Int J Biol Sci 2022; 18(10):4053-4070. doi:10.7150/ijbs.73009 This issue

Research Paper

The TTYH3/MK5 Positive Feedback Loop regulates Tumor Progression via GSK3-β/β-catenin signaling in HCC

Yixiu Wang1#, Yuwei Xie1#, Bingzi Dong2,3#, Weijie Xue4, Shuhai Chen5, Shimada Mitsuo5, Hao Zou1, Yujie Feng1, Kai Ma1, Qian Dong2,6✉, Jingyu Cao1✉, Chengzhan Zhu1,2✉

1. Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China.
2. Shandong Key Laboratory of Digital Medicine and Computer Assisted Surgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266003, China.
3. Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China.
4. Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China.
5. Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima 770‑8503, Japan.
6. Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266003, China.
#These authors contributed equally to this work.

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Citation:
Wang Y, Xie Y, Dong B, Xue W, Chen S, Mitsuo S, Zou H, Feng Y, Ma K, Dong Q, Cao J, Zhu C. The TTYH3/MK5 Positive Feedback Loop regulates Tumor Progression via GSK3-β/β-catenin signaling in HCC. Int J Biol Sci 2022; 18(10):4053-4070. doi:10.7150/ijbs.73009. Available from https://www.ijbs.com/v18p4053.htm

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Abstract

Graphic abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and identification of novel targets is necessary for its diagnosis and treatment. This study aimed to investigate the biological function and clinical significance of tweety homolog 3 (TTYH3) in HCC. TTYH3 overexpression promoted cell proliferation, migration, and invasion and inhibited HCCM3 and Hep3B cell apoptosis. TTYH3 promoted tumor formation and metastasis in vivo. TTYH3 upregulated calcium influx and intracellular chloride concentration, thereby promoting cellular migration and regulating epithelial-mesenchymal transition-related protein expression. The interaction between TTYH3 and MK5 was identified through co-immunoprecipitation assays and protein docking. TTYH3 promoted the expression of MK5, which then activated the GSK3β/β-catenin signaling pathway. MK5 knockdown attenuated the activation of GSK3β/β-catenin signaling by TTYH3. TTYH3 expression was regulated in a positive feedback manner. In clinical HCC samples, TTYH3 was upregulated in the HCC tissues compared to nontumor tissues. Furthermore, high TTYH3 expression was significantly correlated with poor patient survival. The CpG islands were hypomethylated in the promoter region of TTYH3 in HCC tissues. In conclusion, we identified TTYH3 regulates tumor development and progression via MK5/GSK3-β/β-catenin signaling in HCC and promotes itself expression in a positive feedback loop.

Keywords: Tweety homolog 3, hepatocellular carcinoma, tumor metastasis, epithelial-mesenchymal transition, positive feedback