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Updated: Jul 5, 2025
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Transmembrane serine protease 6, a novel target for inhibition of neuronal tumor growth
Yong Zuo1, Jiawei Bai1, Huiyuan Bai1
1Laboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China.
Abstract:
Transmembrane serine protease 6 (Tmprss6) has been correlated with the occurrence and progression of tumors, but any specific molecular mechanism linking the enzyme to oncogenesis has remained elusive thus far. In the present study, we found that Tmprss6 markedly inhibited mouse neuroblastoma N2a (neuro-2a) cell proliferation and tumor growth in nude mice. Tmprss6 inhibits Smad1/5/8 phosphorylation by cleaving the bone morphogenetic protein (BMP) co-receptor, hemojuvelin (HJV). Ordinarily, phosphorylated Smad1/5/8 binds to Smad4 for nuclear translocation, which stimulates the expression of hepcidin, ultimately decreasing the export of iron through ferroportin 1 (FPN1). The decrease in cellular iron levels in neuro-2a cells with elevated Tmprss6 expression limited the availability of the metal forribo nucleotide reductase activity, thereby arresting the cell cycle prior to S phase. Interestingly, Smad4 promoted nuclear translocation of activating transcription factor 3 (ATF3) to activate the p38 mitogen-activated protein kinases signaling pathway by binding to ATF3, inducing apoptosis of neuro-2a cells and inhibiting tumor growth. Disruption of ATF3 expression significantly decreased apoptosis in Tmprss6 overexpressed neuro-2a cells. Our study describes a mechanism whereby Tmprss6 regulates the cell cycle and apoptosis. Thus, we propose Tmprss6 as a candidate target for inhibiting neuronal tumor growth.
Insights
Transmembrane serine protease 6 (Tmprss6) inhibits neuroblastoma growth by reducing iron availability and promoting apoptosis. This enzyme offers a potential therapeutic target for neuronal tumors.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Transmembrane serine protease 6 (Tmprss6) is linked to tumor development, but its precise oncogenic mechanism is unclear.
- Understanding Tmprss6's role is crucial for developing targeted therapies against neuronal tumors.
Purpose of the Study:
- To elucidate the molecular mechanism by which Tmprss6 influences neuroblastoma cell proliferation and tumor growth.
- To investigate Tmprss6's role in regulating cell cycle and apoptosis in neuroblastoma.
Main Methods:
- Utilized mouse neuroblastoma N2a cells and xenograft models in nude mice.
- Investigated Tmprss6's effect on Smad1/5/8 phosphorylation, hemojuvelin (HJV) cleavage, and iron metabolism.
- Examined the involvement of Smad4, activating transcription factor 3 (ATF3), and p38 MAPK signaling in Tmprss6-mediated effects.
Main Results:
- Tmprss6 significantly inhibited neuro-2a cell proliferation and tumor growth.
- Tmprss6 cleaves HJV, reducing Smad1/5/8 phosphorylation and subsequently decreasing iron export via ferroportin 1 (FPN1).
- Reduced cellular iron levels arrested the cell cycle, while Smad4-mediated ATF3 nuclear translocation activated p38 MAPK, inducing apoptosis.
Conclusions:
- Tmprss6 regulates neuroblastoma cell cycle progression and induces apoptosis through a novel molecular pathway involving iron metabolism and ATF3 signaling.
- Tmprss6 represents a promising therapeutic target for inhibiting neuronal tumor growth.
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