- 作者: Che-Yuan Hu, Bing-Hua Su, Ya-Che Lee, Chung-Teng Wang, Mei-Lin Yang, Wan-Ting Shen, Jing-Ting Fu, Shih-Yao Chen, Wei-Yun Huang, Chien-Hui Ou, Yuh-Shyan Tsai, Feng-Chih Kuo, Ai-Li Shiau, Gia-Shing Shieh & Chao-Liang Wu
- 作者服務機構: 1.Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 701401, Taiwan 2.Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 701401, Taiwan 3.Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan 4.Department of Urology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan 5.Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng Li Road, Tainan, 704302, Taiwan 6.Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan, Taiwan 7.Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan 8.Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 9.Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan 10.School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 中文摘要:
- 英文摘要:
Background
Cisplatin-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 methods
Expression 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.
Results
Expression 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.
Conclusions
We 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. - 中文關鍵字:
- 英文關鍵字: HOTAIR, Cachexia, Cisplatin, Bladder cancer, Prothymosin α, EGFR, Chemotherapy