Functional interaction between Env oncogene from Jaagsiekte sheep retrovirus and tumor suppressor Sprouty2
Ebenezer Chitra1, Yi-Wen Lin, Fabian Davamani
1Vaccine R&D Center, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 350, Taiwan.
Background:
Jaagsiekte sheep retrovirus (JSRV) is a type D retrovirus capable of transforming target cells in vitro and in vivo. The Envelope (Env) gene from JSRV and from related retroviruses can induce oncogenic transformation, although the detailed mechanism is yet to be clearly understood. Host cell factors are envisaged to play a critical determining role in the regulation of Env-mediated cell transformation.
Results:
JSRV Env-mediated transformation of a lung adenocarcinoma cell line induced rapid proliferation, anchorage-independent growth and tumor formation, but completely abrogated the migration ability. An analysis of the signaling scenario in the transformed cells suggested the involvement of the ERK pathway regulated by Sprouty2 in cell migration, and the PI3K-Akt and STAT3 pathways in proliferation and anchorage-independence. On the other hand, in a normal lung epithelial cell line, Env-mediated transformation only decreased the migration potential while the other functions remained unaltered. We observed that Env induced the expression of a tumor suppressor, Sprouty2, suggesting a correlation between Env-effect and Sprouty2 expression. Overexpression of Sprouty2 per se not only decreased the migratory potential and tumor formation potential of the target cells but also made them resistant to subsequent Env-mediated transformation. On the other hand, over expression of the functional mutants of Sprouty2 had no inhibitory effect, confirming the role of Sprouty2 as a tumor suppressor.
Conclusions:
Our studies demonstrate that Env and Sprouty2 have a functional relationship, probably through shared signaling network. Sprouty2 functions as a tumor suppressor regulating oncogenic transformation of cells, and it therefore has the potential to be exploited as a therapeutic anti-cancer agent.
Insights
Jaagsiekte sheep retrovirus (JSRV) Envelope (Env) protein transforms lung cells, altering proliferation and migration. Sprouty2 acts as a tumor suppressor, potentially offering a therapeutic target against JSRV-induced cancers.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Jaagsiekte sheep retrovirus (JSRV), a type D retrovirus, can transform cells in vitro and in vivo.
- The JSRV Envelope (Env) gene's oncogenic transformation mechanism requires further elucidation, with host factors playing a key regulatory role.
Purpose of the Study:
- To investigate the role of JSRV Env in cell transformation and identify associated host cell factors.
- To explore the functional relationship between JSRV Env and Sprouty2 in oncogenesis.
Main Methods:
- Transformation of lung adenocarcinoma and normal lung epithelial cell lines with JSRV Env.
- Analysis of cellular signaling pathways (ERK, PI3K-Akt, STAT3) and Sprouty2 expression.
- Overexpression of Sprouty2 and its mutants in target cells.
Main Results:
- JSRV Env-mediated transformation induced proliferation and anchorage-independent growth but abrogated migration in cancer cells.
- Sprouty2 expression was induced by Env, correlating with transformation effects and acting as a tumor suppressor by inhibiting migration and tumor formation.
- Sprouty2's tumor-suppressive function was confirmed by its ability to confer resistance to Env-mediated transformation.
Conclusions:
- JSRV Env and Sprouty2 share a functional relationship, likely via common signaling pathways.
- Sprouty2 acts as a tumor suppressor in JSRV-induced cell transformation.
- Sprouty2 holds potential as a therapeutic agent against JSRV-associated cancers.
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