Li Jie, Luo Qian, Lu Minjie, Lu Chen, Xu Caihong, Ding Jie, Zhan Tian, Zhu Jing, Qian Mengsen, Lin Shuhui, Chang Lisha, Li Juan, Wang Keming
Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Oncology, Taicang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, Jiangsu, China.
Int J Biol Sci. 2025 Jul 24;21(11):4782-4797. doi: 10.7150/ijbs.105391. eCollection 2025.
Lipid reprogramming represents a pivotal stage in tumor progression. N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotic cells, plays a significant role in colorectal cancer (CRC) development, though its specific involvement in lipid reprogramming remains unclear. Bioinformatics analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases revealed differential expression of METTL16 (M16), which was further validated through qRT-PCR and Western blotting in CRC tissues and cell lines. The impact of M16 on CRC proliferation, metastasis, invasion, and lipid reprogramming was evaluated using both and approaches. Regulatory mechanisms underlying M16's role in CRC progression were explored using immunofluorescence (IF) staining, RNA immunoprecipitation (RIP), MERIP assay, RNA pull-down assay, total m6A measurement, RNA stability assay, protein stability analysis, and luciferase reporter assays. Analysis results demonstrated a significant upregulation of the m6A methyltransferase METTL16 in CRC, closely associated with poor prognosis and abnormal lipid droplet accumulation. Functional assays revealed that M16 overexpression markedly promotes CRC cell proliferation, migration, and invasion both and , primarily by enhancing lipid reprogramming. Mechanistically, M16 induces m6A modification of TM7SF2 mRNA, stabilizing it via an IGF2BP1- and IGF2BP2-dependent pathway, thereby upregulating TM7SF2 expression and driving lipid reprogramming in CRC. In conclusion, these findings highlight the critical role of the M16/m6A/TM7SF2 axis in lipid metabolic reprogramming in CRC, offering potential therapeutic targets for its treatment.
脂质重编程是肿瘤进展中的一个关键阶段。N6-甲基腺苷（m6A）是真核细胞中最普遍的RNA修饰，在结直肠癌（CRC）发展中起重要作用，但其在脂质重编程中的具体作用尚不清楚。对癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）的生物信息学分析揭示了METTL16（M16）的差异表达，通过qRT-PCR和蛋白质印迹在CRC组织和细胞系中进一步验证。使用体外和体内方法评估M16对CRC增殖、转移、侵袭和脂质重编程的影响。使用免疫荧光（IF）染色、RNA免疫沉淀（RIP）、甲基化RNA免疫沉淀（MeRIP）分析、RNA下拉分析、总m6A测量、RNA稳定性分析、蛋白质稳定性分析和荧光素酶报告基因分析探索M16在CRC进展中作用的调控机制。分析结果表明，CRC中m6A甲基转移酶METTL16显著上调，与预后不良和脂质滴异常积累密切相关。功能分析表明，M16过表达显著促进CRC细胞的增殖、迁移和侵袭，体内和体外均如此，主要是通过增强脂质重编程。机制上，M16诱导TM7SF2 mRNA的m6A修饰，通过依赖IGF2BP1和IGF2BP2的途径使其稳定，从而上调TM7SF2表达并驱动CRC中的脂质重编程。总之，这些发现突出了M16/m6A/TM7SF2轴在CRC脂质代谢重编程中的关键作用，为其治疗提供了潜在的治疗靶点。
