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Published on: October 27, 2020
TGF-beta signaling is disrupted in endometrioid-type endometrial carcinomas
Dagmara Piestrzeniewicz-Ulanska1, Magdalena Brys, Andrzej Semczuk
1Department of Cytobiochemistry, University of Lodz, 90-237 Lodz, Poland. kalaiste@poczta.wp.pl
Objective:
Previous studies have demonstrated deregulation of the expression and changes in the intracellular distribution of TGF-beta pathway components in human endometrial cancer (EC). The aim of this study was to assess the relationship between the expression of TGF-beta cascade components, including TGF-beta receptor type I (TGF beta RI) and type II (TGF beta RII), SMAD2, SMAD3, SMAD4, and clinicopathological features--tumor grade, FIGO classification, and depth of myometrial invasion--of type I (endometrioid-type) ECs to give some insight into the role of TGF-beta cascade components in endometrial tumorigenesis.
Methods:
The expression of TGF beta RI, TGF beta RII, SMAD2, SMAD3, and SMAD4 was evaluated both at the mRNA and protein level using reverse transcription polymerase chain reaction (RT-PCR) and ELISA, respectively.
Results:
Infiltrating endometrial carcinomas (less and more than half of the myometrial wall thickness) express significantly higher TGF beta RII protein level compared with non-infiltrating tumors (P = 0.04 and P = 0.01, respectively). Decreased level of SMAD2 and SMAD4 mRNAs was observed in the uterine tumors infiltrating less and more than half of the myometrial wall (P = 0.03 and P = 0.02, respectively) compared with noninfiltrating ECs. Significantly higher SMAD4 protein level in the cytoplasmic fraction of ECs was found when tumor grade and depth of myometrial invasion were considered (P < 0.05). Generally, tumor progression was associated with a decreased number of cases characterized by the presence of SMADs in the nuclear fraction only.
Conclusion:
Our data suggest that disturbances of the TGF beta RII and SMAD4 expression as well as localization of SMADs may be important to the infiltration of the myometrial wall by the type I endometrial carcinomas.
Insights
Disturbances in TGF-beta receptor type II (TGF beta RII) and SMAD4 expression and SMAD localization are linked to myometrial wall invasion in endometrial cancer (EC). These findings offer insight into endometrial tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Endometrial cancer (EC) shows altered expression and distribution of TGF-beta pathway components.
- Understanding the role of TGF-beta signaling in EC tumorigenesis is crucial.
Purpose of the Study:
- To investigate the relationship between TGF-beta cascade components (TGF beta RI, TGF beta RII, SMAD2, SMAD3, SMAD4) and clinicopathological features in type I EC.
- To elucidate the role of these components in endometrial tumorigenesis.
Main Methods:
- Evaluated mRNA and protein levels of TGF beta RI, TGF beta RII, SMAD2, SMAD3, and SMAD4.
- Utilized reverse transcription polymerase chain reaction (RT-PCR) and ELISA for expression analysis.
Main Results:
- Higher TGF beta RII protein levels were observed in infiltrating EC compared to non-infiltrating tumors.
- Decreased SMAD2 and SMAD4 mRNA levels correlated with myometrial invasion.
- Increased cytoplasmic SMAD4 protein and reduced nuclear SMAD localization were associated with tumor progression.
Conclusions:
- Alterations in TGF beta RII and SMAD4 expression and SMAD localization are implicated in myometrial invasion in type I EC.
- These molecular changes may play a significant role in endometrial cancer progression.
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