Mir449a-KO Mouse

miR449a is a microRNA belonging to the miR-34/449 family. MicroRNAs are short, non-protein-coding RNAs essential for regulating cellular processes via gene silencing. miR449a is involved in multiple key biological processes and signaling pathways, such as cell cycle arrest, apoptosis, immune responses, and mitochondrial biogenesis [5,3].

In low-birth-weight (LBW) rats, impaired miR449a-induced downregulation of Crhr1 expression was observed. Restraint-induced elevation of miR449a and subsequent downregulation of Crhr1 in the anterior pituitary through glucocorticoids occurred in normal-birth-weight offspring but not in LBW offspring, likely due to increased GAS5 expression in LBW rats, leading to prolonged HPA axis activation [1].

In esophageal squamous cell carcinoma (ESCC), miR-449a was identified as a direct regulator of MEST, and its promoter hypermethylation led to MEST upregulation. Systemically delivered miR-449a mimic could suppress tumor metastasis without overt toxicity [2].

In T-2 toxin-exposed cells, miR449a was strongly inhibited, and the miR449a/SIRT1/deacetylated PGC-1α axis was essential for T-2 toxin-induced mitochondrial biogenesis and ROS production [3].

In EVI1-positive leukaemic cells, EVI1-mediated down-regulation of MIR449A was crucial for cell survival, and reconstitution of MIR449A induced apoptosis, potentially mediated by regulation of NOTCH1 and BCL2 [4].

In the context of cellular senescence, miR-449a reduced senescence, primarily through targeted reduction of p16Ink4a, p21Cip1, and the PI3K-mTOR signaling pathway [6].

In liver transplantation, overexpression of miR-449a inhibited macrophage M1-polarization and improved acute rejection by targeting PLOD1 and inhibiting the NF-κB pathway [7].

A single nucleotide polymorphism rs696 in the miR449a binding site of the NFKBIA gene was correlated with the risk of colorectal cancer [8].

Exosomal circPTGR1 in hepatocellular carcinoma (HCC) cells promoted metastasis via the miR449a-MET pathway [9].

In conclusion, miR449a plays diverse and essential roles in multiple biological processes and disease conditions, including metabolism-related disorders, cancer, and cellular senescence. The use of animal models and functional studies as in the above-mentioned research has revealed its regulatory functions in specific signaling pathways, offering potential therapeutic targets for these diseases.

References:

1. Nemoto, Takahiro, Kakinuma, Yoshihiko, Shibasaki, Tamotsu. 2014. Impaired miR449a-induced downregulation of Crhr1 expression in low-birth-weight rats. In The Journal of endocrinology, 224, 195-203. doi:10.1530/JOE-14-0537. https://pubmed.ncbi.nlm.nih.gov/25480379/

2. Xu, Wen Wen, Liao, Long, Dai, Wei, He, Qing-Yu, Li, Bin. 2023. Genome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis. In EBioMedicine, 92, 104587. doi:10.1016/j.ebiom.2023.104587. https://pubmed.ncbi.nlm.nih.gov/37149929/

3. Ma, Shijie, Zhao, Yurong, Sun, Jianwei, Mu, Peiqiang, Deng, Yiqun. 2018. miR449a/SIRT1/PGC-1α Is Necessary for Mitochondrial Biogenesis Induced by T-2 Toxin. In Frontiers in pharmacology, 8, 954. doi:10.3389/fphar.2017.00954. https://pubmed.ncbi.nlm.nih.gov/29354057/

4. De Weer, An, Van der Meulen, Joni, Rondou, Pieter, Poppe, Bruce, Speleman, Frank. 2011. EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells. In British journal of haematology, 154, 337-48. doi:10.1111/j.1365-2141.2011.08737.x. https://pubmed.ncbi.nlm.nih.gov/21569010/

5. Lv, Jianliang, Zhang, Zhongwang, Pan, Li, Zhang, Yongguang. 2018. MicroRNA-34/449 family and viral infections. In Virus research, 260, 1-6. doi:10.1016/j.virusres.2018.11.001. https://pubmed.ncbi.nlm.nih.gov/30412711/

6. Noureddine, Sarah, Nie, Jia, Schneider, Augusto, Musi, Nicolas, Masternak, Michal M. 2023. microRNA-449a reduces growth hormone-stimulated senescent cell burden through PI3K-mTOR signaling. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2213207120. doi:10.1073/pnas.2213207120. https://pubmed.ncbi.nlm.nih.gov/36976763/

7. Cao, Zhen-Rui, Zheng, Wei-Xiong, Jiang, Yu-Xin, Zong, Ke-Zhen, Wu, Zhong-Jun. 2023. miR-449a ameliorates acute rejection after liver transplantation via targeting procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 in macrophages. In American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 23, 336-352. doi:10.1016/j.ajt.2022.12.009. https://pubmed.ncbi.nlm.nih.gov/36695693/

8. Simonian, Miganoosh, Mosallayi, Meysam, Miraghajani, Maryam, Saberi, Farideh, Salehi, Rasoul. . Single nucleotide polymorphism rs696 in miR449a binding site of NFKBIA gene is correlated with risk of colorectal cancer. In Gastroenterology and hepatology from bed to bench, 11, 48-53. doi:. https://pubmed.ncbi.nlm.nih.gov/29564065/

9. Wang, Guoying, Liu, Wei, Zou, Yong, Yang, Yang, Chen, Guihua. 2019. Three isoforms of exosomal circPTGR1 promote hepatocellular carcinoma metastasis via the miR449a-MET pathway. In EBioMedicine, 40, 432-445. doi:10.1016/j.ebiom.2018.12.062. https://pubmed.ncbi.nlm.nih.gov/30630697/