HOXA5 Derives the Malignant Progression and Cisplatin Resistance of Esophageal Squamous Cell Carcinoma by Regulating USP18-Mediated IFI27 Deubiquitination.
Qiang Wang, Shiheng Ren, Zheng Pan, Yuxin Chen, Xiangyan Liu
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Abstract
Background: Chemo-resistance is a major obstacle to the treatment of esophageal squamous cell carcinoma (ESCC). Interferon alpha-inducible protein 27 (IFI27) has been reported to be associated with ESCC progression. This study is designed to explore the role and mechanism of IFI27 in the cisplatin (DDP) resistance of ESCC.
Methods: IFI27 and Ubiquitin-specific peptidase 18 (USP18) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). IFI27, multidrug resistance-associated protein 1 (MRP1), USP18, and Homeobox A5 (HOXA5) protein levels were determined using western blot. DDP resistance, cell viability, proliferation, apoptosis, invasion, and migration were assessed using MTT, EdU, flow cytometry, transwell, and wound healing. Interaction between USP18 and IFI27 was verified using Co-immunoprecipitation (CoIP) assay. Binding between HOXA5 and USP18 promoter was predicted by JASPAR and validated using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.
Results: IFI27 was upregulated in DDP-resistant ESCC tissues and cells. IFI27 knockdown repressed DDP resistance, cell proliferation, invasion, migration, and induced cell apoptosis in vitro. Mechanistically, USP18 induced the deubiquitination of IFI27 and prevented its degradation. Furthermore, HOXA5 was a transcription factor of USP18 and activated the transcriptional activity of USP18 via binding to its promoter region.
Conclusion: USP18 transcriptionally mediated by HOXA5 could promote cell malignant behaviors and DDP resistance through deubiquitinating IFI27, providing a promising therapeutic target for ESCC treatment.
期刊介绍：
Thoracic Cancer aims to facilitate international collaboration and exchange of comprehensive and cutting-edge information on basic, translational, and applied clinical research in lung cancer, esophageal cancer, mediastinal cancer, breast cancer and other thoracic malignancies. Prevention, treatment and research relevant to Asia-Pacific is a focus area, but submissions from all regions are welcomed. The editors encourage contributions relevant to prevention, general thoracic surgery, medical oncology, radiology, radiation medicine, pathology, basic cancer research, as well as epidemiological and translational studies in thoracic cancer. Thoracic Cancer is the official publication of the Chinese Society of Lung Cancer, International Chinese Society of Thoracic Surgery and is endorsed by the Korean Association for the Study of Lung Cancer and the Hong Kong Cancer Therapy Society.
The Journal publishes a range of article types including: Editorials, Invited Reviews, Mini Reviews, Original Articles, Clinical Guidelines, Technological Notes, Imaging in thoracic cancer, Meeting Reports, Case Reports, Letters to the Editor, Commentaries, and Brief Reports.
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