GBA1-dependent membrane glucosylceramide reprogramming promotes liver cancer metastasis via activation of the Wnt/β-catenin signalling pathway PMID: 35637196

ADC Targets in Oncology

2026-04-10

GBA1-dependent membrane glucosylceramide reprogramming promotes liver cancer metastasis via activation of the Wnt/β-catenin signalling pathway

Cell Death Dis. 2022 May 30;13(5):508. doi: 10.1038/s41419-022-04968-6.

Zhidong Qiu ^# ¹ ² ³ , Xuehong Wang ^# ¹ ² ⁴ , Zebin Yang ² ⁵ , Sicong Liao ² ⁴ , Wei Dong ² ⁵ , Tian Sun ² ⁴ , Huixian Wu ² ⁴ , Qinqin Zhang ⁶ , Zhixiong Pan ² ⁴ , Sin Man Lam ⁷ , Guanghou Shui ⁸ , Junfei Jin ⁹ ¹⁰ ¹¹ ¹²

Affiliations

1. Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
2. Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
3. Department of General Surgery, Yantian District People's Hospital, Shenzhen, 518081, Guangdong, China.
4. Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
5. Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
6. Department of Thyroid and Breast Surgery, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, 541002, China.
7. LipidALL Technologies Company Limited, Changzhou, China.
8. State Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
9. Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
10. Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
11. Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
12. China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
# Contributed equally.

Abstract

The effect of glucosylceramide (GlcCer) reprogramming on liver Cancer metastasis remains poorly understood. In this study, we demonstrated that the protein expression of GBA1, which catalyses the conversion of GlcCer to ceramide, was downregulated in liver Cancer tissue. A clinical relevance analysis revealed that low expression of GBA1 was associated with the metastatic potential of liver Cancer cells. Furthermore, loss- and gain-of-function studies confirmed that low expression of GBA1 promoted metastasis of liver Cancer both in vitro and in vivo. Mechanistic studies indicated that low expression of GBA1 enhanced the metastatic ability of liver Cancer by promoting the epithelial-mesenchymal transition (EMT), in which Wnt signalling pathway is involved. In the plasma membrane (PM), GBA1-dependent GlcCer reprogramming increased LRP6 location in the PM leading to an interaction between GlcCer and LRP6, subsequently promoting LRP6 phosphorylation at Ser1490, and finally activating the Wnt/β-catenin signalling pathway. To our knowledge, this is the first time to be found that GlcCer interacted with a protein. In addition, the results of mass spectrometry indicated that GlcCer d18:1/18:0 was the most notably increased studied species in the PM when GBA1 was downregulated, suggesting that GlcCer d18:1/18:0 may be the major functional lipid that promotes GBA1-dependent liver Cancer metastasis. Thus, GBA1-mediated GlcCer reprogramming in the PM promotes metastasis of liver Cancer via activation of the Wnt/β-catenin signalling pathway, upregulation of GBA1 may be a potential therapeutic strategy to combat liver Cancer metastasis.