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A functional role of LEFTY during progesterone therapy for endometrial carcinoma
- Source :
- Cell Communication and Signaling : CCS, Cell Communication and Signaling, Vol 15, Iss 1, Pp 1-15 (2017)
- Publication Year :
- 2017
- Publisher :
- BioMed Central, 2017.
-
Abstract
- Background The left-right determination factor (LEFTY) is a novel member of the TGF-β/Smad2 pathway and belongs to the premenstrual/menstrual repertoire in human endometrium, but little is known about its functional role in endometrial carcinomas (Em Cas). Herein, we focused on LEFTY expression and its association with progesterone therapy in Em Cas. Methods Regulation and function of LEFTY, as well as its associated molecules including Smad2, ovarian hormone receptors, GSK-3β, and cell cycle-related factors, were assessed using clinical samples and cell lines of Em Cas. Results In clinical samples, LEFTY expression was positively correlated with estrogen receptor-α, but not progesterone receptor (PR), status, and was inversely related to phosphorylated (p) Smad2, cyclin A2, and Ki-67 levels. During progesterone therapy, expression of LEFTY, pSmad2, and pGSK-3β showed stepwise increases, with significant correlations to morphological changes toward secretory features and decreased Ki-67 values. In Ishikawa cells, an Em Ca cell line that expresses PR, progesterone treatment reduced proliferation and induced increased expression of LEFTY and pGSK-3β, although LEFTY promoter regions were inhibited by transfection of PR. Moreover, inhibition of GSK-3β resulted in increased LEFTY expression through a decrease in its ubiquitinated form, suggesting posttranslational regulation of LEFTY protein via GSK-3β suppression in response to progesterone. In addition, overexpression or knockdown of LEFTY led to suppression or enhancement of Smad2-dependent cyclin A2 expression, respectively. Conclusion Upregulation of LEFTY may serve as a useful clinical marker for the therapeutic effects of progesterone for Em Cas, leading to inhibition of tumor cell proliferation through alteration in Smad2-dependent transcription of cyclin A2. Electronic supplementary material The online version of this article (10.1186/s12964-017-0211-0) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
TGF-β
Adult
medicine.drug_class
Lefty
Left-Right Determination Factors
Cyclin A
lcsh:Medicine
Endometrial carcinoma
Smad2 Protein
Biochemistry
03 medical and health sciences
Endometrium
Young Adult
0302 clinical medicine
Downregulation and upregulation
Cell Line, Tumor
Progesterone receptor
medicine
Humans
lcsh:QH573-671
Receptor
Molecular Biology
Progesterone
Smad
Gene knockdown
Progesterone therapy
biology
lcsh:Cytology
Chemistry
Research
lcsh:R
Cell Cycle
Estrogen Receptor alpha
Cell Biology
Cyclin a
Endometrial Neoplasms
Gene Expression Regulation, Neoplastic
030104 developmental biology
Estrogen
030220 oncology & carcinogenesis
Cancer research
biology.protein
Female
Receptors, Progesterone
Cyclin A2
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1478811X
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Cell Communication and Signaling : CCS
- Accession number :
- edsair.doi.dedup.....753702526109d467d7a23281d1f71b33