Wang Junlong, Katsaros Dionyssios, Wang Zhanwei, Ma Li, Casetta Elena, Fei Peiwen, Denti Pietro, Grimaudo Ida, Chen Shaoqiu, Deng Youping, Yu Herbert
Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
Department of Molecular Biosciences & Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA.
Breast Cancer Res Treat. 2025 Jun;211(3):675-685. doi: 10.1007/s10549-025-07682-x. Epub 2025 Mar 18.
Transfer RNA (tRNA) fragments (tRFs) are a group of small non-coding RNAs with biological functions. The involvement of tRNAs in cancer has also been recognized, but most studies focused on nuclear tRFs, very few on mitochondrial tRFs.
We analyzed the TCGA microRNAseq data to identify differentially expressed mitochondrial tRFs (mt-tRFs) in breast tumors and evaluated their associations with the disease outcome. Cox proportional hazards regression was used to determine the associations between mt-tRFs and patient survival while adjusting for clinicopathological variables. Quantitative RT-PCR was developed to measure a specific tRF expression in a validation study.
Our analysis of 1,060 tumor samples from TCGA revealed that mt-tRF-Tyr-GTA-001 (tRF-21-X3OJI8EWB or t00018104) expression, a tRF from mitochondrial tRNA with tyrosine anticodon GTA (mt-tRNA-Tyr-GTA), was significantly lower in breast tumors than the adjacent tissues (p< 0.0001). Patients with low expression had significantly higher risk of death (HR = 1.69, p = 0.0018) regardless of their age at diagnosis, disease stage, tumor grade, and hormone receptor status. This survival association was replicated in an independent study where mt-tRF-Tyr-GTA-001 expression was measured with qRT-PCR. Further analysis suggested that the mt-tRF expression was correlated with ribonuclease ANG and RNase 4 known to cleave tRNAs and upregulated under hypoxia. IPA interrogation of the mt-tRF-Tyr-GTA-001 expression signature indicated the inhibitory effects of mt-tRF-Tyr-GTA-001 on malignant transformation, tumor growth, and cell invasion. In silico analysis showed that the binding targets of mt-tRF-Tyr-GTA-001 included several oncogenic transcription factors (E2Fs, CCNE1, FOXM1). We also found the mt-tRF correlated with the abundances of M0 macrophages and resting mast cells, two of the immune cells known for innate immunity.
In summary, our study suggests that mt-tRF-Tyr-GTA-001, a mitochondrial tRF, may suppress breast cancer progression through its involvement in regulation of cell phenotype and tumor immunity.
转运RNA（tRNA）片段（tRFs）是一类具有生物学功能的小非编码RNA。tRNA在癌症中的作用也已得到认可，但大多数研究集中在细胞核tRFs，而关于线粒体tRFs的研究很少。
我们分析了癌症基因组图谱（TCGA）的微小RNA测序数据，以鉴定乳腺肿瘤中差异表达的线粒体tRFs（mt-tRFs），并评估它们与疾病预后的关联。在调整临床病理变量的同时，使用Cox比例风险回归来确定mt-tRFs与患者生存之间的关联。在一项验证研究中，开发了定量逆转录聚合酶链反应（qRT-PCR）来测量特定tRF的表达。
我们对来自TCGA的1060个肿瘤样本的分析显示，mt-tRF-Tyr-GTA-001（tRF-21-X3OJI8EWB或t00018104）的表达，一种来自具有酪氨酸反密码子GTA的线粒体tRNA（mt-tRNA-Tyr-GTA）的tRF，在乳腺肿瘤中的表达明显低于相邻组织（p<0.0001）。无论诊断时的年龄、疾病分期、肿瘤分级和激素受体状态如何，低表达患者的死亡风险显著更高（风险比=1.69，p=0.0018）。在一项独立研究中重复了这种生存关联，该研究使用qRT-PCR测量了mt-tRF-Tyr-GTA-001的表达。进一步分析表明，mt-tRF的表达与已知可切割tRNA并在缺氧条件下上调的核糖核酸酶ANG和核糖核酸酶4相关。对mt-tRF-Tyr-GTA-001表达特征的IPA分析表明，mt-tRF-Tyr-GTA-001对恶性转化、肿瘤生长和细胞侵袭具有抑制作用。计算机分析表明，mt-tRF-Tyr-GTA-001的结合靶点包括几种致癌转录因子（E2Fs、CCNE1、FOXM1）。我们还发现mt-tRF与M0巨噬细胞和静止肥大细胞的丰度相关，这两种免疫细胞以固有免疫而闻名。
总之，我们的研究表明，线粒体tRF mt-tRF-Tyr-GTA-001可能通过参与细胞表型和肿瘤免疫的调节来抑制乳腺癌进展。
