The role of FGFR3-TACC3 fusion gene in tumor metabolism

Chromosomal translocation leads to gene fusion is a common DNA abnormality in tumors and a target for targeted treatmentPrevious studies have found that 3% of glioblastomas contain FGFR3-TACC3 (F3-T3) fusion gene mutations, which occur similarly in other tumorsThe F3-T3 fusion gene is a primary cancer gene that gives tumor cells sensitivity to FGFR inhibitorsTumors with the F3-T3 fusion gene were found in a transcription subgroup activated by mitochondrial function, according to V?ronique Frattini of the Institute of Cancer Genetics at Columbia University Medical Center in New YorkIn addition, F3-T3 mutant tumors rely on mitochondrial oxidation phosphorylation to provide a new direction for targeted treatment of gliomas, especially those with F3-T3 fusion genes, the results of the study are published in The Nature in January 2018the method of study
the researchers first expressed F3-T3 in the astrocytes of the human brain and compared the changes in the expression spectrum with FGFR tyrosine kinase (TK, PD173074) inhibitorsAccording to the stratified cluster ingestive cluster of gene expression differences, mitochondrial function improved significantly when oxidizing phosphorylation and mitochondrial biosynthetic genes were enriched in F3-T3 mutant cells, resulting in more ATPMitochondrial inhibitors reduce cell activity and inhibit the growth of gliomas with F3-T3 mutations in animal modelsthen, the expression of F3-T3, F3-T3 (K508M) or empty vector of human brain star-shaped glial cells immunocoprecipitation, and then through the liquid chromatography-series mass spectrometry method to identify the relevant phosphorylation proteinIt was found that the cells that expressed the active F3-T3 fusion gene mutation contained proteins such as phosphorylation PIN4, PKM2, DLG3, C1orf50 and GOLGIN84, the most obvious of which were the Y122 site of PIN4, or PIN4 (Y122)Immunized hetinized staining of phosphorylation PIN4 (Y122) in the original GBM showed that the expression level of phosphorylation PIN4 (Y122) was higher in tumors with F3-T3 mutationsThe agar cell experiment suggests that PIN4 (Y122F) overexpression reduces cell cloning formationfurther study of the mechanism by which PIN4 phosphorylation causes metabolic changes, pin4 is necessary for the occurrence and protein synthesis of FGFR3-TACC3-mediated peroxidase, which produces intracellular reactive oxygen (ROS) and raises PGCI alphaPGCI alpha is the main regulator for mitochondria to occur and metabolize, which can promote tumor growthTherefore, the consumption of PGCI alpha in vitro and in vitro can inhibit the growth of F3-T3 fusion gene mutation tumors; Therefore, targeted therapy for tumor oxidative phosphorylation is expected to be used in glioma treatmentconclusion
the F3-T3 fusion protein can activate mitochondrial metabolism and promote protein synthesis to stimulate tumor growth, and by relying on the mechanism of reliance on mitochondrial respiration, FGFR3-TACC3 fusion gene mutation can be used as a new way of treating glioma.