核梭杆菌通过mir -130a-3p介导的AMPK抑制促进结直肠癌中胆固醇的生物合成，这一过程被丁酸盐抵消。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-05-23 DOI:10.1016/j.canlet.2025.217810

Yuting Sun , Jiawei Lu , Effie Yin Tung Lau , Yao Zeng , Sarah Wing Lam Li , Ting Hei Au , Silin Ye , Tingyu Zhou , Francis KL. Chan , Jessie Qiaoyi Liang

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引用次数: 0

摘要

核梭杆菌（Fn）与多种疾病有关，包括结直肠癌（CRC）。本研究阐明了Fn对胆固醇合成的贡献及其与CRC的潜在联系，以及丁酸盐在这一过程中的抵消作用。细胞和小鼠模型分别用Fn和丁酸盐处理，以研究丁酸盐与Fn的致癌特性之间的相互作用。转录组学分析明确了Fn对胆固醇生物合成基因和途径的深远影响。Fn处理上调了参与胆固醇合成的基因（FDPS、FDFT1和SQLE）的表达，增加了细胞和小鼠肠道中SREBF2的活性，升高了细胞、肠道和血清中的胆固醇水平。Fn上调miR-130a-3p，通过转录组学和靶标预测，通过核因子-κB活化鉴定。miR-130a-3p随后下调AMPKα/β1表达，激活SREBF2，上调胆固醇生物合成基因。这些影响主要由丁酸盐减轻。值得注意的是，TCGA数据分析显示，结直肠癌中梭杆菌丰度与FDPS、FDFT1、SQLE和AMPKα/β1的表达显著相关。采用qPCR和RT-qPCR对人粪便中Fn丰度和miRNA表达进行定量分析。从正常受试者到腺瘤患者再到结直肠癌患者，粪便miR-130a-3p水平逐渐升高，与粪便Fn丰度显著相关。此外，粪便Fn丰度升高与结直肠癌患者高胆固醇血症发生率增加有关。Fn通过上调miR-130a-3p促进胆固醇的生物合成，miR-130a-3p下调AMPK蛋白，激活SREBF2。本研究强调了肠道细菌对宿主胆固醇合成的影响。有针对性地调节肠道微生物群以降低胆固醇可能是一种有希望的预防结直肠癌的策略。

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Fusobacterium nucleatum enhances cholesterol biosynthesis in colorectal cancer via miR-130a-3p-mediated AMPK inhibition, a process counteracted by butyrate

Fusobacterium nucleatum (Fn) has been implicated in various diseases, including colorectal cancer (CRC). This study elucidates Fn's contribution to cholesterol synthesis and the underlying link with CRC, as well as butyrate's counteracting effects in this process. Cells and mouse models were treated with Fn followed/accompanied by butyrate treatments to investigate the interplay between butyrate and Fn's oncogenic properties. Transcriptomics analysis pinpointed Fn's profound impact on cholesterol biosynthesis genes and pathways. Fn treatment upregulated the expression of genes involved in cholesterol synthesis (FDPS, FDFT1, and SQLE) and increased SREBF2 activity in cells and mouse intestines, elevating cholesterol levels in cells, intestines, and sera. Fn upregulated miR-130a-3p, identified through transcriptomics and target prediction, through nuclear factor-κB activation. miR-130a-3p subsequently downregulated AMPKα/β1 expression to activate SREBF2 and upregulate cholesterol biosynthesis genes. These effects were predominantly mitigated by butyrate. Notably, analysis of TCGA data revealed that fusobacterial abundance correlated significantly with the expression of FDPS, FDFT1, SQLE, and AMPKα/β1 in CRC. Fn abundance and miRNA expression in human stools were quantified using qPCR and RT-qPCR. Fecal miR-130a-3p levels increased progressively from normal subjects through adenoma patients to CRC patients, correlating significantly with fecal Fn abundance. Additionally, heightened fecal Fn abundance was associated with an increased incidence of hypercholesterolemia in CRC patients. Fn promotes cholesterol biosynthesis by upregulating miR-130a-3p, which downregulates AMPK proteins and activates SREBF2. This study highlights the influence of gut bacteria on host cholesterol synthesis. Targeted modulation of gut microbiota to reduce cholesterol may represent a promising preventive strategy for CRC.

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.