ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Metabolism
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1575809
This article is part of the Research TopicSynthetic Biology and Metabolomics: Novel Insight in Oncology ResearchView all 6 articles
CHML regulates migration and invasion in hepatocellular carcinoma via transcriptional and metabolic reprogramming
Provisionally accepted- 1Changhai Hospital, Second Military Medical University, Shanghai, China
- 2Department of Laboratory Diagnosis, Changhai Hospital, Shanghai, China
- 3Naval Medical University, Shanghai, Shanghai, China
- 4University of Shanghai for Science and Technology, Shanghai, Shanghai Municipality, China
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Hepatocellular carcinoma (HCC), a prevalent malignant neoplasm, presents significant therapeutic challenges. However, the key factors and mechanisms driving HCC metastasis remain incompletely understood. This study aimed to elucidate the mechanism through which CHML regulates the migration and invasion of HCC cells. Following CHML knockout or overexpression, we assessed the proliferative capacity of HCC cells using the Cell Counting Kit-8 (CCK-8) assay, 5ethynyl-2′-deoxyuridine (EdU) incorporation, colony formation assay, and subcutaneous xenograft tumor models in nude mice. Cell migration and invasion were evaluated using wound healing and Transwell assays. Results demonstrated that CHML knockout significantly inhibited the migration and invasion of HCC cells in vitro, whereas CHML overexpression promoted these phenotypes.Transcriptomic sequencing revealed CHML-mediated regulation of migration-associated pathways, whereas untargeted metabolomics identified choline metabolism as a key significantly altered pathway. Notably, the integration of transcriptomics and untargeted metabolomics identified choline metabolism as a pivotal pathway in CHML-regulated migration and invasion. The subsequent mechanistic analysis demonstrated that CHML upregulated the Solute carrier family 44 member 3 (SLC44A3) to enhance choline uptake, thereby increasing phosphatidic acid (PA) production. This metabolic shift activated MAPK and PI3K-AKT signaling cascades, ultimately driving HCC cell migration and invasion. Our findings provide novel insights into metabolic dependencies in HCC metastasis and position CHML as a promising therapeutic target.
Keywords: gene editing, CHML, Hepatocellular Carcinoma, Neoplasm Metastasis, Choline, Metabolism
Received: 13 Feb 2025; Accepted: 11 Jul 2025.
Copyright: © 2025 Cao, Wang, Zhang, Xie, Liu, Kong, Jia, Lu, Jiang and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Junfeng Jiang, Naval Medical University, Shanghai, 200433, Shanghai, China
Shanrong Liu, Changhai Hospital, Second Military Medical University, Shanghai, China
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