NORAD, short for noncoding RNA activated by DNA damage (LINC00657), is a highly conserved long noncoding RNA crucial for maintaining genomic stability. It functions mainly by sequestering Pumilio (PUM) proteins, thereby regulating the stability and translation of mRNAs bound by PUM. This process is involved in multiple biological pathways such as cell cycle, mitosis, DNA replication, and transcription [2,3].

Knockdown of NORAD in in vitro and in vivo models has revealed its significance. In human umbilical vein endothelial cells, NORAD-knockdown induced cell cycle arrest, apoptosis, and senescence, and increased atherosclerotic lesions in ApoE -/- mice, suggesting its role in protecting against endothelial cell injury and atherosclerosis [1]. In multiple myeloma cells, NORAD knockdown promoted apoptosis, induced cell cycle G1 phase arrest, and inhibited cell proliferation, indicating its pro-tumorigenic role in this hematological malignancy via the BMP6/P-ERK1/2 axis [5]. In esophageal squamous cell carcinoma, NORAD knockdown partially arrested cis-diamminedichloro-platinum (CDDP) resistance, highlighting its role in chemotherapy resistance [4].

In conclusion, NORAD is essential for maintaining genomic stability and is involved in various disease conditions. Studies using loss-of-function models, including knockdown in different cell lines and animal models, have significantly contributed to understanding its role in diseases like atherosclerosis, multiple myeloma, and esophageal squamous cell carcinoma, providing potential therapeutic targets for these diseases.

References:

1. Bian, Weihua, Jing, Xiaohong, Yang, Zhiyu, Sun, Yeying, Zhang, Chunxiang. 2020. Downregulation of LncRNA NORAD promotes Ox-LDL-induced vascular endothelial cell injury and atherosclerosis. In Aging, 12, 6385-6400. doi:10.18632/aging.103034. https://pubmed.ncbi.nlm.nih.gov/32267831/

2. Lee, Sungyul, Kopp, Florian, Chang, Tsung-Cheng, Xie, Yang, Mendell, Joshua T. 2015. Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins. In Cell, 164, 69-80. doi:10.1016/j.cell.2015.12.017. https://pubmed.ncbi.nlm.nih.gov/26724866/

3. Capela, Ana Maria, Tavares-Marcos, Carlota, Estima-Arede, Hugo F, Nóbrega-Pereira, Sandrina, Bernardes de Jesus, Bruno. 2024. NORAD-Regulated Signaling Pathways in Breast Cancer Progression. In Cancers, 16, . doi:10.3390/cancers16030636. https://pubmed.ncbi.nlm.nih.gov/38339387/

4. Jia, Yunlong, Tian, Cong, Wang, Hongyan, Wang, Jiali, Liu, Lihua. 2021. Long non-coding RNA NORAD/miR-224-3p/MTDH axis contributes to CDDP resistance of esophageal squamous cell carcinoma by promoting nuclear accumulation of β-catenin. In Molecular cancer, 20, 162. doi:10.1186/s12943-021-01455-y. https://pubmed.ncbi.nlm.nih.gov/34893064/

5. Ma, Tao, Chen, Yan, Yi, Zhi-Gang, Li, Li-Juan, Zhang, Lian-Sheng. 2022. NORAD promotes multiple myeloma cell progression via BMP6/P-ERK1/2 axis. In Cellular signalling, 100, 110474. doi:10.1016/j.cellsig.2022.110474. https://pubmed.ncbi.nlm.nih.gov/36126794/