Mechanism of cancer-associated fibroblasts-derived exosomes-shuttled snail regulating the SOCS6/HIF-1α axis to promote pancreatic cancer stemness and gemcitabine resistance.

Authors

Zhen Luo, Yuqin Hu, Jian Li, Dayong Xu, Jin Xu, Hao Li, Fang Zou

Published in

Cellular signalling. Pages 112876. Sep 05, 2026. Epub Sep 05, 2026.

Abstract

Cancer-associated fibroblasts (CAFs) contribute to pancreatic cancer (PC) progression and therapeutic resistance. This study investigated whether CAF-derived exosomes (CAF-exo)-promote PC cell stemness and gemcitabine (GEM) resistance by delivering Snail and regulating the suppressor of cytokine signaling 6/hypoxia-inducible factor-1α (SOCS6/HIF-1α) axis.
Tumors and paired adjacent tissues from patients with PC were collected. RT-qPCR measured Snail, SOCS6, and HIF-1α mRNA; correlations were assessed by Pearson analysis, and survival by Kaplan-Meier. CAFs and normal fibroblasts were isolated for Exo extraction. PC cells (SW1990/MiaPACa2) were treated with lentiviral sh-Snail-transfected CAF-exo, oe-Snail, oe-SOCS6, or si-HIF-1α. Nanog, octamer-binding transcription factor 4 (OCT4), SRY-box transcription factor 2 (SOX2), Snail, SOCS6, and HIF-1α, as well as spheroid formation, chemoresistance, viability, and apoptosis, were evaluated. Snail's binding to the SOCS6 promoter was confirmed by dual-luciferase and ChIP-qPCR. A xenograft mouse model was established for in vivo validation.
In PC tissues, Snail and HIF-1α were elevated, SOCS6 reduced; Snail negatively correlated with SOCS6 and positively with HIF-1α, and these patterns were associated with poor survival. CAF-exo delivered Snail into PC cells, elevating stemness markers, sphere formation, and GEM resistance, which were reversed by Snail knockdown. Mechanistically, CAF-exo transcriptionally represses SOCS6 via Snail, leading to HIF-1α upregulation. SOCS6 upregulation or HIF-1α knockdown partly attenuated CAF-exo-induced stemness and GEM resistance. In vivo, CAF-exo promoted tumor growth, stemness, and GEM resistance and reduced apoptosis via the Snail-SOCS6/HIF-1α axis.
CAF-exo shuttled Snail, transcriptionally suppressed SOCS6 expression to activate HIF-1α, thereby enhancing PC cell stemness and GEM resistance in PC cells.

PMID:
42700784
Bibliographic data and abstract were imported from PubMed on 06 Sep 2026.

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