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Sphingosine-1-phosphate transporter spinster homolog 2 is essential for iron-regulated metastasis of hepatocellular carcinoma
- Source :
- Molecular Therapy. 30:703-713
- Publication Year :
- 2022
- Publisher :
- Elsevier BV, 2022.
-
Abstract
- Iron dyshomeostasis is associated with hepatocellular carcinoma (HCC) development. However, the role of iron in HCC metastasis is unknown. This study aimed to elucidate the underlying mechanisms of iron’s enhancement activity on HCC metastasis. In addition to the HCC cell lines and clinical samples in vitro, iron deficient (ID) mouse models were generated using iron-free diet and transferrin receptor protein knock out, followed by administration of HCC tumors through either orthotopic or ectopic route. Clinical metastatic HCC samples showed significant ID status, accompanied by overexpression of sphingosine-1-phosphate transporter spinster homologue 2 (SPNS2). Mechanistically, ID increased SPNS2 expression, leading to HCC metastasis in both cell cultures and mouse models. ID not only altered the anti-tumor immunity, which was indicated by phenotypes of lymphatic subsets in the liver and lung of tumor-bearing mice, but also promoted HCC metastasis in a cancer cell autonomous manner through the SPNS2. Since germline knockout of globe SPNS2 showed significantly reduced HCC metastasis, we further developed hepatic-targeting recombinant adeno-associated virus vectors to knockdown SPNS2 expression and to inhibit iron-regulated HCC metastasis. Our observation indicates the role of iron in HCC pulmonary metastasis and suggests SPNS2 as a potential therapeutic target for the prevention of HCC pulmonary metastasis.
- Subjects :
- Carcinoma, Hepatocellular
Iron
Anion Transport Proteins
Transferrin receptor
Biology
Metastasis
Mice
chemistry.chemical_compound
Cell Movement
Sphingosine
Cell Line, Tumor
Drug Discovery
Genetics
medicine
Animals
Sphingosine-1-phosphate
Neoplasm Metastasis
neoplasms
Molecular Biology
Pharmacology
Gene knockdown
Liver Neoplasms
medicine.disease
digestive system diseases
Lymphatic system
chemistry
Cell culture
Hepatocellular carcinoma
Cancer cell
Cancer research
Molecular Medicine
Lysophospholipids
Subjects
Details
- ISSN :
- 15250016
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy
- Accession number :
- edsair.doi.dedup.....677cf63d5708a6b9e72c003741ec8063