Dyrk2 gene transfer suppresses hepatocarcinogenesis by promoting the degradation of Myc and Hras
Hiroshi Kamioka,
Satomi Yogosawa,
Tsunekazu Oikawa,
Daisuke Aizawa,
Kaoru Ueda,
Chisato Saeki,
Koichiro Haruki,
Masayuki Shimoda,
Toru Ikegami,
Yuji Nishikawa,
Masayuki Saruta,
Kiyotsugu Yoshida
Affiliations
Hiroshi Kamioka
Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Satomi Yogosawa
Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
Tsunekazu Oikawa
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan; Corresponding authors. Addresses: Department of Biochemistry, The Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan; Tel.: +81-3-3433-1111, Fax: +81-3-3435-1922 (K. Yoshida); Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan; Tel.: +81-3-3433-1111, Fax: +81-3-3435-0569 (T. Oikawa).
Daisuke Aizawa
Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
Kaoru Ueda
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Chisato Saeki
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Koichiro Haruki
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
Masayuki Shimoda
Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
Toru Ikegami
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
Yuji Nishikawa
Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
Masayuki Saruta
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Kiyotsugu Yoshida
Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan; Corresponding authors. Addresses: Department of Biochemistry, The Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan; Tel.: +81-3-3433-1111, Fax: +81-3-3435-1922 (K. Yoshida); Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan; Tel.: +81-3-3433-1111, Fax: +81-3-3435-0569 (T. Oikawa).
Background & Aims: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and has a poor prognosis. However, the molecular mechanisms underlying hepatocarcinogenesis and progression remain unknown. In vitro gain- and loss-of-function analyses in cell lines and xenografts revealed that dual-specificity tyrosine-regulated kinase 2 (DYRK2) influences tumour growth in HCC. Methods: To investigate the role of Dyrk2 during hepatocarcinogenesis, we developed liver-specific Dyrk2 conditional knockout mice and an in vivo gene delivery system with a hydrodynamic tail vein injection and the Sleeping Beauty transposon. The antitumour effects of Dyrk2 gene transfer were investigated in a murine autologous carcinogenesis model. Results: Dyrk2 expression was reduced in tumours, and that its downregulation was induced before hepatocarcinogenesis. Dyrk2 gene transfer significantly suppressed carcinogenesis. It also suppresses Myc-induced de-differentiation and metabolic reprogramming, which favours proliferative, and malignant potential by altering gene profiles. Dyrk2 overexpression caused Myc and Hras degradation at the protein level rather than at the mRNA level, and this degradation mechanism was regulated by the proteasome. Immunohistochemical analyses revealed a negative correlation between DYRK2 expression and MYC and longer survival in patients with HCC with high-DYRK2 and low-MYC expressions. Conclusions: Dyrk2 protects the liver from carcinogenesis by promoting Myc and Hras degradation. Our findings would pave the way for a novel therapeutic approach using DYRK2 gene transfer. Impact and Implications: Hepatocellular carcinoma (HCC) is one of the most common cancers, with a poor prognosis. Hence, identifying molecules that can become promising targets for therapies is essential to improve mortality. No studies have clarified the association between DYRK2 and carcinogenesis, although DYRK2 is involved in tumour growth in various cancer cells. This is the first study to show that Dyrk2 expression decreases during hepatocarcinogenesis and that Dyrk2 gene transfer is an attractive approach with tumour suppressive activity against HCC by suppressing Myc-mediated de-differentiation and metabolic reprogramming that favours proliferative and malignant potential via Myc and Hras degradation.
