Zuojinwan Antagonizes Drug Resistance Transmission of Gastric Cancer Induced by Hypoxia Through Exosomal Mir-30a Mediated Hedgehog/ PD-L1 Signalling.

Introduction: Our previous studies have demonstrated that the traditional Chinese medicine (TCM) formula, Zuo Jin Wan (ZJW), could significantly enhance the sensitivity of chemoresistance in gastric cancer cells. However, the role and molecular mechanism of ZJW in gastric cancer under hypoxia remain poorly understood. The aim of this study was to investigate the anti-cancer effects of ZJW on GC development and its underlying mechanisms.

Materials and methods: Exosomes were isolated by differential centrifugation and characterized by transmission electron microscopy and Western blotting. Quantitative real-time PCR was used to measure miR-30a levels. CCK-8, colony formation assays, and flow cytometry (FCM) analysis were performed to investigate the effects of hypoxia-induced exosomes on cisplatin resistance. We used a specific exo-miR-30a inhibitor to explore the role of this miRNA in the transfer of chemoresistance from hypoxic to normoxic cells. Inhibition rates in tumor in vitro assays were measured, and xenograft models were established to investigate the effect of exosomes derived from ZJW treatment on GC chemotherapy sensitivity.

Results: Exosomes derived from hypoxic, cisplatin-resistant gastric cancer cells promote cisplatin resistance in normoxic gastric cancer cells, which is inhibited by ZJW.

Discussion: This study reveals a novel mechanism whereby inhibition of miR-30a in hypoxic exosomes reversed the chemoresistance effect by inhibiting the activation of Hedgehog-mediated PD-L1 signaling.

Conclusion: These results indicate that hypoxia-induced exosomal miR-30a, derived from GCresistant drug cells, may promote chemoresistance in gastric cancer cells by activating Hedgehog- mediated PD-L1 signaling and can be attenuated by the involvement of ZJW.