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Loss of endogenous TGF-beta effect induces mouse hepatoma malignancy by correlation with cyclooxygenase-2 and VEGF
Kye Young Kim1, June Woo Lee, Byeong Woo Ahn
1Division of Cardiovascular Disease, Department of Biomedical Sciences, National Institute of Health, #5 Nokbun-dong, Eunpyung-gu, 122-701, Seoul, South Korea
Abstract:
The relation between transforming growth factor-beta (TGF-beta) and cyclooxygenase (COX) in hepatoma malignancy is not understood yet. To investigate regulation mechanism of endogenous TGF-beta on hepatoma, we established MH129F mouse hepatoma cell overexpressing the cytoplasmic domain of type II TGF-beta receptor (TRII). MH129F cell apoptosis was elevated almost 20% after 5 ng/ml TGF-beta1 treatment. However, soluble TRII-overexpressing cells (MH129F/TRIIs) did not show any change of growth pattern after TGF-beta1 treatment because MH129F/TRIIs cells blocked the growth inhibitory effect of TGF-beta1. In MH129F/TRIIs cells, expression of cycooxygenase-2 (COX-2) and bcl-2 was remarkably elevated, and then enhancement of COX-2 mediated induction of prostaglandin E(2) (PGE(2)) production up to 7-fold. Especially, vascular endothelial growth factor (VEGF) expression was regulated by COX-2 in MH129F/TRIIs cells, which were inhibited endogenous TGF-beta response. Implantation of 5x10(6) MH129F/TRIIs cells into nude mice showed the significantly enhanced tumor formation, and intensity of COX-2 expression was slightly higher in MH129F/TRIIs tumor section than control. Moreover, a strong antitumor response was observed in MH129F/TRIIs-bearing mice that were treated with a specific COX-2 inhibitor, celecoxib. Therefore, we suggest that COX-2 mediate the tumorigenicity of hepatoma cells blocking endogenous TGF-beta effect via VEGF regulation.
Insights
Transforming growth factor-beta (TGF-beta) normally inhibits hepatoma growth. However, cyclooxygenase-2 (COX-2) can block this effect, promoting tumor growth via vascular endothelial growth factor (VEGF) and responding to celecoxib treatment.
Area of Science:
- Hepatocellular carcinoma research
- Molecular oncology
- Cell signaling pathways
Background:
- The role of transforming growth factor-beta (TGF-beta) in hepatoma malignancy remains unclear.
- Investigating endogenous TGF-beta's regulatory mechanisms in hepatoma is crucial for understanding cancer progression.
Purpose of the Study:
- To elucidate the relationship between TGF-beta and cyclooxygenase (COX) in hepatoma.
- To explore how endogenous TGF-beta regulates hepatoma cells through COX pathways.
Main Methods:
- Established MH129F mouse hepatoma cells overexpressing the type II TGF-beta receptor (TRII).
- Treated cells with TGF-beta1 and analyzed apoptosis, growth patterns, and gene/protein expression (COX-2, bcl-2, PGE(2), VEGF).
- Implanted cells into nude mice and evaluated tumor formation, COX-2 expression, and response to celecoxib treatment.
Main Results:
- TGF-beta1 treatment increased apoptosis in MH129F cells but not in MH129F/TRIIs cells, indicating blocked growth inhibition.
- MH129F/TRIIs cells showed elevated COX-2, bcl-2, and PGE(2) production (up to 7-fold).
- COX-2 regulated VEGF expression in MH129F/TRIIs cells, and celecoxib treatment demonstrated a strong antitumor effect.
Conclusions:
- Cyclooxygenase-2 (COX-2) mediates hepatoma cell tumorigenicity by blocking endogenous TGF-beta effects.
- VEGF regulation by COX-2 is a key mechanism in this process.
- Targeting COX-2 with inhibitors like celecoxib shows promise for treating hepatoma.
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