Zhang Zheng, Li Fanrong, Dai Xiaoxiao, Deng Jieqiong, Wang Yirong, Zhang Shenghua, Liu Wei, Xie Ying, Pan Yacheng, Wang Jieyu, Zhao Tong, Wang Shuang, Li Wanqiu, Jin Congnan, Zhang Hebin, Lu Jiachun, Guo Binbin, Zhou Yifeng
Department of Genetics, Medical College of Soochow University, Suzhou, 215123, China.
Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Oncogene. 2025 Mar;44(8):513-529. doi: 10.1038/s41388-024-03240-9. Epub 2024 Dec 2.
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and poses a treatment challenge due to high recurrence risk. Consequently, there is an urgent need for novel and efficacious therapies targeting TNBC. In this context, our study delineates the identification and characterization of a long non-coding RNA (lncRNA)-derived micropeptide miPEP205. Notably, the micropeptide exerts a significant inhibitory effect on the growth and metastasis of TNBC. Moreover, we observed a substantial down-regulation of micropeptide expression in clinical samples, which was markedly associated with a poor prognosis. Mechanistically, our research demonstrated that EGR3 governs lncRNA MIR205HG and the micropeptide expression, while miPEP205 boosts GSK-3β phosphorylation at Tyr216. This cascade causes β-catenin degradation, deactivating the GSK-3β/β-catenin signaling pathway and ultimately inhibits TNBC progression. Remarkably, our experiments in the spontaneous breast cancer mice model MMTV-PyMT demonstrated that the introduction of the miPEP205 gene or exogenous administration of the micropeptide miPEP205 significantly curtailed tumor growth and lung metastasis, and enhanced the overall survival among tumor-bearing mice. In conclusion, our study uncovers a previously uncharacterized micropeptide derived from a lncRNA, showcasing potent antitumor properties. These findings position miPEP205 as a promising novel target for therapeutic intervention in TNBC.
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，由于复发风险高，给治疗带来了挑战。因此，迫切需要针对TNBC的新型有效疗法。在此背景下，我们的研究描述了一种源自长链非编码RNA（lncRNA）的微小肽miPEP205的鉴定和特征。值得注意的是，该微小肽对TNBC的生长和转移具有显著的抑制作用。此外，我们观察到临床样本中微小肽表达显著下调，这与预后不良明显相关。从机制上讲，我们的研究表明EGR3调控lncRNA MIR205HG和微小肽的表达，而miPEP205促进GSK-3β在Tyr216位点的磷酸化。这一级联反应导致β-连环蛋白降解，使GSK-3β/β-连环蛋白信号通路失活，最终抑制TNBC的进展。值得注意的是，我们在自发性乳腺癌小鼠模型MMTV-PyMT中的实验表明，引入miPEP205基因或外源性给予微小肽miPEP205可显著抑制肿瘤生长和肺转移，并提高荷瘤小鼠的总体生存率。总之，我们的研究发现了一种以前未被表征的源自lncRNA的微小肽，具有强大的抗肿瘤特性。这些发现使miPEP205成为TNBC治疗干预的一个有前景的新靶点。
