Qu Xianzhi, Liu Buhan, Jin Duo, Ma Yue, Liu Mingjun, Yan Xiaoyu, Su Jing, Zhou Lei
Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China.
Department of Pathology, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China.
Front Pharmacol. 2025 May 30;16:1549373. doi: 10.3389/fphar.2025.1549373. eCollection 2025.
Hypoxia is one of the major characteristics of the tumor microenvironment, and it promotes mitochondrial energy metabolic remodeling for hepatocellular carcinoma (HCC) progression. It is believed that under dual control of the mitochondrial genome (mtDNA) and the nuclear genome (nDNA) mitochondria coordinate multiple signals to alter energy metabolism under hypoxic stress. Currently, it has been found that hypoxia promotes tRNA cleavage to produce tRFs (tRNA-derived fragment), which have attracted attention as potential biomarkers and therapeutic targets. In this study, we found that hypoxic stress could drive HCC cell invasion and migration. Furthermore, the expression of core oxidative phosphorylation (OXPHOS) proteins encoded by nDNA and mtDNA were uncoordinated under hypoxia. Therefore, the human mitochondrial peptide deformylase (HsPDF) which was essential for mtDNA-encoded protein translation and respiratory chain maintenance has been brought into focus. We found that hypoxic stress significantly suppressed HsPDF which was responsible for mtDNA-encoded protein inhibition. To further explore the possible mechanism, high-throughput sequencing was used to map tRF expression patterns in HCC cells under hypoxia. We found that hypoxic stress altered their subtype distributions and that the high expression of tRF-3, which has functions in transcription and translation regulation, may potentially bind to the 3'-UTR of HsPDF. Upregulated tRF-3 could inhibit HsPDF and mitochondrial OXPHOS function. Furthermore, the orthotopic liver cancer model in mice also indicated that the tRF-3 inhibitor significantly suppressed tumor progression. These results collectively suggested that tRFs may have roles in mitochondrial protein coordination and become novel pharmacological targets for mitochondrial remodeling under tumor microenvironment remodeling of HCC therapy.
缺氧是肿瘤微环境的主要特征之一，它促进线粒体能量代谢重塑以推动肝细胞癌（HCC）进展。据信，在线粒体基因组（mtDNA）和核基因组（nDNA）的双重控制下，线粒体在缺氧应激时协调多种信号以改变能量代谢。目前，已发现缺氧促进tRNA切割产生tRFs（tRNA衍生片段），它们作为潜在的生物标志物和治疗靶点已引起关注。在本研究中，我们发现缺氧应激可驱动HCC细胞侵袭和迁移。此外，缺氧条件下nDNA和mtDNA编码的核心氧化磷酸化（OXPHOS）蛋白的表达不协调。因此，对mtDNA编码蛋白翻译和呼吸链维持至关重要的人线粒体肽脱甲酰基酶（HsPDF）受到了关注。我们发现缺氧应激显著抑制了负责mtDNA编码蛋白抑制的HsPDF。为进一步探究可能的机制，利用高通量测序绘制缺氧条件下HCC细胞中tRF的表达模式。我们发现缺氧应激改变了它们的亚型分布，并且在转录和翻译调控中起作用的tRF-3的高表达可能潜在地与HsPDF的3'-UTR结合。上调的tRF-3可抑制HsPDF和线粒体OXPHOS功能。此外，小鼠原位肝癌模型也表明tRF-3抑制剂显著抑制肿瘤进展。这些结果共同表明，tRFs可能在线粒体蛋白协调中发挥作用，并成为HCC治疗肿瘤微环境重塑中线粒体重塑的新型药理学靶点。
