For its diagnosis and treatment, hepatocellular carcinoma (HCC), one of the global causes of cancer-related mortality, requires the discovery of new targets. For a study, researchers sought to examine the biological role and clinical importance of tweety homolog 3 (TTYH3) in HCC.

Through its overexpression and knockdown in HCC cell lines, the biological role of TTYH3 was examined in vitro and in vivo. They investigated how TTYH3 regulates HCC cell invasion and metastasis at the molecular level. In HCC tissues, the expression and clinical importance of TTYH3 were examined. Microarray and pyrosequencing were used to investigate the DNA methylation in TTYH3. Co-immunoprecipitation tests and protein docking were used to find the interaction between TTYH3 and MK5. TTYH3 expression in clinical HCC samples was examined, and its relationship to patient survival was also examined.

TTYH3 overexpression reduced apoptosis in HCCM3 and Hep3B cells while promoting cell growth, migration, and invasion. In vivo, TTYH3 encouraged the growth and spread of tumors. TTYH3 increased intracellular chloride concentration and calcium influx, which promoted cellular motility and controlled the production of proteins linked to the epithelial-mesenchymal transition. Co-immunoprecipitation tests and protein docking were used to find the interaction between TTYH3 and MK5. TTYH3 encouraged MK5 to express itself, and this, in turn, stimulated the GSK3β/β-catenin signaling pathway. The stimulation of GSK3β/β-catenin signaling by TTYH3 was reduced by MK5 knockdown. The findings indicated that TTYH3 expression was controlled in a positive feedback way based on site-mutant TTYH3. TTYH3 was more highly expressed in clinical HCC samples’ HCC tissues than nontumor tissues. Furthermore, a weak correlation between high TTYH3 expression and poor patient survival was found. In HCC tissues, the CpG islands in the TTYH3 promoter region were hypomethylated.

They discovered that TTYH3 controls tumor growth and progression in HCC by promoting its own expression through a positive feedback loop involving MK5/GSK3β/β-catenin signaling.

Reference: annalsofoncology.org/article/S0923-7534(22)01887-7/fulltext