Ddit4-KO Mouse

Ddit4, also known as REDD1, is a protein-coding gene. It plays a crucial role in regulating the cellular energy hub mTORC1. Under certain stress conditions like DNA damage, hypoxia, and chemotherapy, its expression level increases. It is involved in multiple biological processes such as autophagy, cell proliferation, and the regulation of reactive oxygen species (ROS) production [1,2,3,4,7].

In stomach metaplasia, Ddit4-deficient mice showed that paligenotic Ddit4 -/- chief cells maintained constitutively high mTORC1, leading to increased mitosis of metaplastic cells despite DNA damage, and increased spontaneous tumorigenesis after multiple rounds of paligenosis. This indicates that during injury-induced metaplastic proliferation, failure of licensing mTORC1 reactivation due to Ddit4 deficiency is related to increased proliferation of cells with DNA damage, as well as increased tumor formation [1]. In triple-negative breast cancer and pancreatic cancer, targeting the lncRNA DDIT4-AS1, which is related to Ddit4, can affect autophagy and cancer stemness respectively, influencing chemosensitivity [2,3]. In head and neck squamous cell carcinoma, knockdown of Ddit4 inhibited cell proliferation, invasion, and migration, and its overexpression was negatively correlated with immune score and immune cell infiltrations [5]. In lung adenocarcinoma, high expression of Ddit4 was correlated with poor overall survival [6].

In conclusion, Ddit4 is essential in regulating mTORC1-related processes and has a significant impact on tumor-related biological behaviors. Gene-knockout mouse models, especially Ddit4-deficient mice, have provided important insights into the role of Ddit4 in tumorigenesis, such as in gastric, breast, pancreatic, head and neck, and lung cancers, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Miao, Zhi-Feng, Sun, Jing-Xu, Adkins-Threats, Mahliyah, Wang, Zhen-Ning, Mills, Jason C. 2020. DDIT4 Licenses Only Healthy Cells to Proliferate During Injury-induced Metaplasia. In Gastroenterology, 160, 260-271.e10. doi:10.1053/j.gastro.2020.09.016. https://pubmed.ncbi.nlm.nih.gov/32956680/

2. Jiang, Ting, Zhu, Jiaojiao, Jiang, Shilong, Zhou, Wenhu, Cheng, Yan. 2023. Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2207257. doi:10.1002/advs.202207257. https://pubmed.ncbi.nlm.nih.gov/37096846/

3. Zhang, Yi, Liu, Xiaomeng, Wang, Yan, Wang, Hongquan, Tang, Bo. 2022. The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway. In Molecular cancer, 21, 174. doi:10.1186/s12943-022-01647-0. https://pubmed.ncbi.nlm.nih.gov/36056355/

4. Li, Zilong, Zhao, Qianwen, Lu, Yunjie, Duan, Yunfei, Xu, Yong. 2021. DDIT4 S-Nitrosylation Aids p38-MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 8, e2101957. doi:10.1002/advs.202101957. https://pubmed.ncbi.nlm.nih.gov/34310076/

5. Zhang, Zhenxing, Zhu, Haoran, Zhao, Chifeng, Ying, Yukang, Zhong, Yuan. 2022. DDIT4 promotes malignancy of head and neck squamous cell carcinoma. In Molecular carcinogenesis, 62, 332-347. doi:10.1002/mc.23489. https://pubmed.ncbi.nlm.nih.gov/36453700/

6. Song, Li, Chen, Zhiyao, Zhang, Menghua, Li, Chunsun, Miao, Liyan. 2021. DDIT4 overexpression associates with poor prognosis in lung adenocarcinoma. In Journal of Cancer, 12, 6422-6428. doi:10.7150/jca.60118. https://pubmed.ncbi.nlm.nih.gov/34659532/

7. Wang, Yijing, Yang, Si, Hao, Chaoju, Wang, Jinglei, Xu, Linlin. 2023. DDIT4 is essential for DINP-induced autophagy of ovarian granulosa cells. In Ecotoxicology and environmental safety, 268, 115686. doi:10.1016/j.ecoenv.2023.115686. https://pubmed.ncbi.nlm.nih.gov/37976928/