MicroRNA-375 restrains the progression of lung squamous cell carcinoma by modulating the ERK pathway via UBE3A-mediated DUSP1 degradation

Cell Death Discovery

Article

Shan Liu¹  Juan Zhao¹  Guannan Mu¹  Qi Li¹  Yu Zhang¹  Yangjiazi Wu¹  Jiade Li¹  Xinling Wang¹  Wei Jiang¹  Xiaoyi Huang²  Junqing Gan³  Dehai Che³  Qingwei Meng³  Xiaomei Li⁴ 

[1] Biotherapy Center, Harbin Medical University Cancer Hospital, 150081, Harbin, Heilongjiang, China;Biotherapy Center, Harbin Medical University Cancer Hospital, 150081, Harbin, Heilongjiang, China;NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, 150001, Harbin, China;Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150081, Harbin, Heilongjiang, China;Department of Pathology, Harbin Medical University Cancer Hospital, 150081, Harbin, Heilongjiang, China;

关键词: ;   

DOI  :  10.1038/s41420-023-01499-7

 received in 2022-12-24, accepted in 2023-06-16,  发布年份 2023

来源: Springer

【 摘 要 】

MiRNA-375 has been reported to play critical roles in a variety of cancers. To unravel its biological roles, especially its specific mechanisms of action in lung squamous cell carcinoma (LUSC), LUSC tissue microarrays and miRNAscope were performed to identify the miR-375 expression. Associations with clinicopathologic features, survival, and the prognostic value of miR-375 in LUSC were clarified in a retrospective study of 90 pairs of LUSC tissues. In vitro and in vivo gain- and loss-of-function assays were conducted to validate the effects and mechanism of miR-375 in LUSC. The mechanism responsible for interactions was verified by dual-luciferase reporter gene assay, immunoprecipitation (IP) analysis, immunofluorescence (IF) assay and ubiquitination assay. We found that miR-375 had higher expression in noncancerous adjacent tissues than in LUSC tissues. Clinicopathologic analyses showed that miR-375 expression was correlated with pathologic stage and was an independent predictor of overall survival (OS) for LUSC. MiR-375, as a tumor inhibitor, inhibited proliferation and metastasis while promoting apoptosis of LUSC cells. Mechanistic research indicated that miR-375 targeted ubiquitin-protein ligase E3A (UBE3A), which in turn promoted the activity of the ERK signaling pathway via ubiquitin-mediated dual-specificity protein phosphatase 1 (DUSP1) degradation. Collectively, we propose a novel mechanism of tumorigenesis and metastasis of LUSC via the miR-375/UBE3A/DUSP1/ERK axis, which could potentially facilitate new strategies for the treatment of LUSC.

【 授权许可】

CC BY   
© The Author(s) 2023

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