Chih‐Yu PengTung‐Yuan WangShiuan‐Shinn LeePei‐Ling HsiehYi‐Wen LiaoLo‐Lin TsaiChih‐Yuan FangCheng‐Chia YuChing‐Shui Hsieh2026-01-272026-01-272018-04-1710.1111/jop.12711https://scholars.csmu.edu.tw/handle/123456789/3065<jats:sec><jats:title>Background</jats:title><jats:p>The let‐7 family of microRNAs has been considered as tumor suppressors in various cancers; however, the role of let‐7c in oral squamous cell carcinoma has not been determined yet.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In this study, phenotypical behaviors and the radio/chemoresistance were examined subsequent to overexpression of let‐7c. In addition, the expression of let‐7c in cancer stem cells (CSCs) was evaluated and the effect of let‐7c on stemness characteristics was assessed. Also, luciferase activity assays were performed to test whether interleukin (IL)‐8 was a putative target of let‐7c.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Our results confirmed that the expression of let‐7c in CSCs was reduced, while overexpression of let‐7c attenuated the oncogenicity. Moreover, ectopic expression of let‐7c in CSCs downregulated the stemness hallmarks and the radio/chemoresistance. Expression and secretion of IL‐8 in oral CSCs were both reduced following overexpression of let‐7c. Besides, the inhibitory effect of let‐7c on various stemness phenotypes was reverted by IL‐8, indicating that lower expression of let‐7c may confer higher cancer stemness through a failure to downregulate IL‐8.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These findings revealed the significance of let‐7c in the contribution of oral cancer stemness and radio/chemoresistance. Targeting let‐7c and its downstream IL‐8 may be beneficial to prevent cancer recurrence and metastasis of oral squamous cell carcinoma.</jats:p></jats:sec>[SDGs]SDG3journal-article