2. Academic Validation
  3. GP73-dependent regulation of exosome biogenesis promotes colorectal cancer liver metastasis

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

  • Mol Cancer. 2025 May 26;24(1):151. doi: 10.1186/s12943-025-02350-6.
Linfei Huang # 1,  Meng Wei # 2 3,  Huilong Li # 1,  Mingxin Yu # 4,  Luming Wan # 1,  Ruzhou Zhao # 1,  Qi Gao 5,  Lijuan Sun 5,  Xufeng Hou 5,  Yunhai Mo 2 3,  Qing Huang 2 3,  Lan Zhen 2 3,  Xiaopan Yang 1,  Jingfei Li 1,  Nan Wang 6,  Chundong Zhang 7,  Haoran Jin 8,  Li Zhou 1,  Yixin Xu 2 3,  Haotian Lin 1,  Xuhui Zhang 5,  Boan Li 9,  Yue Han 10,  Jing Yuan 11,  Rui Zhang 12,  Feixiang Wu 13 14,  Hui Zhong 15,  Congwen Wei 16
Affiliations

Affiliations

  • 1 Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China.
  • 2 Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, China.
  • 3 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China.
  • 4 Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, State Key Laboratory of Digestive Health, Beijing Key Laboratory of Early Gastrointestinal Cancer Medicine and Medical Devices, No. 95 Yong'an Road, Xicheng District, Beijing, 100050, China.
  • 5 Beijing Youngen Technology Co. Ltd, No. 55 Qingfeng West Road, Daxing District, Beijing, 102629, China.
  • 6 Department of Radiotherapy, Changzhi People's Hospital, No. 502, Changxing Middle Road, Luzhou District, Changzhi, Shanxi, 046000, China.
  • 7 Department of Surgical Oncology and Central Laboratory, the Fourth Affiliated Hospital of China Medical University, No. 4, Chongshan East Road, Huanggu District, Shenyang, Liaoning, 110032, China.
  • 8 Department of Colorectal Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, No. 44 Xiaoheyan Road, Dadong Distrct, Shenyang, Liaoning, 110042, China.
  • 9 Clinical Laboratory, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, No. 100 Xisihuan Middle Road, Beijing, 100039, China. lba@263.net.
  • 10 Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan South Road, Chaoyang District, Beijing, 100021, China. doctorhan@163.com.
  • 11 Capital Institute of Pediatrics, Capital Center for Children's Health, Capital Medical University, No. 2 Yabao Road, Chaoyang District, Beijing, 100020, China. yuanjing6216@163.com.
  • 12 Department of Colorectal Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, No. 44 Xiaoheyan Road, Dadong Distrct, Shenyang, Liaoning, 110042, China. zhangrui@cancerhosp-ln-cmu.com.
  • 13 Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, China. wufx2013@163.com.
  • 14 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China. wufx2013@163.com.
  • 15 Beijing Youngen Technology Co. Ltd, No. 55 Qingfeng West Road, Daxing District, Beijing, 102629, China. hui.zhong@youngenbiomed.com.cn.
  • 16 Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China. weicongwen@aliyun.com.
  • # Contributed equally.
PMID: 40414849 DOI: 10.1186/s12943-025-02350-6
Abstract

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.

Keywords

Colorectal cancer; Exosome; Golgi protein 73; Metastasis.

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