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Oral diseases

IF: 2.9
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Metformin overcomes chemoresistance by regulating stemness via KLF4 in oral squamous cell carcinoma

Published:1 February 2025 DOI: 10.1111/odi.15075 PMID: 39039738
Tong Zhou,?Xuefeng Zhang,?Dan Yang,?Weideng Wei,?Jianguo Gan,?Xiaoqiang Xia,?Qianming Chen,?Jian Jiang,?Xiaodong Feng

Abstract

Objective: Chemoresistance is a common event after chemotherapy, including oral squamous cell carcinoma (OSCC). Accumulated evidence suggests that the cancer stemness significantly contributes to therapy resistance. An unresolved question remains regarding how to effectively overcome OSCC chemoresistance by targeting stemness. This study aims to investigate the antitumor effect of metformin and clarify the potential molecular mechanisms.

Methods: Cellular models resistant to chemotherapy were established, and their viability and sphere-forming ability were assessed using CCK-8 and soft agar formation assays, respectively. RNA-seq and Western blotting analyses were employed to delve into the molecular pathways. Furthermore, to corroborate the inhibitory effects of metformin and cisplatin at an animal level, a subcutaneous tumor transplantation model was instituted.

Results: Metformin as a monotherapy exhibited inhibition of stemness traits via Krüppel-like factor 4 (KLF4). Metformin and cisplatin can synergically inhibit cell proliferation and induce cell apoptosis. Animal experiments confirmed the inhibitory effect of cisplatin and metformin on tumor in mice.

Conclusion: Our study proposes a potential therapeutic approach of combining chemotherapy with metformin to overcome chemoresistance in OSCC.

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