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Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells
Published on: April 7, 2017
Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma
Hee Kyung Kim1, Hong Zhang, Hui Li
1Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Abstract:
Slits are a group of secreted glycoproteins that play a role in the regulation of cell migration. Previous studies suggested that Slit2 might be a tumor-suppressor gene. However, it remained to be determined whether Slit2 suppressed tumor growth and metastasis in animal models. We showed that Slit2 expression was decreased or abolished in human esophageal squamous cell carcinomas (SCCs) compared to normal tissues by in situ hybridization. Stable transfection of human SCC A431 and fibrosarcoma HT1080 cells with Slit2 gene suppressed tumor growth in athymic nude mice. Apoptosis in Slit2-transfected tumors was increased, whereas proliferating cells were decreased, suggesting a mechanism for Slit2-mediated tumor suppression. This was supported by further analysis indicating that antiapoptotic molecules Bcl-2 and Bcl-xl and cell cycle molecules Cdk6 and Cyclin D1 were down-regulated in Slit2-transfected tumors. Furthermore, wound healing and Matrigel invasion assays showed that the transfection with Slit2 inhibited tumor cell migration and invasion. Slit2-transfected tumors showed a high level of keratin 8/18 and a low level of N-cadherin expression compared to empty vector-transfected tumors. More importantly, Slit2 transfection suppressed the metastasis of HT1080 tumor cells in lungs after intravenous inoculation. Collectively, our study has demonstrated that Slit2 inhibits tumor growth and metastasis of fibrosarcoma and SCC and that its effect on cell cycle and apoptosis signal pathways is an important mechanism for Slit2-mediated tumor suppression.
Insights
Slit2, a secreted glycoprotein, suppresses tumor growth and metastasis in esophageal squamous cell carcinoma and fibrosarcoma models. This involves regulating apoptosis and cell cycle pathways, highlighting its potential as a tumor suppressor.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Slits are secreted glycoproteins regulating cell migration.
- Slit2 has been proposed as a tumor suppressor gene.
- Its role in suppressing tumor growth and metastasis in vivo requires further investigation.
Purpose of the Study:
- To investigate the role of Slit2 in suppressing tumor growth and metastasis in animal models.
- To elucidate the molecular mechanisms underlying Slit2-mediated tumor suppression.
Main Methods:
- In situ hybridization to assess Slit2 expression in human esophageal squamous cell carcinomas (SCCs).
- Stable transfection of SCC A431 and fibrosarcoma HT1080 cells with the Slit2 gene.
- Tumorigenicity assays in athymic nude mice.
- Analysis of apoptosis, proliferation, and expression of key regulatory molecules (Bcl-2, Bcl-xl, Cdk6, Cyclin D1).
- Wound healing and Matrigel invasion assays to assess cell migration and invasion.
- Immunohistochemical analysis of keratin 8/18 and N-cadherin.
- Intravenous inoculation to evaluate lung metastasis.
Main Results:
- Slit2 expression was decreased in human esophageal SCCs compared to normal tissues.
- Slit2 transfection suppressed tumor growth, increased apoptosis, and decreased proliferation in vivo.
- Slit2 transfection down-regulated antiapoptotic (Bcl-2, Bcl-xl) and cell cycle (Cdk6, Cyclin D1) molecules.
- Slit2 inhibited tumor cell migration and invasion in vitro.
- Slit2 transfection suppressed lung metastasis of fibrosarcoma cells.
- Slit2-transfected tumors showed increased keratin 8/18 and decreased N-cadherin expression.
Conclusions:
- Slit2 demonstrates significant tumor suppressor activity against fibrosarcoma and SCC growth and metastasis.
- Slit2 exerts its tumor-suppressive effects by modulating apoptosis and cell cycle pathways.
- These findings underscore the therapeutic potential of Slit2 in cancer treatment.
