scholarly journals Prolactin Enhances the Proliferation of Proliferative Endometrial Glandular Cells and Endometrial Cancer Cells

2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Munekage Yamaguchi ◽  
Chimeddulam Erdenebaatar ◽  
Fumitaka Saito ◽  
Ritsuo Honda ◽  
Takashi Ohba ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Menstrual Cycle ◽  
Cell Lines ◽  
Estrogen Receptor Alpha ◽  
Prolactin Receptor ◽  
Receptor Expression ◽  
Serum Prolactin ◽  
Long Term Effects ◽  
Ishikawa Cells ◽  
Glandular Cells

Abstract To elucidate the mechanism of endometrial cancer (EC) development in young hyperprolactinemic women, this study assessed the hormonal receptor expression, proliferation, and signaling induced by prolactin in endometrial glands (EG) and EC. Prolactin receptor (PRLR) and estrogen receptor alpha (ER-α) in EG were evaluated during the menstrual cycle by immunohistochemistry. The following parameters were compared between EM-E6/E7/TERT cells, which originated from proliferative EG and Ishikawa cells. The expression levels of PRLR, pJAK2 (phosphorylated Janus Activating Kinase 2), its downstream pathways (MAPK, PI3K, and STAT), and ER-α were assessed after adding prolactin by Western blotting. U0126 was used as a MAPK inhibitor. The proliferation caused by estradiol was also examined by MTS assay after adding prolactin. PRLR expression in the EG was significantly higher in the proliferative phase than in the secretory phase, and it was correlated with ER-α expression during the menstrual cycle. After adding prolactin, the expression of pJAK2, PRLR and ER-α was significantly increased in both cell lines, MAPK was activated after adding prolactin in both cell lines, and PI3K and STAT were activated only in EM-E6/E7/TERT cells. The increased proliferation induced by estradiol was enhanced after adding prolactin in both cell lines. All changes caused by prolactin were inhibited in Ishikawa cells pretreated with U0126. Long-term effects of serum prolactin on persistent proliferative endometrium in the presence of estradiol may induce abnormal proliferation of EG in hyperprolactinemic women. Prolactin-PRLR signaling via MAPK may play a crucial role in the progression of EC in hyperprolactinemic women.

scholarly journals Sirtuin 2 in Endometrial Cancer: A Potential Regulator for Cell Proliferation, Apoptosis and RAS/ERK Pathway

2020 ◽  
Vol 19 ◽  
pp. 153303382098078
Author(s):  
Yanjuan Guo ◽  
Nannan Zhao ◽  
Jianli Zhou ◽  
Jianxin Dong ◽  
Xing Wang
Keyword(s):  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Western Blot ◽  
Cell Line ◽  
Cell Lines ◽  
Erk Pathway ◽  
Uterine Epithelial Cell ◽  
Knock Down ◽  
Ishikawa Cells ◽  
And Control

Objective: The present study aimed to explore the function of sirtuin 2 (SIRT2) on cell proliferation, apoptosis, rat sarcoma virus (RAS)/ extracellular signal-regulated kinase (ERK) pathway in endometrial cancer (EC). Methods: SIRT2 expression in human EC cell lines and human endometrial (uterine) epithelial cell (HEEC) line was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. SIRT2 knock-down and control knock-down plasmids were transfected into HEC1A cells, respectively; SIRT2 overexpression and control overexpression plasmids were transfected into Ishikawa cells, respectively. After transfection, SIRT2, HRas proto-oncogene, GTPase (HRAS) expressions were evaluated by RT-qPCR and western blot. ERK and phosphorylated ERK (pERK) expressions were evaluated by western blot. Meanwhile, cell proliferation and cell apoptosis were measured. Results: Compared to normal HEEC cell line, SIRT2 mRNA and protein expressions were increased in most human EC cell lines (including HEC1A, RL952 and AN3CA), while were similar in Ishikawa cell line. In HEC1A cells, SIRT2 knock-down decreased cell proliferation but increased apoptosis. In Ishikawa cells, SIRT2 overexpression induced cell proliferation but inhibited apoptosis. For RAS/ERK pathway, SIRT2 knock-down reduced HRAS and inactivated pERK in HEC1A cells, whereas SIRT2 overexpression increased HRAS and activated pERK in Ishikawa cells, suggesting that SIRT2 was implicated in the regulation of RAS/ERK pathway in EC cells. Conclusion: SIRT2 contributes to the EC tumorigenesis, which appears as a potential therapeutic target.

scholarly journals Hsa_Circ_0001860 Promotes Smad7 to Enhance MPA Resistance in Endometrial Cancer via miR-520h

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuang Yuan ◽  
Panchan Zheng ◽  
Xiao Sun ◽  
Judan Zeng ◽  
Wenjiao Cao ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Lines ◽  
Noncoding Rna ◽  
Histological Grade ◽  
Human Tumor ◽  
Circular Rna ◽  
Resistant Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Ishikawa Cells

Background: Medroxyprogesterone acetate (MPA) is one of the most commonly prescribed progestin for the treatment of endometrial cancer (EC). Despite initial benefits, many patients ultimately develop progesterone resistance. Circular RNA (circRNA) is a kind of noncoding RNA, contributing greatly to the development of human tumor. However, the role of circular RNA in MPA resistance is unknown.Methods: We explored the expression profile of circRNAs in Ishikawa cells treated with (ISK/MPA) or without MPA (ISK) by RNA sequencing, and identified a key circRNA, hsa_circ_0001860. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verify its expression in MPA-resistant cell lines and tissues. CCK8, Transwell, and flow cytometry were used to evaluate the functional roles of hsa_circ_0001860 in MPA resistance. The interaction between hsa_circ_0001860 and miR-520 h was confirmed by bioinformatics analysis, luciferase reporter assay, and RNA pull-down assay.Results: The expression of hsa_circ_0001860 was significantly downregulated in MPA-resistant cell lines and tissues, and negatively correlated with lymph node metastasis and histological grade of EC. Functional analysis showed that hsa_circ_0001860 knockdown by short hairpin RNA (shRNA) promoted the proliferation, inhibited the apoptosis of Ishikawa cells, and promoted the migration and invasion of Ishikawa cells treated with MPA. Mechanistically, hsa_circ_0001860 promoted Smad7 expression by sponging miR-520 h.Conclusion: Hsa_circ_0001860 plays an important role in the development of MPA resistance in EC through miR-520h/Smad7 axis, and it could be targeted to reverse the MPA resistance in endometrial cancer.

Serum Prolactin Contributes to Enhancing Prolactin Receptor and pJAK2 in Type I Endometrial Cancer Cells in Young Women Without Insulin Resistance

2019 ◽  
Vol 38 (4) ◽  
pp. 318-325 ◽  
Author(s):  
Chimeddulam Erdenebaatar ◽  
Munekage Yamaguchi ◽  
Mahina Monsur ◽  
Fumitaka Saito ◽  
Ritsuo Honda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endometrial Cancer ◽  
Cancer Cells ◽  
Young Women ◽  
Prolactin Receptor ◽  
Serum Prolactin ◽  
Type I

scholarly journals Hsa-circ-0001860 promotes Smad7 to enhance MPA resistance in endometrial cancer via miR-520h

2020 ◽  
Author(s):  
Shuang Yuan ◽  
Panchan Zheng ◽  
Judan Zeng ◽  
Xiao Sun ◽  
Lihua Wang
Keyword(s):  
Endometrial Cancer ◽  
Cell Lines ◽  
Noncoding Rna ◽  
Histological Grade ◽  
Human Tumor ◽  
Circular Rna ◽  
Resistant Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Ishikawa Cells

Abstract Background Medroxyprogesterone acetate (MPA) is one of the most commonly prescribed progestin for the treatment of endometrial cancer (EC). Despite initial benefits, many patients ultimately develop progesterone resistance. Circular RNA (circRNA) is a kind of noncoding RNA, contributing greatly to the development of human tumor. However, the role of circular RNA in MPA resistance is unknown. Methods We explored the expression profile of circRNAs in Ishikawa cells treated with (ISK/MPA) or without MPA (ISK) by RNA sequencing, and identified a key circRNA hsa_circ_0001860. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verify its expression in MPA-resistant cell lines and tissues. CCK8, Transwell and flow cytometry were used to evaluate the functional roles of hsa_circ_0001860 in MPA resistance. The interaction between hsa_circ_0001860 and miR-520h was confirmed by bioinformatics analysis and luciferase reporter assay. Results The expression of hsa_circ_0001860 was significantly downregulated in MPA-resistant cell lines and tissues, and negatively correlated with lymph node metastasis and histological grade of EC. Functional analysis showed that hsa_circ_0001860 knockdown by shRNA promoted the proliferation, migration and invasion and inhibited the apoptosis of Ishikawa cells treated with MPA. Mechanistically, hsa_circ_0001860 promoted Smad7 expression by sponging miR-520h. Conclusion Hsa_circ_0001860 plays an important role in the development of MPA resistance in EC through miR-520h / Smad7 axis, and it could be targeted to reverse the MPA resistance in endometrial cancer.

scholarly journals Alternatively Constructed Estrogen Receptor Alpha-Driven Super-Enhancers Result in Similar Gene Expression in Breast and Endometrial Cell Lines

2020 ◽  
Vol 21 (5) ◽  
pp. 1630 ◽  
Author(s):  
Dóra Bojcsuk ◽  
Gergely Nagy ◽  
Bálint László Bálint
Keyword(s):  
Estrogen Receptor ◽  
Cell Lines ◽  
Estrogen Receptor Alpha ◽  
Receptor Alpha ◽  
Highly Active ◽  
Ishikawa Cells ◽  
Cell Type Specific ◽  
The Individual ◽  
Similar Gene ◽  
Mcf 7

Super-enhancers (SEs) are clusters of highly active enhancers, regulating cell type-specific and disease-related genes, including oncogenes. The individual regulatory regions within SEs might be simultaneously bound by different transcription factors (TFs) and co-regulators, which together establish a chromatin environment conducting to effective transcription. While cells with distinct TF profiles can have different functions, how different cells control overlapping genetic programs remains a question. In this paper, we show that the construction of estrogen receptor alpha-driven SEs is tissue-specific, both collaborating TFs and the active SE components greatly differ between human breast cancer-derived MCF-7 and endometrial cancer-derived Ishikawa cells; nonetheless, SEs common to both cell lines have similar transcriptional outputs. These results delineate that despite the existence of a combinatorial code allowing alternative SE construction, a single master regulator might be able to determine the overall activity of SEs.

Evidence for oestrogenic regulation of heat shock protein expression in human endometrium and steroid-responsive cell lines

1995 ◽  
Vol 133 (5) ◽  
pp. 598-605 ◽  
Author(s):  
Pei-Zhong Tang ◽  
Michael J Gannon ◽  
Alison Andrew ◽  
David Miller
Keyword(s):  
Menstrual Cycle ◽  
Heat Shock ◽  
Progesterone Receptor ◽  
Heat Shock Protein ◽  
Protein Expression ◽  
Cell Lines ◽  
Oestrogen Receptor ◽  
Receptor Expression ◽  
Heat Shock Protein Expression ◽  
Responsive Cell

Tang P-Z, Gannon MJ, Andrew A, Miller D. Evidence for oestrogenic regulation of heat shock protein expression in human endometrium and steroid-responsive cell lines. Eur J Endocrinol 1995;133:598–605. ISSN 0804–4643 Gene amplification with target-specific primers (reverse-transcription polymerase chain reaction (RTPCR)) was used to monitor the relative expression of oestrogen and progesterone receptor mRNAs alongside the mRNAs for heat shock proteins HSP 90α, HSP 90β and HSP 70a in normal samples of human endometrial tissue over the whole menstrual cycle and in short-term cultures of steroidresponsive (T47-D) and unresponsive (HRT-18) cell lines exposed to oestradiol and progesterone over a 24-h incubation period. In endometrium, oestrogen and progesterone receptors followed the expected patterns of expression at the protein level during the menstrual cycle and also showed a positive correlation of expression with each other throughout (r = 0.514). Of the HSPs only HSP 90α expression correlated positively with oestrogen receptor (r = 0.687), while HSP 70a expression, which peaked in the late secretory stage, displayed a significantly inverse correlation with HSP 90β expression (r = −0.526). All p values < 0.05. In T47-D cell cultures, oestrogen receptor expression was stimulated transiently by oestradiol (10−7 mol/l) and more persistently by progesterone (10−7 mol/l). Progesterone receptor expression was depressed by progesterone and weakly stimulated by oestradiol. HSP 70a and HSP 90α expression were stimulated by oestradiol. Progesterone generally depressed HSP 90α expression and simultaneous addition of both oestradiol and progesterone to the culture medium was antagonistic to HSP 90α expression. No clear effect of agonist addition on HSP mRNA expression was apparent in the HRT-18 cultures. A possible mechanism for observed oestrogenic effects on HSP expression is put forward. David Miller, Institute of Pathology, Department of Clinical Medicine, Algernon Firth Building, University of Leeds, Leeds, LS2 9JT UK

scholarly journals The Regulation and Function of the Forkhead Transcription Factor, Forkhead Box O1, Is Dependent on the Progesterone Receptor in Endometrial Carcinoma

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1942-1950 ◽  
Author(s):  
Erin C. Ward ◽  
Anna V. Hoekstra ◽  
Leen J. Blok ◽  
P. Hanifi-Moghaddam ◽  
John R. Lurain ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Progesterone Receptor ◽  
Cell Lines ◽  
Type I ◽  
Ishikawa Cell ◽  
Protein Levels ◽  
Forkhead Box ◽  
Ishikawa Cells ◽  
Presence And Absence ◽  
And Function

In many type I endometrial cancers, the PTEN gene is inactivated, which ultimately leads to constitutively active Akt and the inhibition of Forkhead box O1 (FOXO1), a member of the FOXO subfamily of Forkhead/winged helix family of transcription factors. The expression, regulation, and function of FOXO1 in endometrial cancer were investigated in this study. Immunohistochemical analysis of 49 endometrial tumor tissues revealed a decrease of FOXO1 expression in 95.9% of the cases compared with the expression in normal endometrium. In four different endometrial cancer cell lines (ECC1, Hec1B, Ishikawa, and RL95), FOXO1 mRNA was expressed at similar levels; however, protein levels were low or undetectable in Ecc1, Ishikawa, and RL95 cells. Using small interfering RNA technology, we demonstrated that the low levels of FOXO1 protein were due to the involvement of Skp2, an oncogenic subunit of the Skp1/Cul1/F-box protein ubiquitin complex, given that silencing Skp2 increased FOXO1 protein expression in Ishikawa cells. Inhibition of Akt in Ishikawa cells also increased nuclear FOXO1 protein levels. Additionally, progestins increased FOXO1 protein levels, specifically through progesterone receptor B (PRB) as determined by using stably transfected PRA-specific and PRB-specific Ishikawa cell lines. Finally, overexpression of triple mutant (Tm) FOXO1 in the PR-specific Ishikawa cell lines caused cell cycle arrest and significantly decreased proliferation in the presence and absence of the progestin, R5020. Furthermore, TmFOXO1 overexpression induced apoptosis in PRB-specific cells in the presence and absence of ligand. Taken together, these data provide insight into the phosphoinositide-3-kinase/Akt/FOXO pathway for the determination of progestin responsiveness and the development of alternate therapies for endometrial cancer.

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