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TROP-2 exhibits tumor suppressive functions in cervical cancer by dual inhibition of IGF-1R and ALK signaling.
- Source :
-
Gynecologic Oncology . Jan2019, Vol. 152 Issue 1, p185-193. 9p. - Publication Year :
- 2019
-
Abstract
- Abstract Objective Inactivation 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. Methods The 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. Results In 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. Conclusions Collectively, our results support that TROP-2 exhibits tumor suppressor functions in cervical cancer through inhibiting the activity of IGF-1R and ALK. Highlights • TROP-2 exhibits potent tumor suppressive functions in cervical cancer cells both in vitro and in vivo. • TROP-2 exerts its tumor suppressive effects by inhibiting the activity of IGF-1R and ALK receptors. • TROP-2 sequesters the ligands of IGF-1R and ALK through protein interactions. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00908258
- Volume :
- 152
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Gynecologic Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 133825252
- Full Text :
- https://doi.org/10.1016/j.ygyno.2018.10.039