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CHML regulates migration and invasion in hepatocellular carcinoma via transcriptional and metabolic reprogramming

ABSTRACT:

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, 5-ethynyl-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.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12789 | MetaboLights | 2025-07-28

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12789_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS12789_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12789_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS12789_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Background: JAG-1 is a ligand of Notch signaling and can regulate cell differentiation and proliferation in cancers. Recent studies indicated that JAG1 is a gene associated with cancer progression. Therefore, we investigated the role of JAG1 in lung cancer progression. Methods: The expression of JAG1 was manipulated by overexpression or RNA silencing in several human lung cell lines. The effect of JAG1 on tumorigenesis and invasion was assessed by the cell anchorage-independent growth, cell proliferation, cell migration and invasion assays in vitro as well as metastasis in vivo. The potential downstream genes of JAG1 were identified by oligonucleotide microarrays and quantitative reverse transcriptionÂ¡Vpolymerase chain reaction (RT-PCR). We further measured JAG1 expression in lung cancer specimens by RT-PCR. Correlation between JAG1 expression and overall survival of lung cancer patients was determined by using the log-rank test and multivariable Cox proportional hazards regression analysis. All statistical tests were two-sided. Results: JAG1 enhanced anchorage-independent growth, cell migration, invasion in the lower invasive cells, CL1-0. JAG1 also increased the capability of migration and invasion in the other two lung cancer cell lines (A549 and NCI-H226). The silencing of JAG1 inhibited migration and invasion activities of the higher invasive cells, CL1-5, by siRNA technology. The invasion-promoting activity of JAG1 was also demonstrated in vivo by using a mouse metastasis model. By microarray analysis, we found that the expression of heat shock 70kDa protein 2 (HSPA2) was activated by JAG1 overexpression and eliminated by JAG1 silencing. Moreover, lung cancer patients with high JAG1 expressing tumors had shorter overall survival than those with low-expressing tumors. Conclusion: JAG1 might be an oncogene which promotes colonogenesis and metastasis, and high JAG1 expression is associated with shorten survival in lung cancer. In this investigation, we used a lung cancer invasion cell model to identify the genes involved in cancer progression. JAG1 is a potential oncogene whose expression is correlated to the survival of patients with breast, prostate and liver cancers. However, the role of JAG1 in lung caner progression has not been reported, particularly in metastasis. Here, JAG1 was ectopically expressed in lower invasive lung cancer cell line its impact on colonogenesis, migration and invasiveness was assessed. The underlying mechanism was explored by JAG1-expressed transfectants and microarrays and the clinical relevance was evaluated by quantitative RT-PCR.

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CHML regulates migration and invasion in hepatocellular carcinoma via transcriptional and metabolic reprogramming

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