高血糖导致的 tRF-Cys-GCA-029 下调通过上调 PRKCG 翻译促进糖尿病乳腺癌的肿瘤发生和糖酵解

IF 6.1 1区医学 Q1 ONCOLOGY

Breast Cancer Research Pub Date : 2024-07-22 DOI:10.1186/s13058-024-01870-1

Yongyi Huang, Cheng Chen, Yang Liu, Binbin Tan, Qin Xiang, Qianqian Chen, Yiling Wang, Wenhan Yang, Jingsong He, Duanyang Zhou, Yuting Wang, Kaiping Gao, Duo Zheng, Rihong Zhai

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引用次数: 0

摘要

多达三分之一的乳腺癌（BC）患者患有糖尿病（DM）。同时患有乳腺癌和糖尿病（BC-DM）的患者预后会恶化。尽管如此，人们对导致 BC-DM 预后的分子机制仍然知之甚少。通过tRF测序和qRT-PCR检测了肿瘤组织和细胞中的tRF水平。在体外等血糖和高血糖条件下评估了tRF对BC细胞恶性程度的影响。代谢变化通过乳酸、丙酮酸和细胞外酸化率（ECAR）测定进行评估。糖尿病动物模型用于评估 tRF 对 BC 肿瘤生长的影响。研究人员通过RNA测序（RNA-seq）、qRT-PCR、Western印迹、多聚酶谱分析、荧光素酶报告实验和拯救实验来探索tRF在BC-DM中的调控机制。我们发现，tRF-Cys-GCA-029在BC-DM组织和高血糖条件下的BC细胞中被下调。从功能上讲，tRF-Cys-GCA-029的下调以葡萄糖水平依赖性的方式促进了BC细胞的增殖和迁移。值得注意的是，注射 tRF-Cys-GCA-029 mimic 能显著抑制糖尿病小鼠 BC 肿瘤的生长。从机理上讲，tRF-Cys-GCA-029通过两种方式与PRKCG相互作用，调节BC细胞的恶性程度和糖酵解：与PRKCG mRNA的编码序列（CDS）结合，调节其转录；改变多聚体PRKCG mRNA的表达，改变其翻译。tRF-Cys-GCA-029-PRKCG-糖酵解轴可能是 BC-DM 的潜在治疗靶点。

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Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation

Diabetes mellitus (DM) affects up to one-third of breast cancer (BC) patients. Patients with co-existing BC and DM (BC-DM) have worsened BC prognosis. Nevertheless, the molecular mechanisms orchestrating BC-DM prognosis remain poorly understood. tRNA-derived fragments (tRFs) have been shown to regulate cancer progression. However, the biological role of tRFs in BC-DM has not been explored. tRF levels in tumor tissues and cells were detected by tRF sequencing and qRT-PCR. The effects of tRF on BC cell malignancy were assessed under euglycemic and hyperglycemic conditions in vitro. Metabolic changes were assessed by lactate, pyruvate, and extracellular acidification rate (ECAR) assays. Diabetic animal model was used to evaluate the impacts of tRF on BC tumor growth. RNA-sequencing (RNA-seq), qRT-PCR, Western blot, polysome profiling, luciferase reporter assay, and rescue experiments were performed to explore the regulatory mechanisms of tRF in BC-DM. We identified that tRF-Cys-GCA-029 was downregulated in BC-DM tissues and under hyperglycemia conditions in BC cells. Functionally, downregulation of tRF-Cys-GCA-029 promoted BC cell proliferation and migration in a glucose level-dependent manner. tRF-Cys-GCA-029 knockdown also enhanced glycolysis metabolism in BC cells, indicated by increasing lactate/pyruvate production and ECAR levels. Notably, injection of tRF-Cys-GCA-029 mimic significantly suppressed BC tumor growth in diabetic-mice. Mechanistically, tRF-Cys-GCA-029 regulated BC cell malignancy and glycolysis via interacting with PRKCG in two ways: binding to the coding sequence (CDS) of PRKCG mRNA to regulate its transcription and altering polysomal PRKCG mRNA expression to modify its translation. Hyperglycemia-downregulated tRF-Cys-GCA-029 enhances the malignancy and glycolysis of BC cells. tRF-Cys-GCA-029-PRKCG-glycolysis axis may be a potential therapeutic target against BC-DM.

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来源期刊

Breast Cancer Research 医学-肿瘤学

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期刊介绍： Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.