CircNOLC1 通过与 AZGP1 相互作用并海绵 miR-212-5p 调节氧化戊糖磷酸途径的重编程来促进结直肠癌肝转移,Advanced Science

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CircNOLC1 通过与 AZGP1 相互作用并海绵 miR-212-5p 调节氧化戊糖磷酸途径的重编程来促进结直肠癌肝转移
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-23 , DOI: 10.1002/advs.202205229
Menglang Yuan _{1,

2} , Xinsheng Zhang ₁ , Fangxia Yue ₃ , Feifan Zhang ₁ , Sufen Jiang ₃ , Xu Zhou ₃ , Jinjuan Lv ₃ , Zhenyu Zhang ₃ , Yuzhu Sun ₃ , Zihao Chen ₁ , Han Wu ₃ , Xiaoqian Liu ₃ , Xiaoqi Yu ₃ , Bowen Wei ₃ , Kexin Jiang ₃ , Fang Lin ₃ , Yunfei Zuo ₃ , Shuangyi Ren ₁

Affiliation

肝转移是进展性结直肠癌患者的常见死亡原因，但其分子机制仍不清楚。据报道，保守的氧化戊糖磷酸途径相关的环状RNA circNOLC1在结直肠癌肝转移中发挥着至关重要的作用。研究发现，circNOLC1沉默可减少氧化戊糖磷酸途径相关的中间代谢产物，提高NADP ⁺ /NADPH比值和细胞内ROS水平，从而减弱结直肠癌细胞的增殖、迁移和肝转移。circNOLC1与AZGP1相互作用激活mTOR/SREBP1信号，或海绵miR-212-5p上调c-Met表达，两者均可进一步诱导G6PD激活结直肠癌肝转移中的氧化戊糖磷酸途径。此外，circNOLC1 受转录因子 YY1 调节，并且特异性稳定的 HuR 诱导其亲代基因 mRNA 表达。circNOLC1 和这些信号分子之间的关联在原发性 CRC 和相应的肝转移组织中得到了验证。这些发现表明，circNOLC1与AZGP1和circNOLC1/miR-212-5p/c-Met轴的相互作用在氧化戊糖磷酸途径介导的结直肠癌肝转移中发挥关键作用，这可能为结直肠癌的精准医疗提供新的靶点。

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CircNOLC1 Promotes Colorectal Cancer Liver Metastasis by Interacting with AZGP1 and Sponging miR-212-5p to Regulate Reprogramming of the Oxidative Pentose Phosphate Pathway

Liver metastasis is a common cause of death in progressive colorectal cancer patients, but the molecular mechanisms remain unclear. Here, it is reported that a conserved and oxidative pentose phosphate pathway-associated circular RNA, circNOLC1, plays a crucial role in colorectal cancer liver metastasis. It is found that circNOLC1 silencing reduces the oxidative pentose phosphate pathway-related intermediate metabolites and elevates NADP⁺/NADPH ratio and intracellular ROS levels, thereby attenuating colorectal cancer cell proliferation, migration, and liver metastasis. circNOLC1 interacting with AZGP1 to activate mTOR/SREBP1 signaling, or sponging miR-212-5p to upregulate c-Met expression, both of which can further induce G6PD to activate oxidative pentose phosphate pathway in colorectal cancer liver metastasis. Moreover, circNOLC1 is regulated by the transcription factor YY1 and specifically stabilized HuR induces its parental gene mRNA expression. The associations between circNOLC1 and these signaling molecules are validated in primary CRC and corresponding liver metastasis tissues. These findings reveal that circNOLC1 interacting with AZGP1 and circNOLC1/miR-212-5p/c-Met axis plays a key role in oxidative pentose phosphate pathway-mediated colorectal cancer liver metastasis, which may provide a novel target for precision medicine of colorectal cancer.

更新日期：2023-10-23

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