gp73依赖性外泌体生物发生调控促进结直肠癌肝转移。

IF 33.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-05-26 DOI:10.1186/s12943-025-02350-6

Linfei Huang,Meng Wei,Huilong Li,Mingxin Yu,Luming Wan,Ruzhou Zhao,Qi Gao,Lijuan Sun,Xufeng Hou,Yunhai Mo,Qing Huang,Lan Zhen,Xiaopan Yang,Jingfei Li,Nan Wang,Chundong Zhang,Haoran Jin,Li Zhou,Yixin Xu,Haotian Lin,Xuhui Zhang,Boan Li,Yue Han,Jing Yuan,Rui Zhang,Feixiang Wu,Hui Zhong,Congwen Wei

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引用次数: 0

摘要

结直肠癌（CRC）肝转移是癌症相关死亡的主要原因。肝脏如何影响细胞间通讯以支持结直肠癌肝转移尚不清楚。在此，我们将GP73与外泌体生物发生和结直肠癌肝转移联系起来。GP73在肝细胞中的慢性上调会引发小鼠非肥胖代谢功能障碍相关的脂肪变性肝病（MASLD）。高肝脏GP73表达的小鼠以外泌体依赖的方式增加结直肠癌的肝转移。GP73调节内体腔室中的胆固醇含量，促进外泌体的产生。定量蛋白质组学显示GP73重塑肝细胞外泌体蛋白质组，产生富含nav2的外泌体。临床上，结直肠癌合并肝转移患者血清GP73水平与外泌体NAV2水平呈正相关。在GP73诱导的非肥胖小鼠中，肝脏NAV2的敲低抑制了CRC肝转移的增强，而GP73的阻断则减轻了高脂或高果糖饮食诱导的肥胖小鼠CRC肝转移的增加。我们的研究结果表明GP73阻断是减轻结直肠癌肝转移的潜在治疗策略。

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GP73-dependent regulation of exosome biogenesis promotes colorectal cancer liver metastasis.

Colorectal cancer (CRC) liver metastasis is the main cause of cancer-related mortality. How liver influences intercellular communication to support CRC liver metastasis remains unknown. Herein, we link GP73, whose chronic upregulation in hepatocytes triggers non-obese metabolic-dysfunction associated steatotic liver disease (MASLD) in mice, with exosome biogenesis and CRC liver metastasis. Mice with high liver GP73 expression exhibited increased CRC liver metastasis in an exosome-dependent manner. GP73 modulated the cholesterol contents in endosomal compartments to promote exosome production. Quantitative proteomics revealed GP73 reshaped hepatocyte exosomal proteome and produced NAV2-rich exosomes. Clinically, serum GP73 levels positively correlated with exosomal NAV2 levels in CRC patients with liver metastasis. Knockdown of liver NAV2 suppressed enhanced CRC liver metastasis in GP73-induced non-obese mice, and GP73 blockade mitigated the increased CRC liver metastasis in obese mice fed by high-fat diet or high-fructose diet. Our findings suggest GP73 blockade as a potential therapeutic strategy for mitigating CRC liver metastasis.

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.