Interruption of the long non-coding RNA HOTAIR signaling axis ameliorates chemotherapy-induced cachexia in bladder cancer

Journal of Biomedical Science

Research

Wan-Ting Shen¹  Jing-Ting Fu¹  Wei-Yun Huang²  Chung-Teng Wang²  Mei-Lin Yang³  Ai-Li Shiau³  Shih-Yao Chen⁴  Ya-Che Lee⁵  Chien-Hui Ou⁶  Yuh-Shyan Tsai⁶  Gia-Shing Shieh⁷  Chao-Liang Wu⁸  Feng-Chih Kuo⁹  Che-Yuan Hu^1,10  Bing-Hua Su^1,11 

[1] Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1 University Road, 701401, Tainan, Taiwan;Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, 1 University Road, 701401, Tainan, Taiwan;Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, 1 University Road, 701401, Tainan, Taiwan;Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan;Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan;Department of Urology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan;Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng Li Road, 704302, Tainan, Taiwan;Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng Li Road, 704302, Tainan, Taiwan;Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan, Taiwan;Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan;Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1 University Road, 701401, Tainan, Taiwan;Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng Li Road, 704302, Tainan, Taiwan;School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan;

关键词: HOTAIR;    Cachexia;    Cisplatin;    Bladder cancer;    Prothymosin α;    EGFR;    Chemotherapy;   

DOI  :  10.1186/s12929-022-00887-y

 received in 2022-05-25, accepted in 2022-11-22,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundCisplatin-based chemotherapy is the first line of treatment for bladder cancer. However, cisplatin induces muscle wasting associated with NF-κB and cancer cachexia. HOTAIR, an oncogenic long non-coding RNA (lncRNA), promotes cancer progression in different cancers. Crosstalk between HOTAIR and NF-κB is documented. Prothymosin α (ProT) plays important roles in cancer progression and inflammation. However, the potential link between HOTAIR, ProT, and cisplatin-induced cancer cachexia remains unexplored. Here, we investigated the contribution of HOTAIR in cisplatin-induced cancer cachexia and dissected the potential signaling cascade involving the epidermal growth factor receptor (EGFR), ProT, NF-κB, and HOTAIR.Materials and methodsExpression of ProT and HOTAIR transcripts and their correlations in tumor tissues of bladder cancer patients and bladder cancer cell lines were determined by RT-qPCR. Next, levels of phospho-EGFR, EGFR, phospho-NF-κB, and NF-κB were examined by immunoblot analysis in human bladder cancer cells treated with cisplatin. Expression of HOTAIR in cisplatin-treated cells was also assessed by RT-qPCR. Pharmacological inhibitors and overexpression and knockdown approaches were exploited to decipher the signaling pathway. The murine C2C12 myoblasts were used as an in vitro muscle atrophy model. The syngeneic murine MBT-2 bladder tumor was used to investigate the role of mouse Hotair in cisplatin-induced cancer cachexia.ResultsExpression of ProT and HOTAIR was higher in bladder tumors than in normal adjacent tissues. There were positive correlations between ProT and HOTAIR expression in clinical bladder tumors and bladder cancer cell lines. Cisplatin treatment increased EGFR and NF-κB activation and upregulated ProT and HOTAIR expression in bladder cancer cells. ProT overexpression increased, whereas ProT knockdown decreased, HOTAIR expression. Notably, cisplatin-induced HOTAIR upregulation was abrogated by EGFR inhibitors or ProT knockdown. ProT-induced HOTAIR overexpression was diminished by NF-κB inhibitors. HOTAIR overexpression enhanced, whereas its knockdown reduced, cell proliferation, cachexia-associated pro-inflammatory cytokine expression, and muscle atrophy. Cachexia-associated symptoms were ameliorated in mice bearing Hotair-knockdown bladder tumors undergoing cisplatin treatment.ConclusionsWe demonstrate for the first time a critical role for HOTAIR and identify the involvement of the EGFR-ProT-NF-κB-HOTAIR signaling axis in cisplatin-induced cachexia in bladder cancer and likely other cancers. Our findings also provide therapeutic targets for this disease.

【 授权许可】

CC BY   
© The Author(s) 2022

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