TROP-2 exhibits tumor suppressive functions in cervical cancer by dual inhibition of IGF-1R and ALK signaling |
| |
Authors: | Sarah T.K. Sin Yan Li Ming Liu Stephanie Ma Xin-Yuan Guan |
| |
Affiliation: | 1. Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong;2. Department of Biology, Southern University of Science and Technology of China, Shenzhen, China;3. School of Basic Sciences, Guangzhou Medical University, Guangzhou, China;4. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong;5. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China |
| |
Abstract: | ObjectiveInactivation of tumor suppressor genes promotes initiation and progression of cervical cancer. This study aims to investigate the tumor suppressive effects of TROP-2 in cervical cancer cells and to explain the underlying mechanisms.MethodsThe tumor suppressive functions of TROP-2 in cervical cancer cells were examined by in vitro and in vivo tumorigenic functional assays. Downstream factors of TROP-2 were screened using Human Phospho-Receptor Tyrosine Kinase Array. Small molecule inhibitors were applied to HeLa cells to test the TROP-2 effects on the oncogenicity of IGF-1R and ALK. Protein interactions between TROP-2 and the ligands of IGF-1R and ALK were detected via immunoprecipitation assay and protein-protein affinity prediction.ResultsIn vitro and in vivo functional assays showed that overexpression of TROP-2 significantly inhibited the oncogenicity of cervical cancer cells; while knockdown of TROP-2 exhibited opposite effects. Human Phospho-Receptor Tyrosine Kinase Array showed that the activity of IGF-1R and ALK was stimulated by TROP-2 knockdown. Small molecule inhibitors AG1024 targeting IGF-1R and Crizotinib targeting ALK were treated to HeLa cells with and without TROP-2 overexpression, and results from cell viability and migration assays indicated that the oncogenicity of vector-transfected cells was repressed to a greater extent by the inhibition of either IGF-1R or ALK than that of the TROP-2-overexpressed cells. Immunoprecipitation assay and protein-protein affinity prediction suggested protein interactions between TROP-2 and the ligands of IGF-1R and ALK.ConclusionsCollectively, our results support that TROP-2 exhibits tumor suppressor functions in cervical cancer through inhibiting the activity of IGF-1R and ALK. |
| |
Keywords: | TROP-2 trophoblast antigen 2 IGF-1R insulin-like growth factor 1 receptor ALK anaplastic lymphoma kinase XTT 2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide RTK Receptor Tyrosine Kinase Cervical cancer Tumor suppressor IGF-1R ALK |
本文献已被 ScienceDirect 等数据库收录! |
|