ALYREF, also known as Aly/REF export factor, is an mRNA export adaptor that plays a crucial role in mRNA metabolism. It specifically recognizes 5-methylcytosine (m5C) modification in mRNAs, which is mainly catalyzed by NSUN2. This recognition is involved in processes such as pre-mRNA processing, mRNA stability, and nuclear-cytoplasmic shuttling, and is essential for mRNA export and post-transcriptional regulation [2].

In cancer research, ALYREF has been found to be closely associated with tumorigenesis and progression. In bladder cancer, ALYREF stabilizes PKM2 mRNA by binding to its m5C sites in 3'-untranslated regions, promoting cell proliferation through PKM2-mediated glycolysis, and high expression of ALYREF predicts poor survival [1]. In non-small cell lung cancer, LINC02159 binds to ALYREF to enhance the stability of YAP1 mRNA via m5C modification, promoting cancer progression [3]. In urothelial bladder cancer, ALYREF and NSUN2 are frequently co-expressed, and ALYREF enhances cell proliferation and invasion in an m5C-dependent manner by promoting splicing and stabilization of RABL6 and TK1 mRNAs [4]. In nasopharyngeal carcinoma, ALYREF upregulates NOTCH1 expression by enhancing its RNA stability in an m5C-modification-dependent manner, facilitating metastasis [5]. In colorectal cancer, ALYREF forms a complex with ELAVL1 to promote m5C recognition and nuclear export of RPS6KB2 and RPTOR mRNAs, supporting cancer growth and migration [6].

In conclusion, ALYREF is a key factor in mRNA m5C-related regulation, playing a significant role in cancer development and progression. Studies using in vivo models, though not specifically KO/CKO mouse models in the provided references, have revealed its multiple oncogenic mechanisms in different cancers, highlighting its potential as a prognostic biomarker and therapeutic target for cancer treatment [1,3,4,5,6].

References:

1. Wang, Jing-Zi, Zhu, Wei, Han, Jie, Wei, Ji-Fu, Yang, Haiwei. 2021. The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. In Cancer communications (London, England), 41, 560-575. doi:10.1002/cac2.12158. https://pubmed.ncbi.nlm.nih.gov/33991457/

2. Yang, Xin, Yang, Ying, Sun, Bao-Fa, Sun, Ying-Pu, Yang, Yun-Gui. 2017. 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m5C reader. In Cell research, 27, 606-625. doi:10.1038/cr.2017.55. https://pubmed.ncbi.nlm.nih.gov/28418038/

3. Yang, Qiurong, Wang, Maoye, Xu, Jing, Gu, Jianmei, Zhang, Xu. 2023. LINC02159 promotes non-small cell lung cancer progression via ALYREF/YAP1 signaling. In Molecular cancer, 22, 122. doi:10.1186/s12943-023-01814-x. https://pubmed.ncbi.nlm.nih.gov/37537569/

4. Wang, Ning, Chen, Ri-Xin, Deng, Min-Hua, Liu, Zhuo-Wei, Zhou, Fang-Jian. 2023. m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization. In Cell death & disease, 14, 139. doi:10.1038/s41419-023-05661-y. https://pubmed.ncbi.nlm.nih.gov/36806253/

5. Jin, Yanan, Yao, Jijin, Fu, Jianchang, Xia, Tianliang, Xia, Liangping. 2024. ALYREF promotes the metastasis of nasopharyngeal carcinoma by increasing the stability of NOTCH1 mRNA. In Cell death & disease, 15, 578. doi:10.1038/s41419-024-06959-1. https://pubmed.ncbi.nlm.nih.gov/39117671/

6. Zhong, Longhua, Wu, Jingxun, Zhou, Bingqian, Ye, Feng, Lin, Xiaoting. 2024. ALYREF recruits ELAVL1 to promote colorectal tumorigenesis via facilitating RNA m5C recognition and nuclear export. In NPJ precision oncology, 8, 243. doi:10.1038/s41698-024-00737-0. https://pubmed.ncbi.nlm.nih.gov/39455812/