Xu Tong-Peng, Yu Tao, Xie Meng-Yan, Fang Yuan, Xu Ting-Ting, Pan Yu-Tian, Ma Pei, Shu Yong-Qian
Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.
Gastric Cancer. 2023 Mar;26(2):169-186. doi: 10.1007/s10120-022-01348-z. Epub 2022 Oct 25.
LIN28B plays a critical role in the Warburg effect. However, its underlying mechanism remains elusive. Recently, it has been reported that LIN28B could collaborate with IGF2BP3, which can bind to m6A-modified c-MYC transcripts. Therefore, this study investigated if LIN28B recognises methylated c-MYC mRNA to promote the Warburg effect in gastric cancer.
Effects of LIN28B on gastric cancer were confirmed in vitro and in vivo. On the basis of bioinformatics analysis, the association between LIN28B and c-MYC mRNA was shown using RNA immunoprecipitation (RIP) and luciferase reporter assays. The role of m6A was identified by RNA pull-down assays. We further performed RIP-seq to search for long non-coding RNAs (lncRNAs) participating in the LIN28B binding process. Chromatin immunoprecipitation was used to show the impact of c-MYC on transcription of LIN28B and lncRNAs.
LIN28B was identified to stabilize c-MYC mRNA by recognizing m6A. Furthermore, the interaction between c-MYC mRNA and LIN28B is speculated to be supported by LOC101929709, which binds to both LIN28B and IGF2BP3. Functional experiments revealed that LOC101929709 promotes the proliferation, migration and glycolysis of gastric cancer. Mechanistically, LOC101929709 enriched in the cytoplasm helps LIN28B stabilize c-MYC mRNA. Moreover, c-MYC promoted the transcription of both LOC101929709 and LIN28B. Additionally, LOC101929709 also activated the PI3K/AKT pathway.
The c-MYC/LOC101929709/LIN28B axis promotes aerobic glycolysis and tumour progression. Thus, LOC101929709 can be a novel potential target for gastric cancer treatment.
LIN28B在瓦伯格效应中起关键作用。然而，其潜在机制仍不清楚。最近，有报道称LIN28B可与IGF2BP3协作，后者能与m6A修饰的c-MYC转录本结合。因此，本研究调查了LIN28B是否通过识别甲基化的c-MYC mRNA来促进胃癌中的瓦伯格效应。
在体外和体内证实了LIN28B对胃癌的影响。基于生物信息学分析，使用RNA免疫沉淀（RIP）和荧光素酶报告基因检测显示了LIN28B与c-MYC mRNA之间的关联。通过RNA下拉检测确定了m6A的作用。我们进一步进行了RIP-seq以寻找参与LIN28B结合过程的长链非编码RNA（lncRNA）。采用染色质免疫沉淀来显示c-MYC对LIN28B和lncRNA转录的影响。
确定LIN28B通过识别m6A来稳定c-MYC mRNA。此外，推测c-MYC mRNA与LIN28B之间的相互作用得到LOC101929709的支持，它能同时与LIN28B和IGF2BP3结合。功能实验表明，LOC101929709促进胃癌的增殖、迁移和糖酵解。机制上，富集于细胞质中的LOC101929709有助于LIN28B稳定c-MYC mRNA。此外，c-MYC促进了LOC101929709和LIN28B的转录。另外，LOC101929709还激活了PI3K/AKT通路。
c-MYC/LOC101929709/LIN28B轴促进有氧糖酵解和肿瘤进展。因此，LOC101929709可成为胃癌治疗的一个新的潜在靶点。
