m5C-modified circRREB1 promotes lung cancer progression by inducing mitophagy.

IF 12.8 1区 医学 Q1 ONCOLOGY
Dunyu Cai, Xingcai Chen, Haotian Xu, Qingyun Zhao, Xiaodong Zhou, Jiaxi Wu, Shengyi Yuan, Yihong Gao, Deqing Li, Ruirui Zhang, Wenyi Peng, Gang Li, Aruo Nan
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Abstract

Background: Lung cancer is the most common malignant tumour and the leading cause of cancer-related death. circular RNAs (circRNAs) have important biological functions and are closely related to tumour development. The 5-methylcytosine (m5C) modification can regulate the molecular fate of RNA molecules and thus influence disease development.

Methods: High-throughput RNA sequencing was used to construct the differential expression profiles of circRNAs. The m5C modification of circRREB1 was explored through methylated RNA immunoprecipitation (MeRIP) and crosslinking-immunoprecipitation (CLIP). RNA stability experiments, fluorescence in situ hybridization (FISH), and nuclear-cytoplasmic fractionation experiments were performed to explore the effects of the m5C modification on circRREB1. A system for the silencing and overexpression of circRREB1 was established, and in vitro and in vivo experiments were conducted to study the biological functions of circRREB1. Tagged RNA affinity purification (TRAP), RNA immunoprecipitation (RIP), and coimmunoprecipitation (Co-IP) experiments were conducted to reveal the molecular mechanisms of circRREB1.

Results: In this study, we found that circRREB1 is highly expressed in lung cancer tissues and cells and that patients with high circRREB1 expression have a poor prognosis. We discovered that circRREB1 undergoes the m5C modification mediated by the methyltransferase NSUN2. This modification facilitates its nuclear export via the m5C reader ALYREF. Functional studies demonstrated that circRREB1 promotes lung cancer progression both in vitro and in vivo. Mechanistically, circRREB1 directly binds to HSPA8 and stabilizes it by inhibiting ubiquitin-dependent degradation, thereby inducing mitophagy through the HSPA8/PINK1/Parkin signalling axis and ultimately promoting the development of lung cancer.

Conclusions: This study revealed the presence of m5C modifications on circRREB1 and showed that m5C-modified circRREB1 can induce mitophagy, ultimately promoting lung cancer. These findings provide not only a theoretical basis for further exploration of the mechanisms underlying lung cancer development but also potential targets for lung cancer therapy.

m5c修饰的circRREB1通过诱导线粒体自噬促进肺癌进展。
背景:肺癌是最常见的恶性肿瘤,也是癌症相关死亡的主要原因。环状rna (circRNAs)具有重要的生物学功能,与肿瘤的发展密切相关。5-甲基胞嘧啶(m5C)修饰可以调节RNA分子的分子命运,从而影响疾病的发展。方法:采用高通量RNA测序技术构建circRNAs差异表达谱。通过甲基化RNA免疫沉淀(MeRIP)和交联免疫沉淀(CLIP)研究circRREB1的m5C修饰。通过RNA稳定性实验、荧光原位杂交(fluorescence in situ hybridization, FISH)和核细胞质分离实验,探讨m5C修饰对circRREB1的影响。我们建立了circRREB1的沉默和过表达系统,并进行了体外和体内实验,研究circRREB1的生物学功能。通过标记RNA亲和纯化(TRAP)、RNA免疫沉淀(RIP)和共免疫沉淀(Co-IP)实验揭示circRREB1的分子机制。结果:本研究中,我们发现circRREB1在肺癌组织和细胞中高表达,circRREB1高表达的患者预后较差。我们发现circRREB1经历了甲基转移酶NSUN2介导的m5C修饰。这一修改有利于其通过m5C阅读器ALYREF进行核出口。功能研究表明circRREB1在体内和体外都能促进肺癌的进展。在机制上,circRREB1直接与HSPA8结合,并通过抑制泛素依赖性降解来稳定HSPA8,从而通过HSPA8/PINK1/Parkin信号轴诱导线粒体自噬,最终促进肺癌的发展。结论:本研究揭示了m5C修饰circRREB1的存在,表明m5C修饰的circRREB1可以诱导有丝分裂,最终促进肺癌。这些发现不仅为进一步探索肺癌发生机制提供了理论基础,也为肺癌治疗提供了潜在靶点。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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