytology

Abstract 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, β-catenin, and PPARδ, while downregulating these proteins reversed the effect. Furthermore, RNAi-mediated CXCR4 knockdown suppressed β-catenin and PPARδ expression, while β-catenin inhibition effectively downregulated PPARδ without affecting CXCR4; however, treatment with a PPARδ inhibitor did not inhibit CXCR4 or β-catenin expression. Additionally, pairwise analysis revealed that high expression of CXCR4, β-catenin, and PPARδ correlated positively with 75 human lung adenocarcinoma tissues, which was predictive of poor prognosis. Thus, targeting the CAF-derived, SDF-1-mediated CXCR4 β-catenin/ PPARδ cascade may serve as an effective targeted approach for lung cancer treatment.