Expression of nuclear progesterone receptors (nPRs), membrane progesterone receptors (mPRs) and progesterone receptor membrane components (PGRMCs) in the human endometrium after 6 months levonorgestrel low dose intrauterine therapy

Sletten, Elise Thoresen; Smaglyukova, Natalia; Ørbo, Anne; Sager, Georg

doi:10.1016/j.jsbmb.2020.105701

Cited by 8 publications

(7 citation statements)

References 35 publications

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“…Contrary to the literature, the current study observed no signi cant change in mRNA expression of PR in all three primary LNG resistant cells. Research has shown that LNG-IUS treatment can lead to downregulation of nuclear PRs (44) therefore, despite previous research showing PR to have the potential to predict negative response to treatment, it would not make an e cacious predictive biomarker due to its expression being somewhat reliant on treatment (44).…”

Section: Discussionmentioning

confidence: 99%

Characterisation of Levonorgestrel Resistant Endometrial Cancer cells

Dore

Filoche

Danielson

et al. 2021

Preprint

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Background Endometrial Cancer (EC) is the most common gynaecologic malignancy in the developed world, and incidence is increasing in premenopausal women. The Levonorgestrel Intrauterine System (LNG-IUS) is gaining traction as an alternative treatment for hyperplasia and early-stage EC for women who are unable to undergo surgery. Thirty to 50% of women do not respond to this treatment, making the unknown mechanisms of Levonorgestrel (LNG) resistance a critical obstacle for the conservative management of EC. This study aimed to characterise LNG-IUS treatment resistance in early-stage endometrial cancer in cell line models. Method: LNG resistant endometrial cancer cell lines (MFE296R and MFE319R) and cultures from three early stage endometrial cancer patients were developed. The behavioural profile of MFE296R and MFE319R were analysed using proliferation, adhesion, migration (wound healing and transwell) and invasion (spheroid) assays. LNG sensitive cell lines (MFE296S and MFE319S) were compared to LNGR cell lines (MFE296R and MFE319R). A literature search was conducted to identify possible candidate biomarkers of LNG resistance. RT-qPCR was used to analyse the mRNA expression of 17 candidate biomarkers in MFE296R and MFE319R. mRNA expression of the top differentially expressed genes was measured using RT-qPCR in primary cultures. Results LNG resistance did not affect proliferation or invasion in immortalised endometrial cancer cells, however significantly increased transwell migration in MFE319R cells (p = 0.03). LNG resistance led to a decrease in cellular adhesion in both MFE296R cells (p = 0.012) and MFE319R cells (p = 0.04) compared to LNG sensitive clones. mRNA expression of KLF4 and SATB2 was significantly amplified in MFE296R and MFE319R cells compared to their LNG sensitive clones. mRNA expression of KLF4 was significantly upregulated and mRNA expression of ER was significantly downregulated in LNG resistant primary cell lines compared to their LNG sensitive clones. Conclusion LNG resistant cells may be slightly more aggressive and therefore, have more oncogenic potential than their LNG sensitive counterparts. There were significant changes in the mRNA profile of LNG resistant cells compared to LNG sensitive cells, with relative expression of KLF4 and SATB2 significantly upregulated in resistant immortalised cell lines. This study presents promising preliminary results in biomarker discovery for guiding LNG-IUS treatment of early stage endometrial cancer.

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Section: Discussionmentioning

confidence: 99%

Characterisation of Levonorgestrel Resistant Endometrial Cancer cells

Dore

Filoche

Danielson

et al. 2021

Preprint

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“…Tissue and cellular mRNA was determined with RT-qPCR and used as a surrogate marker for receptor (protein) expression. The present data are connected to the related article entitled “Expression of nuclear progesterone receptors (nPRs), membrane progesterone receptors (mPRs) and progesterone receptor membrane components (PGRMCs) in the human endometrium after 6 months levonorgestrel low dose intrauterine therapy” [8] .…”

mentioning

confidence: 84%

Data on RT-qPCR assay of nuclear progesterone receptors (nPR), membrane progesterone receptors (mPR) and progesterone receptor membrane components (PGRMC) from human uterine endometrial tissue and cancer cells of the Uterine Cervix

et al. 2020

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A previous investigation showed that the endometrium normalized in women with endometrial hyperplasia after three months treatment with high dose levonorgestrel IUS (intrauterine system) [1] . The effect was maintained even if immunohistochemical analyses of the endometrium showed that nuclear progesterone receptors (nPRs) were completely downregulated. These observations indicated that some type of non-genomic effect existed [2] . We conducted new investigations of endometrial hyperplasia, now with 6 months low dose levonorgestrel IUS treatment. Again, the growth disturbances were reversed with normalization of the endometrium [ 3 , 4 ]. In the context of these studies, RT-qPCR analyses of the endometrium were performed before and after treatment, to determine expression of nuclear progesterone receptors (nPRA+ B and nPRB), membrane progesterone receptors (mPR, α-, β- and γ-subtypes) and progesterone receptor membrane components (PGRMC1and PGRMC2). The human cervical cell line (C-4 I) [5] with no detectable nPRs [ 6 , 7 ] , was included in the investigation as biological control .The gene expression of nPRs, mPRs and PGRMCs was determined in the logarithmic growth phase. Tissue and cellular mRNA was determined with RT-qPCR and used as a surrogate marker for receptor (protein) expression. The present data are connected to the related article entitled “Expression of nuclear progesterone receptors (nPRs), membrane progesterone receptors (mPRs) and progesterone receptor membrane components (PGRMCs) in the human endometrium after 6 months levonorgestrel low dose intrauterine therapy” [8] .

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“…Additionally, reduced PGRMC2, mPRα, mPRβ, and mPRγ expression has been observed in endometrial hyperplasia and endometriosis [ 11 , 162 , 163 ]. This finding confirms the role of PGRMC2 up-regulation in the secretory phase and how P4 acts through these receptors to inhibit cell proliferation.…”

Section: Pgr In the Uterusmentioning

confidence: 99%

“…Despite their unknown contribution to physiological P4 action in the human cervix, non-classical PGR seem to play a key role in premalignant and malignant diseases of the female cervix. For instance, lower PGRMC2 levels have been detected in nodal metastasis of uterine endocervical adenocarcinomas, which suggests a potential role of this receptor as a tumor suppressor [ 174 ], while mPRs have been detected in cervical cancer cell lines HeLa [ 54 ] and C4-I [ 162 ].…”

Section: Pgr In the Uterusmentioning

confidence: 99%

What Do We Know about Classical and Non-Classical Progesterone Receptors in the Human Female Reproductive Tract? A Review

Medina-Laver

Rodríguez-Varela

Salsano

et al. 2021

IJMS

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The progesterone hormone regulates the human menstrual cycle, pregnancy, and parturition by its action via the different progesterone receptors and signaling pathways in the female reproductive tract. Progesterone actions can be exerted through classical and non-classical receptors, or even a combination of both. The former are nuclear receptors whose activation leads to transcriptional activity regulation and thus in turn leads to slower but long-lasting responses. The latter are composed of progesterone receptors membrane components (PGRMC) and membrane progestin receptors (mPRs). These receptors rapidly activate the appropriate intracellular signal transduction pathways, and they can subsequently initiate specific cell responses or even modulate genomic cell responses. This review covers our current knowledge on the mechanisms of action and the relevance of classical and non-classical progesterone receptors in female reproductive tissues ranging from the ovary and uterus to the cervix, and it exposes their crucial role in female infertility.

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Expression of nuclear progesterone receptors (nPRs), membrane progesterone receptors (mPRs) and progesterone receptor membrane components (PGRMCs) in the human endometrium after 6 months levonorgestrel low dose intrauterine therapy

Cited by 8 publications

References 35 publications

Characterisation of Levonorgestrel Resistant Endometrial Cancer cells

Characterisation of Levonorgestrel Resistant Endometrial Cancer cells

Data on RT-qPCR assay of nuclear progesterone receptors (nPR), membrane progesterone receptors (mPR) and progesterone receptor membrane components (PGRMC) from human uterine endometrial tissue and cancer cells of the Uterine Cervix

What Do We Know about Classical and Non-Classical Progesterone Receptors in the Human Female Reproductive Tract? A Review

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