Cancer-Associated Fibroblast-Derived Exosomal circTBPL1 Regulates NSCLC Cell Stemness and Cisplatin Resistance via the miR-152-3p/Gli1 Axis
- 1The Fourth Hospital of Hebei Medical University , , ,
Abstract
Drug resistance and cancer stem cell maintenance drive poor outcomes in non-small cell lung cancer (NSCLC), yet the role of cancer-associated fibroblast (CAF)-derived exosomal circular RNAs remains insufficiently defined. This study investigated whether CAF-derived exosomal circTBPL1 regulates NSCLC stemness and cisplatin resistance through the miR-152-3p/Gli1 axis. Exosomal circRNAs from CAFs and normal fibroblasts were profiled by high-throughput sequencing, and circTBPL1 was validated using qRT-PCR, RNase R, actinomycin D, and fluorescence in situ hybridization. Functional assays, xenograft models, dual-luciferase reporter assays, RNA immunoprecipitation, RNA pull-down, rescue experiments, and TCGA analyses were performed. circTBPL1 was enriched in CAF-derived exosomes and displayed circular RNA stability and cytoplasmic localization. CAF-derived exosomal circTBPL1 promoted NSCLC cell proliferation, migration, invasion, tumor-sphere formation, stemness marker expression, and cisplatin resistance. circTBPL1 silencing in CAFs reduced cisplatin IC50 values, inhibited resistant-cell proliferation, and suppressed xenograft growth. Mechanistically, circTBPL1 acted as a competing endogenous RNA by binding miR-152-3p, relieving repression of Gli1 and activating Hedgehog-related resistance signaling. miR-152-3p inhibition or Gli1 overexpression partially reversed circTBPL1-knockdown effects. TCGA analysis linked high Gli1 expression with poorer survival in lung adenocarcinoma, supporting circTBPL1 as a potential biomarker candidate and therapeutic target requiring further clinical validation.
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BibTeX
@article{mi2026cancerassociated,
title = {{Cancer-Associated Fibroblast-Derived Exosomal circTBPL1 Regulates NSCLC Cell Stemness and Cisplatin Resistance via the miR-152-3p/Gli1 Axis}},
author = {Yuan Mi and Ge Chen and Shifei Zhang and Yuxiang Liang and Fan Yu and Yaozhong Zhang and Kuankuan Li and Haidi Xu and Ziqiang Li and Lei Wang},
journal = {ACS Omega},
year = {2026},
month = nov,
doi = {10.1021/acsomega.6c07441},
url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c07441/5465081/Cancer-Associated-Fibroblast-Derived-Exosomal},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Cancer-Associated Fibroblast-Derived Exosomal circTBPL1 Regulates NSCLC Cell Stemness and Cisplatin Resistance via the miR-152-3p/Gli1 Axis
AU - Yuan Mi
AU - Ge Chen
AU - Shifei Zhang
AU - Yuxiang Liang
AU - Fan Yu
AU - Yaozhong Zhang
AU - Kuankuan Li
AU - Haidi Xu
AU - Ziqiang Li
AU - Lei Wang
PY - 2026
DA - 2026/11/05
JO - ACS Omega
DO - 10.1021/acsomega.6c07441
UR - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c07441/5465081/Cancer-Associated-Fibroblast-Derived-Exosomal
AB - Drug resistance and cancer stem cell maintenance drive poor outcomes in non-small cell lung cancer (NSCLC), yet the role of cancer-associated fibroblast (CAF)-derived exosomal circular RNAs remains insufficiently defined. This study investigated whether CAF-derived exosomal circTBPL1 regulates NSCLC stemness and cisplatin resistance through the miR-152-3p/Gli1 axis. Exosomal circRNAs from CAFs and normal fibroblasts were profiled by high-throughput sequencing, and circTBPL1 was validated using qRT-PCR, RNase R, actinomycin D, and fluorescence in situ hybridization. Functional assays, xenograft models, dual-luciferase reporter assays, RNA immunoprecipitation, RNA pull-down, rescue experiments, and TCGA analyses were performed. circTBPL1 was enriched in CAF-derived exosomes and displayed circular RNA stability and cytoplasmic localization. CAF-derived exosomal circTBPL1 promoted NSCLC cell proliferation, migration, invasion, tumor-sphere formation, stemness marker expression, and cisplatin resistance. circTBPL1 silencing in CAFs reduced cisplatin IC50 values, inhibited resistant-cell proliferation, and suppressed xenograft growth. Mechanistically, circTBPL1 acted as a competing endogenous RNA by binding miR-152-3p, relieving repression of Gli1 and activating Hedgehog-related resistance signaling. miR-152-3p inhibition or Gli1 overexpression partially reversed circTBPL1-knockdown effects. TCGA analysis linked high Gli1 expression with poorer survival in lung adenocarcinoma, supporting circTBPL1 as a potential biomarker candidate and therapeutic target requiring further clinical validation.
SN - 2470-1343
ER -