TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression

• Published in: Cell death & disease 2021-01, Vol.12 (1), p.125-125, Article 125
• Main Authors: Li, Lei, Wei, Jia-Ru, Song, Ye, Fang, Shuo, Du, Yanyu, Li, Zhuo, Zeng, Ting-Ting, Zhu, Ying-Hui, Li, Yan, Guan, Xin-Yuan
• Format: Article
• Language: English
• Subjects: 13/1; 13/51; 13/89; 14/34; 42/109; 631/67/395; 631/80/83; 64/60; AKT protein; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell activation; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Biology; Cell Culture; Cell cycle; Cell Proliferation; Cisplatin; Disease Progression; Dyrk Kinases; Ectopic expression; Hepatocellular carcinoma; Humans; Immunology; Kinases; Life Sciences; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver transplantation; Male; Malignancy; Mice; Mice, Nude; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Ribonucleic acid; RNA; Therapeutic applications; Therapeutic targets; Transfection; Tyrosine
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03422-3

Hepatocellular carcinoma (HCC) is one of the common malignancy and lacks effective therapeutic targets. Here, we demonstrated that ectopic expression of trophinin-associated protein (TROAP) dramatically drove HCC cell growth assessed by foci formation in monolayer culture, colony formation in soft agar and orthotopic liver transplantation in nude mice. Inversely, silencing TROAP expression with short-hairpin RNA attenuated the malignant proliferation of HCC cells in vitro and in vivo. Next, mechanistic investigation revealed that TROAP directly bound to dual specificity tyrosine phosphorylation regulated kinase 1A/B (DYRK1A/B), resulting in the cytoplasmic retention of proteins DYRK1A/B and promoting cell cycle process via activation of Akt/GSK-3β signaling. Combination of cisplatin with an inhibitor of DYRK1 AZ191 effectively inhibited tumor growth in mouse model for HCC cells with high level of TROAP. Clinically, TROAP was significantly upregulated by miR-142-5p in HCC tissues, which predicted the poor survival of patients with HCC. Therefore, TROAP/DYRK1/Akt axis may be a promising therapeutic target and prognostic indicator for patients with HCC.