非编码RNA在衰老和癌症中的新功能

诸平

据日本癌症研究基金会（Japanese Foundation For Cancer Research简称JFCR）2021年8月23日提供的消息(A novel function of noncoding RNA in senescence and cancer)，该基金会旗下的癌症研究所（Cancer Institute at JFCR）的一项研究成果，于8月23日在领先的国际科学期刊《美国国家科学院院刊》（Proceedings of the National Academy of Sciences）网站发表——Kenichi Miyata, Yoshinori Imai, Satoshi Hori, Mika Nishio, Tze Mun Loo, Ryo Okada,Liying Yang, Tomoyoshi Nakadai, Reo Maruyama, Risa Fujii, Koji Ueda, Li Jiang, Hao Zheng,Shinya Toyokuni, Toyonori Sakata, Katsuhiko Shirahige, Ryosuke Kojima,Mizuho Nakayama, Masanobu Oshima, Satoshi Nagayama, Hiroyuki Seimiya,Toru Hirota, Hideyuki Saya, Eiji Hara, Akiko Takahashi. Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer. Proceedings of the National Academy of Sciences, August 31, 2021; 118 (35): e2025647118. https://doi.org/10.1073/pnas.2025647118。此文揭示了来自于中心点周围重复序列的非编码RNA会在衰老和癌症中引发炎症基因表达。参与此项研究的除了有来自JFCR旗下的癌症研究所的研究人员之外，还有JFCR旗下的癌症精准医学中心（Cancer Precision Medicine Center）、名古屋大学医学院（Nagoya University Graduate School of Medicine）、东京大学定量生物科学研究所（Institute for Quantitative Biosciences, The University of Tokyo）、东京大学医学研究生院（Graduate School of Medicine, The University of Tokyo）、日本科学技术振兴机构（Japan Science and Technology Agency）、日本金泽大学癌症研究所（Cancer Research Institute, Kanazawa University）、JFCR’s癌症研究所医院（Cancer Institute Hospital, Japanese Foundation for Cancer Research）、JFCR’s癌症化疗中心（Cancer Chemotherapy Center, Japanese Foundation for Cancer Research）、日本庆应大学医学院高级医学研究所（Institute for Advanced Medical Research, Keio University School of Medicine）、大阪大学微生物疾病研究所（Research Institute for Microbial Diseases, Osaka University）、日本医学研发机构（Japan Agency for Medical Research and Development）的研究人员以及日本癌症研究基金会NEXT-Ganken项目（NEXT-Ganken Program, Japanese Foundation for Cancer Research）癌细胞交流项目（Cancer Cell Communication Project）组成员。

衰老是一种本质上不可逆的细胞周期阻滞状态，由多种应激源（stressors）引起，即衰老、肥胖、放疗和化疗。衰老过程中体内积累的衰老细胞通过产生促炎蛋白（proinflammatory proteins）与周围组织沟通，称为衰老相关分泌表型(senescence associated secretory phenotype简称SASP)，发挥多种生理和病理作用。在老年人中，炎性SASP因子促进许多与年龄相关的疾病，包括癌症（cancer）。因此，阐明SASP的调控机制对于开发新的年龄相关性癌症的预防和治疗策略至关重要。

JFCR的一组研究人员假设，在衰老细胞中观察到的异常染色质结构（aberrant chromatin architecture）可能与SASP有关，并已开始使用下一代测序技术分析全基因组染色质（genome-wide chromatin）相互作用和基因表达（gene expression）。他们发现，含有被称为人类2号卫星(human satellite II 简称hSATII)的中心点周围重复序列的区域，在正常细胞中是表观遗传沉默的，但在衰老细胞（senescent cells）中显示出明显的开放状态。此外，非编码RNA (noncoding RNA ，也就是hSATII RNA)的表达在细胞衰老过程中显著上调。进一步的分析表明，hSATII RNA通过CCCTC结合因子(CCCTC-binding factor 简称CTCF)的功能性损伤，干扰部分SASP基因区域（SASP gene regions）的染色质相互作用，从而上调SASP样炎症基因的表达（SASP-like inflammatory gene expression），这对维持基因组完整性至关重要。

“肿瘤和基质细胞（stromal cells）分泌的细胞外小泡(extracellular vesicles简称EVs)在肿瘤微环境中以非细胞自主的方式（non-cell-autonomous manner）动态促进肿瘤的发病率和进展。有趣的是，来自衰老细胞的小EVs中hSATII RNA的含量高于来自增殖细胞（proliferating cells）的小EVs中hSATII RNA的含量。因此，我们的数据提示，来自衰老基质细胞（senescent stromal cells）的hSATII RNA通过小EVs转移到周围细胞中，在肿瘤微环境中发挥SASP样炎症因子（SASP-like inflammatory factor）的作用。”

此外，研究人员发现，在原发结肠癌患者的手术标本的癌细胞中，hSATII RNA可被高度检测到。值得注意的是，在癌相关成纤维细胞（cancer-associated fibroblasts）中，hSATII RNA阳性细胞的数量明显高于正常间质组织的成纤维细胞中的hSATII RNA阳性细胞的数量。

“这些发现突出了hSATII RNA的新作用，它通过分泌SASP样炎症因子和小EVs，支持肿瘤以非细胞自主的方式发展。了解这一分子机制有助于未来针对年龄相关疾病的新型预防和治疗策略的开发。”上述介绍，仅供参考。欲了解更多信息敬请注意浏览原文或者相关报道。

New mechanism by which senescent cells turn on genes encoding for tumor-regulating factors

Significance

During the aging process, senescent cells secrete inflammatory factors, causing various age-related pathologies. Thus, controlling the senescence-associated secretory phenotype (SASP) can tremendously benefit human health. Although SASP seems to be induced by the alteration of chromosomal organization, its underlying mechanism remains unclear. Here, it has been revealed that noncoding RNA (ncRNA) transcribed from pericentromeric repetitive elements impairs the DNA binding of CCCTC-binding factor, resulting in the alteration of chromosomal accessibility and the activation of SASP-like inflammatory genes. Notably, the ncRNA was transferred into surrounding cells via small extracellular vesicles, acting as a tumorigenic SASP factor. Our study highlights a novel mechanism regulating chromatin interaction and inflammatory gene expression in senescence and cancer.

Abstract

Cellular senescence causes a dramatic alteration of chromatin organization and changes the gene expression profile of proinflammatory factors, thereby contributing to various age-related pathologies through the senescence-associated secretory phenotype (SASP). Chromatin organization and global gene expression are maintained by the CCCTC-binding factor (CTCF); however, the molecular mechanism underlying CTCF regulation and its association with SASP gene expression remains unclear. We discovered that noncoding RNA (ncRNA) derived from normally silenced pericentromeric repetitive sequences directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of SASP-like inflammatory genes, promoting malignant transformation. Notably, pericentromeric ncRNA was transferred into surrounding cells via small extracellular vesicles acting as a tumorigenic SASP factor. Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the down-regulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression. In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non–cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.