Gene Transfer Suppresses Hepatocarcinogenesis by Promoting the Degradation of Myc and Hras

Overview

Journal JHEP Rep

Specialty Gastroenterology

Date 2023 Jun 19

PMID 37333975

Authors

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

Soon will be listed here.

Abstract

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. 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 conditional knockout mice and an gene delivery system with a hydrodynamic tail vein injection and the Sleeping Beauty transposon. The antitumour effects of 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. 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 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.

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Functional Roles of DYRK2 as a Tumor Regulator.

Mochimaru Y, Yoshida K Curr Issues Mol Biol. 2023; 45(10):8539-8551.

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