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Published on: January 17, 2012
TGFβ signaling promotes juvenile granulosa cell tumorigenesis by suppressing apoptosis
Nadéra Mansouri-Attia1, Swamy K Tripurani, Nisha Gokul
1Department of Pathology and Immunology (N.M.-A., S.K.T., H.P., M.L.A., K.E., S.A.P.), Department of Obstetrics and Gynecology (M.L.A.), Graduate Program in Molecular and Cell Biology (N.G.), and Department of Molecular and Cellular Biology (S.A.P.), Baylor College of Medicine, Houston, Texas 77030.
Abstract:
Molecular changes that give rise to granulosa cell tumors of the ovary are not well understood. Previously, we showed that deletion in granulosa cells of the bone morphogenetic protein receptor-signaling transcription factors, Smad1 and Smad5, causes development of metastatic granulosa cell tumors that phenocopy the juvenile form of granulosa cell tumors (JGCTs) in humans. The TGFβ-SMAD2/3 pathway is active in JGCTs, but its role is unknown. We tested the in vivo contribution of TGFβ-SMAD signaling to JGCT development by genetically deleting the common Smad4 from Smad1/5 double knockout mice. Smad1/5/4 triple knockout mice were sterile and had significantly increased survival and delayed tumor development compared to those for the Smad1/5 double knockout mice. The few tumors that did develop were smaller, showed no evidence of metastasis, and had increased apoptosis. In the human JGCT cell line COV434, TGFβ1 increased viability by inhibiting apoptosis through a TGFβ type I receptor-dependent repression of caspase activity and inhibition of poly(ADP-ribose) polymerase cleavage. These data support a tumor-promoting function of TGFβ in JGCTs through its ability to repress apoptosis.
Insights
Deleting TGFβ-SMAD signaling in mice delayed tumor development and reduced metastasis in granulosa cell tumors. TGFβ1 promotes cancer cell survival by inhibiting apoptosis, suggesting a tumor-promoting role in ovarian cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Granulosa cell tumors (GCTs) of the ovary are not well understood at the molecular level.
- Previous research linked Smad1 and Smad5 deletion in granulosa cells to metastatic GCTs resembling human juvenile GCTs (JGCTs).
- The role of the transforming growth factor beta (TGFβ)-SMAD2/3 pathway in JGCT development is currently unknown.
Purpose of the Study:
- To investigate the in vivo role of TGFβ-SMAD signaling in the development of JGCTs.
- To determine if inhibiting TGFβ-SMAD signaling impacts tumor progression and survival.
Main Methods:
- Genetic deletion of the common Smad4 gene in Smad1/5 double knockout mice to create Smad1/5/4 triple knockout mice.
- Analysis of tumor development, survival rates, metastasis, and apoptosis in knockout mouse models.
- In vitro experiments using the human JGCT cell line COV434 treated with TGFβ1.
Main Results:
- Smad1/5/4 triple knockout mice exhibited increased survival and delayed tumor development compared to Smad1/5 double knockout mice.
- Tumors in triple knockout mice were smaller, lacked metastasis, and showed increased apoptosis.
- TGFβ1 treatment in human JGCT cells increased viability by inhibiting apoptosis via TGFβ type I receptor-dependent mechanisms.
Conclusions:
- TGFβ-SMAD signaling appears to have a tumor-promoting role in JGCTs.
- Inhibition of TGFβ signaling may represent a therapeutic strategy for ovarian granulosa cell tumors.
- TGFβ promotes cancer cell survival by repressing apoptosis, highlighting a key mechanism in JGCT progression.
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