ArticleMolecular endocrinology (Baltimore, Md.)2013
Betaglycan alters NFκB-TGFβ2 cross talk to reduce survival of human granulosa tumor cells.
Article in Molecular endocrinology (Baltimore, Md.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 29 citations in OpenAlex.
- Human umbilical cord mesenchymal stem cells conditioned medium exerts anti-tumor effects on KGN cells in a cell density-dependent manner through activation of the Hippo pathway.Stem cell research & therapy · 2023Article
- Immunohistochemical markers of prognosis in adult granulosa cell tumors of the ovary - a review.Journal of ovarian research · 2023Review
- Krüppel-like factors in tumors: Key regulators and therapeutic avenues.Frontiers in oncology · 2023Review
- Adult-type granulosa cell tumor of the ovary.American journal of cancer research · 2022Review
- The attributes of plakins in cancer and disease: perspectives on ovarian cancer progression, chemoresistance and recurrence.Cell communication and signaling : CCS · 2021Review
- Keratin-14 (KRT14) Positive Leader Cells Mediate Mesothelial Clearance and Invasion by Ovarian Cancer Cells.Cancers · 2019Article
- The molecular mechanism of ovarian granulosa cell tumors.Journal of ovarian research · 2018Review
- Multiple Soluble TGF-β Receptors in Addition to Soluble Endoglin Are Elevated in Preeclamptic Serum and They Synergistically Inhibit TGF-β Signaling.The Journal of clinical endocrinology and metabolism · 2017Article
- Granulosa Cell Tumors: Novel Predictors of Recurrence in Early-stage Patients.International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists · 2017Article
- SMAD3 Activation: A Converging Point of Dysregulated TGF-Beta Superfamily Signaling and Genetic Aberrations in Granulosa Cell Tumor Development?Biology of reproduction · 2016Review
- Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis.Oncotarget · 2016Article
- FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development.Molecular endocrinology (Baltimore, Md.) · 2015Article
- TGFβ signaling promotes juvenile granulosa cell tumorigenesis by suppressing apoptosis.Molecular endocrinology (Baltimore, Md.) · 2014Article
- FOXL2, GATA4, and SMAD3 co-operatively modulate gene expression, cell viability and apoptosis in ovarian granulosa cell tumor cells.PloS one · 2014Article
- Characterization of the inhibitor of kappaB kinase (IKK) complex in granulosa cell tumors of the ovary and granulosa cell tumor-derived cell lines.Hormones & cancer · 2013Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The molecular pathways controlling granulosa cell tumor (GCT) survival are poorly understood. In many cell types, nuclear factor-κB (NFκB) and TGFβ coordinately regulate cell survival to maintain tissue homeostasis. Because GCT cell lines exhibit constitutively activated NFκB, we hypothesized that NFκB blocks TGFβ-mediated cell death in GCT cells. To test this hypothesis, we used the human GCT cell line KGN, which exhibits loss of betaglycan, a TGFβ co-receptor. After inhibition of NFκB in KGN cells, re-expression of betaglycan resulted in a decrease in cell viability, which was further decreased by TGFβ2. Intriguingly, TGFβ2 increased NFκB reporter activity in control cells, but betaglycan expression suppressed both basal and TGFβ2-stimulated NFκB activity. Chemical inhibition of Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signaling or SMAD2/3 gene silencing revealed that both SMADs contributed to cell survival. Furthermore, inhibiting NFκB activity resulted in a specific reduction in SMAD3 expression. Conversely, overexpression of SMAD3 increased basal NFκB activity and countered betaglycan-mediated suppression of NFκB activity. Finally, ERK1/2 activation emerged as the point of convergence of NFκB, SMAD3, and TGFβ2/betaglycan governance of GCT cell viability. Key findings in KGN cells were reproduced in a second GCT cell line, COV434. Collectively, our data establish that both SMAD2/3 and NFκB signaling pathways support GCT cell viability and suggest the existence of a positive feedback loop between NFκB and SMAD3 signaling in late-stage GCT. Furthermore, our data suggest that loss of betaglycan during tumor progression in GCT alters the functional outcomes generated by NFκB and TGFβ pathway cross talk.
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