慢性应激诱导的ADRB2 m7G帽修饰失调磷酸戊糖途径促进食管鳞状细胞癌进展
Chronic Stress-Induced m7G Cap Modification of ADRB2 Dysregulates the Pentose Phosphate Pathway to Promote Esophageal Squamous Cell Carcinoma Progression.
作者
作者单位
- Zhengzhou University Zhengzhou, Henan China.
- Institute of Advanced Bio-medical Science Zhengzhou, Henan China.
- China-US (Henan) Hormel Cancer Institute China.
- Henan Cancer Hospital China.
- Zhengzhou University China.
- Henan Cancer Hospital ZhengZhou China.
- Henan Cancer Hospital zheng zhou China.
摘要
中文
慢性应激日益被认识为癌症代谢的驱动因素,强调需要阐明慢性应激与代谢重编程之间的联系机制。在此,我们对食管鳞状细胞癌(ESCC)患者的血清样本进行了非靶向代谢组学分析,并将结果与临床和应激相关评估相结合,揭示了在具有应激相关特征的患者中磷酸戊糖途径(PPP)富集伴随肾上腺素水平升高。由慢性应激激活的β2-肾上腺素能受体(ADRB2)通过竞争性置换VHL来稳定MYCBP,从而增强MYC转录活性并上调关键PPP酶,包括G6PD和TKT。出乎意料的是,应激相关刺激不仅激活了ADRB2信号传导,还增加了ADRB2蛋白丰度。机制上,应激暴露增强了依赖RNMT的ADRB2 mRNA N7-甲基鸟苷(m7G)帽修饰,从而提高其翻译效率。总之,这些发现定义了一个RNMT-ADRB2-MYCBP-PPP轴,该轴整合了表观转录调控与肾上腺素能信号传导,以促进ESCC的代谢重编程和恶性进展。应激相关的RNA修饰-代谢回路包含克服应激相关ESCC进展的潜在治疗靶点。
English
Chronic stress is increasingly recognized as a driver of cancer metabolism, highlighting the need to elucidate the mechanism linking chronic stress to metabolic reprogramming. Here, we performed untargeted metabolomics on serum samples from esophageal squamous cell carcinoma (ESCC) patients and integrated the results with clinical and stress-related assessments, revealing pentose phosphate pathway (PPP) enrichment accompanied by elevated epinephrine levels in patients with stress-associated features. β2-adrenergic receptor (ADRB2) activated by chronic stress stabilized MYCBP by competitively displacing VHL, thereby enhancing MYC transcriptional activity and upregulating key PPP enzymes, including G6PD and TKT. Unexpectedly, stress-associated stimulation not only activated ADRB2 signaling but also increased ADRB2 protein abundance. Mechanistically, stress exposure enhanced RNMT-dependent N7-methylguanosine (m7G) cap modification of ADRB2 mRNA, thereby increasing its translational efficiency. Together, these findings define an RNMT-ADRB2-MYCBP-PPP axis that integrates epitranscriptomic regulation with adrenergic signaling to promote metabolic reprogramming and malignant progression in ESCC. The stress-associated RNA modification-metabolism circuitry comprises potential therapeutic targets to overcome stress-associated ESCC progression.
分类与指标
- 研究类型
- 基础研究
- 病种
- 食管癌
- JCR 分区
- Q1
- 影响因子
- 22.6
- 新锐分区
- 1区