中国发现三阴性乳腺癌特洛伊疗法

　　在漫长的人类进化过程中，大量病毒的外源性基因组通过逆转录，以RNA为模板逆向合成DNA，稳定地融入人类生殖细胞的基因组，随着生殖遗传到人类下一代，直至内源化为人类基因的一部分。人类内源性逆转录病毒虽然不编码蛋白质，但是对于乳腺癌病情恶化具有重要影响，其具体机制尚不明确。

　　2019年3月6日，美国科学促进会《科学》旗下《科学进展》在线发表复旦大学金希、徐晓恩、江一舟、刘依熔、孙伟、郭雅洁、任毅行、左文佳、胡欣、黄胜林、沈宏杰、蓝斐、狄根红、何祥火、李大强、柳素玲、余科达、邵志敏、中国科学院上海生命科学研究院贺云飞、胡国宏等学者的研究报告，发现被称为特洛伊（TROJAN）的人类内源性逆转录病毒长链非编码RNA可以促进三阴性乳腺癌病情恶化，有望成为三阴性乳腺癌的治疗靶点。

　　该研究对人类内源性逆转录病毒全部基因组的转录物组进行分析，结果表明被称为TROJAN的灵长类动物长链非编码RNA高度表达于人类三阴性乳腺癌，可以促进三阴性乳腺癌的繁殖和浸润，并且与患者的不良结局显著相关。该研究进一步证实，TROJAN可以与具有转移抑制作用的蛋白激酶C结合蛋白（ZMYND8）结合，并且通过泛素→蛋白酶体通路，抑制锌指蛋白592（ZNF592），从而增加ZMYND8的降解。对于多种细胞株，TROJAN还可以通过表观遗传，在不改变基因序列的情况下，提高转移相关基因的表达水平。随后，根据临床标本分析，证实了TROJAN和ZMYND8之间的相关性。此外，该研究证实，针对TROJAN的反义寡核苷酸疗法可以有力抑制体内三阴性乳腺癌病情恶化。

　　因此，该研究结果表明，TROJAN可以促进三阴性乳腺癌病情恶化，有望成为三阴性乳腺癌的治疗靶点。

Sci Adv. 2019 Mar 6;5(3):eaat9820.

The endogenous retrovirus-derived long noncoding RNA TROJAN promotes triple-negative breast cancer progression via ZMYND8 degradation.

Xi Jin, Xiao-En Xu, Yi-Zhou Jiang, Yi-Rong Liu, Wei Sun, Ya-Jie Guo, Yi-Xing Ren, Wen-Jia Zuo, Xin Hu, Sheng-Lin Huang, Hong-Jie Shen, Fei Lan, Yun-Fei He, Guo-Hong Hu, Gen-Hong Di, Xiang-Huo He, Da-Qiang Li, Suling Liu, Ke-Da Yu, Zhi-Ming Shao.

Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Human endogenous retroviruses (HERVs) play pivotal roles in the development of breast cancer. However, the detailed mechanisms of noncoding HERVs remain elusive. Here, our genome-wide transcriptome analysis of HERVs revealed that a primate long noncoding RNA, which we dubbed TROJAN, was highly expressed in human triple-negative breast cancer (TNBC). TROJAN promoted TNBC proliferation and invasion and indicated poor patient outcomes. We further confirmed that TROJAN could bind to ZMYND8, a metastasis-repressing factor, and increase its degradation through the ubiquitin-proteasome pathway by repelling ZNF592. TROJAN also epigenetically up-regulated metastasis-related genes in multiple cell lines. Correlations between TROJAN and ZMYND8 were subsequently confirmed in clinical samples. Furthermore, our study verified that antisense oligonucleotide therapy targeting TROJAN substantially suppressed TNBC progression in vivo. In conclusion, the long noncoding RNA TROJAN promotes TNBC progression and serves as a potential therapeutic target.

DOI: 10.1126/sciadv.aat9820

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