Qinghai Zeng1,2, Ke Cao3, Rui Liu1, Jinhua Huang2, Kun Xia4, Jintian Tang5, Xiang Chen6, Ming Zhou7, Huiqing Xie8, Jianda Zhou1. 1. a Department of Plastic and Reconstructive Surgery , Third Xiangya Hospital of Central South University , Changsha , China. 2. b Department of Dermatology , Third Xiangya Hospital of Central South University , Changsha , China. 3. c Department of Oncology , Third Xiangya Hospital of Central South University , Changsha , China. 4. d State Key Laboratory of Medical Genetics, Central South University , Changsha , China. 5. e Institute of Medical Physics and Engineering , Department of Engineering Physics, Tsinghua University , Beijing , China. 6. f Department of Dermatology , Xiangya Hospital of Central South University , Changsha , China. 7. g Cancer Research Institute, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University , Changsha , China. 8. h Department of Rehabilitation , Third Xiangya Hospital of Central South University , Changsha , China.
Abstract
BACKGROUND: Although recent studies have revealed TAR (trans-activating response region) DNA binding protein (TDP-43) as a potential therapeutic target for cancers, its role and clinical association with melanoma have not been explored. OBJECTIVE: To identify the role and function of TDP-43 during melanoma pathogenesis. METHODS: Firstly, the relationship between TDP-43 expression and patient survival was explored. Then TDP-43 expression level in melanoma tissue and different melanoma cell lines was measured. After silencing TDP-43 expression in melanoma cells, the impacts of TDP-43 on cellular proliferation, metastasis, glucose uptake, and glucose transporters levels were studied. In the end, effect of TDP-43 depletion on tumorigenicity of melanoma cells was tested in vivo. RESULTS: Our results showed that TDP-43 was overexpressed in melanoma paraffin samples compared with that in nevi tissues. The high expression level of TDP-43 was associated with poor patient survival. By silencing TDP-43, we saw significant inhibition of cell proliferation and metastasis in A375 and WM451 cells. TDP-43 knockdown could suppress glucose transporter type-4 (GLUT4) expression and reduce glucose uptake. And downregulation of GLUT4 in melanoma cells induced inhibition of cell proliferation and metastasis. TDP-43 knockdown significantly slowed down tumor growth and decreased GLUT4 expression in vivo. CONCLUSION: TDP-43 is a novel oncogene in melanoma and regulates melanoma proliferation and metastasis potentially through modulation of glucose metabolism.
BACKGROUND: Although recent studies have revealed TAR (trans-activating response region) DNA binding protein (TDP-43) as a potential therapeutic target for cancers, its role and clinical association with melanoma have not been explored. OBJECTIVE: To identify the role and function of TDP-43 during melanoma pathogenesis. METHODS: Firstly, the relationship between TDP-43 expression and patient survival was explored. Then TDP-43 expression level in melanoma tissue and different melanoma cell lines was measured. After silencing TDP-43 expression in melanoma cells, the impacts of TDP-43 on cellular proliferation, metastasis, glucose uptake, and glucose transporters levels were studied. In the end, effect of TDP-43 depletion on tumorigenicity of melanoma cells was tested in vivo. RESULTS: Our results showed that TDP-43 was overexpressed in melanomaparaffin samples compared with that in nevi tissues. The high expression level of TDP-43 was associated with poor patient survival. By silencing TDP-43, we saw significant inhibition of cell proliferation and metastasis in A375 and WM451 cells. TDP-43 knockdown could suppress glucose transporter type-4 (GLUT4) expression and reduce glucose uptake. And downregulation of GLUT4 in melanoma cells induced inhibition of cell proliferation and metastasis. TDP-43 knockdown significantly slowed down tumor growth and decreased GLUT4 expression in vivo. CONCLUSION:TDP-43 is a novel oncogene in melanoma and regulates melanoma proliferation and metastasis potentially through modulation of glucose metabolism.
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