加拿大多伦多大学Housheng Hansen He小组的一项最新研究探明了环状RMST与谱系驱动转录因子共同调控神经内分泌转分化。相关论文于2025年4月17日发表在《癌细胞》杂志上。

课题组研究人员发现circRMST是一个异常丰富的circRNA，主要在NEPC和SCLC中表达，在人和小鼠之间具有很强的保守性。以shRNA、siRNA、CRISPR-Cas13和Cas9为主题的功能研究一致表明，circRMST对于肿瘤生长和ASCL1的表达至关重要，ASCL1是神经内分泌命运的主要调节因子。在NEPC基因工程小鼠模型中，基因敲除Rmst可阻止神经内分泌转分化，维持肿瘤处于腺癌状态。从机制上讲，circRMST与谱系转录因子NKX2-1和SOX2相互作用。circRMST的缺失通过自噬-溶酶体途径诱导NKX2-1蛋白降解，并改变SOX2的基因组结合，共同导致ASCL1转录缺失。

研究人员表示，环状RNA （circRNA）是一类具有调控潜能的非编码RNA。它在前列腺和肺腺癌向神经内分泌前列腺癌（NEPC）和小细胞肺癌（SCLC）的转分化中的作用尚不清楚。

附：英文原文

Title: Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation

Author: Mona Teng, Jiacheng Guo, Xin Xu, Xinpei Ci, Yulin Mo, Yakup Kohen, Zuyao Ni, Sujun Chen, Wang Yuan Guo, Martin Bakht, Shengyu Ku, Michael Sigouros, Wenqin Luo, Colette Maya Macarios, Ziting Xia, Moliang Chen, Sami Ul Haq, Wen Yang, Alejandro Berlin, Theo van der Kwast, Leigh Ellis, Amina Zoubeidi, Gang Zheng, Jie Ming, Yuzhuo Wang, Haissi Cui, Benjamin H. Lok, Brian Raught, Himisha Beltran, Jun Qin, Housheng Hansen He

Issue&Volume: 2025-04-17

Abstract: Circular RNA (circRNA) is a class of noncoding RNA with regulatory potentials. Its role in the transdifferentiation of prostate and lung adenocarcinoma into neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC) remains unexplored. Here, we identified circRMST as an exceptionally abundant circRNA predominantly expressed in NEPC and SCLC, with strong conservation between humans and mice. Functional studies using shRNA, siRNA, CRISPR-Cas13, and Cas9 consistently demonstrate that circRMST is essential for tumor growth and the expression of ASCL1, a master regulator of neuroendocrine fate. Genetic knockout of Rmst in NEPC genetic engineered mouse models prevents neuroendocrine transdifferentiation, maintaining tumors in an adenocarcinoma state. Mechanistically, circRMST physically interacts with lineage transcription factors NKX2-1 and SOX2. Loss of circRMST induces NKX2-1 protein degradation through autophagy-lysosomal pathway and alters the genomic binding of SOX2, collectively leading to the loss of ASCL1 transcription.

DOI: 10.1016/j.ccell.2025.03.027

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00128-X