长链非编码 RNA MNX1-AS1 通过阻止 CACYBP 降解介导一碳代谢调控以促进肺癌进展
Long noncoding RNA MNX1-AS1 mediated regulation of one-carbon metabolism by preventing CACYBP degradation to promote lung cancer progression.
作者
作者单位
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. 21518450@zju.edu.cn.
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
- Department of Pathology, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China.
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. Cheneg@zju.edu.cn.
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. yanlu76@zju.edu.cn.
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. pyliu@zju.edu.cn.
摘要
中文
肺癌仍是全球癌症相关死亡的首要原因，长链非编码 RNA（lncRNAs）已被证实参与其肿瘤发生与进展。然而，lncRNA 在肺癌中的作用尚未完全阐明。本研究揭示了 lncRNA MNX1 Antisense RNA 1（MNX1-AS1）作为一碳代谢重编程重要调控因子的关键作用。谷氨酰胺缺失改变染色质可及性，导致 MNX1-AS1 表达下调，而 MNX1-AS1 的高表达与非小细胞肺癌患者的不良预后相关。功能研究表明，MNX1-AS1 在体外促进细胞增殖和球形体形成，并在体内促进皮下及原位肿瘤生长。机制上，MNX1-AS1 直接结合钙周期素结合蛋白（CACYBP），保护其免受泛素介导的降解；因此 MNX1-AS1/CACYBP 复合物通过 Wnt/β-catenin 通路加速关键一碳代谢相关基因的转录。MNX1-AS1/CACYBP/β-catenin 轴上调关键一碳代谢相关基因，这些基因对于生成相关代谢物和维持细胞氧化还原平衡以支持肺癌细胞增殖至关重要。这些发现确立了 lncRNA MNX1-AS1 作为非小细胞肺癌一碳代谢重编程关键驱动因素，并提示新发现的 MNX1-AS1/CACYBP/β-catenin 轴可能成为肺癌干预的潜在预后生物标志物和治疗靶点。
English
Lung cancer remains the leading cause of cancer-related death worldwide, and long noncoding RNAs (lncRNAs) have been implicated in its tumourigenesis and progression. However, the roles lncRNAs play in lung cancer remain unclear. In this study, we discovered an important role for the lncRNA MNX1 Antisense RNA 1 (MNX1-AS1) as a critical regulator of one-carbon metabolism reprogramming. Glutamine depletion altered chromatin accessibility, leading to downregulation of MNX1-AS1, while elevated expression of MNX1-AS1 was correlated with poor prognosis in patients with non-small cell lung cancer. Functional studies showed that MNX1-AS1 promoted cell proliferation and sphere formation in vitro, and subcutaneous and orthotopic tumour growth in vivo. Mechanistically, MNX1-AS1 directly binds to calcyclin binding protein (CACYBP), protecting it from ubiquitin-mediated degradation; thus, the MNX1-AS1/CACYBP complex accelerates the transcription of key one-carbon metabolism-related genes through the Wnt/β-catenin pathway. MNX1-AS1/CACYBP/β-catenin axis upregulated key one-carbon metabolism-related genes, which were essential for generating related metabolites and maintaining cellular redox balance to support lung cancer cell proliferation. These findings established that the lncRNA MNX1-AS1 acts as a crucial driver of one-carbon metabolism reprogramming in non-small cell lung cancer and highlight that the newly identified MNX1-AS1/CACYBP/β-catenin axis may serve as a potential prognostic biomarker and therapeutic target for lung cancer intervention.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 13.6
- 新锐分区
- 1区