Ma Zenghui, Zhu Jianbin, Chen Min, Wu Guangming, Liu Xiaolong, Hu Zhanjun, Feng Yufei, Wang Xiaoliang, Liu Feng
Department of Pediatric Surgery, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Department of Hepatobiliary Surgery, Pudong Hospital, Fudan University, Shanghai, China.
Cancer Rep (Hoboken). 2025 Mar;8(3):e70179. doi: 10.1002/cnr2.70179.
Colorectal cancer (CRC) stands as the second most prevalent cause of cancer-related mortality globally, while its incidence holds the third position among newly diagnosed cancer cases worldwide. Colorectal carcinogenesis is complicated, and the processes are triggered by the complex interaction of some genetic and environmental factors, including DNA methylation. Previous studies showed that RALYL is hypermethylated in CRC. We aimed to explore the role of RALYL in CRC involved in MNK2 alternative splicing in the present study.
Bioinformatics analysis, detection in CRC samples, and experiments in vitro and in vivo combined with gene knockdown and overexpression were conducted. Cell proliferation and tumor growth assays were performed.
Results showed that hypermethylated RALYL is lowly expressed in CRC. Overexpression of RALYL suppresses cell proliferation in vitro and tumor growth in vivo in CRC. MNK2 alternative splicing is essential for the tumor suppressive role of RALYL, along with RALYL regulating MNK2 alternative splicing via HNRNPC in CRC.
RALYL potentially exerts an inhibitory effect on CRC by engaging with HNRNPC to orchestrate the alternative splicing of MNK2. RALYL binds to HNRNPC to promote MNK2 splicing into MNK2a instead of MNK2b, consequently activating the p38 MAPK signaling pathway and inhibiting tumor proliferation in CRC. Our findings suggest that RALYL might suppress CRC through binding to HNRNPC to promote MNK2 splicing toward MNK2a, thereby activating the p38 MAPK signaling cascade.
结直肠癌（CRC）是全球癌症相关死亡的第二大常见原因，其发病率在全球新诊断癌症病例中位居第三。结直肠癌的发生过程复杂，是由一些遗传和环境因素（包括DNA甲基化）的复杂相互作用引发的。先前的研究表明，RALYL在结直肠癌中发生高甲基化。在本研究中，我们旨在探讨RALYL在结直肠癌中参与MNK2可变剪接的作用。
进行生物信息学分析、在结直肠癌样本中进行检测，并结合基因敲低和过表达进行体外和体内实验。进行细胞增殖和肿瘤生长测定。
结果表明，高甲基化的RALYL在结直肠癌中低表达。RALYL的过表达抑制结直肠癌体外细胞增殖和体内肿瘤生长。MNK2可变剪接对于RALYL的肿瘤抑制作用至关重要，并且在结直肠癌中RALYL通过HNRNPC调节MNK2可变剪接。
RALYL可能通过与HNRNPC结合来协调MNK2的可变剪接，从而对结直肠癌发挥抑制作用。RALYL与HNRNPC结合，促进MNK2剪接为MNK2a而非MNK2b，从而激活p38 MAPK信号通路并抑制结直肠癌中的肿瘤增殖。我们的研究结果表明，RALYL可能通过与HNRNPC结合促进MNK2向MNK2a的剪接，从而激活p38 MAPK信号级联反应来抑制结直肠癌。
