Targeting RNA helicase DHX33 blocks Ras‐driven lung tumorigenesis in vivo

• Published in: Cancer science Vol. 111; no. 10; pp. 3564 - 3575
• Main Authors: Wang, Xingshun, Feng, Weimin, Peng, Cheng, Chen, Shiyun, Ji, Hongbin, Zhong, Hanbing, Ge, Wei, Zhang, Yandong
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-10-2020; John Wiley and Sons Inc
• Subjects: Adenoviruses; Animals; Antibodies; Apoptosis; Apoptosis - genetics; Biosynthesis; Biotechnology; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell cycle; Cell Cycle - genetics; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell Proliferation - genetics; DEAD-box RNA Helicases - genetics; Deoxyribonucleic acid; DHX33; DNA; DNA helicase; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Genetic testing; Glycolysis; Lung - pathology; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Mice, Knockout; Mutation; oncogene; Original; Penicillin; Proteins; Ras; ras Proteins - genetics; RNA helicase; Tumorigenesis; Wnt protein; Wnt Signaling Pathway - genetics; lung cancer; DHX33; oncogene; Ras; RNA helicase
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14601

Ras has been found to be mutated in 30% of non‐small cell lung cancers, and its mutation has been regarded as a causal factor underlying tumorigenesis. However, no successful medicine has been developed so far to inhibit Ras for lung cancer treatment. We have previously identified DHX33 as a Ras downstream effector, promoting cell cycle progression and cell growth. In this study, with the K‐Ras (G12D);DHX33 (lox/lox) mouse model, we discovered that genetic ablation of DHX33 inhibited tumor development. We further found that ablation of DHX33 altered the expression of nearly 2000 genes which are critical in cancer development such as cell cycle, apoptosis, glycolysis, Wnt signaling, and cell migration. Our study for the first time demonstrates the pivotal role of the DHX33 in Ras‐driven lung cancer development in vivo and highlights that pharmacological targeting DHX33 can be a feasible option in treating Ras‐mutant lung cancers.
Our study provides the initial evidence in vivo to reveal the critical role of DHX33 in Ras‐driven lung tumorigenesis. This study highlights a novel therapeutic target in treating human cancers.