Wu Yazhou, Li Hanhua, Long Yin, Zhang Zhenzhen, Zhang Fanping, Pan Runyu, Meng Leijun, Ma Zhan, Wang Kaijing, Zheng Bing, Qie Zhonghong, Gao Wei
Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Laboratory Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Mol Carcinog. 2025 Mar;64(3):475-489. doi: 10.1002/mc.23859. Epub 2024 Dec 4.
Colorectal cancer (CRC) is a significant health issue worldwide. Recent studies highlight the critical role of miRNAs in CRC development, particularly miR-137, which acts as a key tumor suppressor. Despite its known role, further exploration of miR-137's downstream signaling is needed to understand its biology and therapeutic potential. We examined the methylation status of miR-137 using one TCGA data and three GEO data sets. A clinical validation cohort of 78 samples was analyzed using MSP for miR-137 promoter methylation. Various in vitro molecular/cellular and animal experiments were conducted to elucidate miR-137's role in CRC. Bioinformatic analysis indicated frequent methylation of miR-137 in CRC tissues, correlating with suppressed expression. EZH2-mediated H3K27 trimethylation silences miR-137 in CRC cells by increasing chromatin compaction, reversible by EZH2 siRNA or inhibitor GSK343. miR-137 inhibits CRC cell proliferation, migration, invasion, and xenograft tumor growth, confirming its tumor-suppressive role. Using the miRWalk repository showed that miR-137 regulates the Wnt signaling pathway by reducing typical protein expression in HCT116 and SW480 cells. miR-137 directly targets RNF4, leading to its downregulation at transcriptional and protein levels, with an observed inverse correlation in CRC tissues. miR-137 accelerates c-Myc and β-catenin degradation by inhibiting RNF4, impacting protein stability and Wnt pathway inhibition. miR-137 is epigenetically silenced through DNA methylation and EZH2-mediated H3K27 trimethylation. It regulates the Wnt signaling pathway by targeting RNF4, leading to c-Myc and β-catenin destabilization. Restoring miR-137 or inhibiting RNF4 suppresses CRC cell proliferation, migration, invasion, and tumor growth, highlighting its therapeutic potential in CRC.
结直肠癌（CRC）是全球范围内一个重要的健康问题。最近的研究强调了微小RNA（miRNA）在CRC发生发展中的关键作用，尤其是miR-137，它作为一种关键的肿瘤抑制因子发挥作用。尽管其作用已为人所知，但仍需要进一步探索miR-137的下游信号传导，以了解其生物学特性和治疗潜力。我们使用一个TCGA数据集和三个GEO数据集检查了miR-137的甲基化状态。使用甲基化特异性PCR（MSP）分析了一个包含78个样本的临床验证队列中miR-137启动子的甲基化情况。进行了各种体外分子/细胞和动物实验，以阐明miR-137在CRC中的作用。生物信息学分析表明，CRC组织中miR-137频繁发生甲基化，与表达受抑制相关。EZH2介导的H3K27三甲基化通过增加染色质致密化使CRC细胞中的miR-137沉默，EZH2小干扰RNA（siRNA）或抑制剂GSK343可使其恢复。miR-137抑制CRC细胞增殖、迁移、侵袭和异种移植肿瘤生长，证实了其肿瘤抑制作用。使用miRWalk数据库显示，miR-137通过降低HCT116和SW480细胞中的典型蛋白表达来调节Wnt信号通路。miR-137直接靶向RNF4，导致其在转录和蛋白水平下调，在CRC组织中观察到两者呈负相关。miR-137通过抑制RNF4加速c-Myc和β-连环蛋白的降解，影响蛋白稳定性并抑制Wnt通路。miR-137通过DNA甲基化和EZH2介导的H3K27三甲基化在表观遗传上被沉默。它通过靶向RNF4调节Wnt信号通路，导致c-Myc和β-连环蛋白不稳定。恢复miR-137或抑制RNF4可抑制CRC细胞增殖、迁移、侵袭和肿瘤生长，突出了其在CRC中的治疗潜力。
