Targeting RNA helicase DHX33 blocks Ras-driven lung tumorigenesis in vivo
Xingshun Wang1,2, Weimin Feng1, Cheng Peng1,2
1Department of Biology, Southern University of Science and Technology, Shenzhen, China.
Abstract:
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.
Insights
Targeting DHX33, a Ras downstream effector, inhibits tumor development in Ras-mutant lung cancer. This study reveals DHX33
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ras mutations drive 30% of non-small cell lung cancers (NSCLC).
- No effective drugs currently target Ras for NSCLC treatment.
- DHX33 was previously identified as a Ras downstream effector promoting cell growth.
Purpose of the Study:
- To investigate the role of DHX33 in Ras-driven lung cancer development in vivo.
- To explore DHX33 as a potential therapeutic target for Ras-mutant NSCLC.
Main Methods:
- Utilized a K-Ras (G12D);DHX33 (lox/lox) mouse model.
- Performed genetic ablation of DHX33.
- Analyzed gene expression changes following DHX33 ablation.
Main Results:
- Genetic ablation of DHX33 significantly inhibited tumor development.
- DHX33 ablation altered the expression of approximately 2000 genes.
- Affected genes are critical for cell cycle, apoptosis, glycolysis, Wnt signaling, and cell migration.
Conclusions:
- DHX33 plays a pivotal role in Ras-driven lung cancer development.
- Pharmacological targeting of DHX33 presents a feasible strategy for treating Ras-mutant lung cancers.
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