Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma

Flannery, Clare; Saleh, Farrah L.; Choe, Gina; Selen, Daryl J.; Kodaman, Pinar H.; Kliman, Harvey J.; Wood, Teresa L.; Taylor, Hugh S.

doi:10.1210/jc.2016-1795

Cited by 28 publications

(20 citation statements)

References 42 publications

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“…IR-A was overexpressed during the normal proliferative phase (20-fold more than IR-B) in 87 women with either normal, or hyperplastic or neoplastic endometrium, suggesting that IR-A overexpression may be a mechanism involved in estrogen-independent endometrial proliferation [ 37 ]. In women with normal glucose tolerance or type 2 diabetes, IR-A was overexpressed in 75.7% endometrial cancer specimens compared to 35% of normal endometrial specimens and IR-A activation was documented to promote cancer cell growth [ 36 ].…”

Section: Deregulation Of Ir In Cancermentioning

confidence: 99%

Insulin Receptor Isoforms in Cancer

Vella

Milluzzo

Scalisi

et al. 2018

IJMS

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The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.

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Section: Deregulation Of Ir In Cancermentioning

confidence: 99%

Insulin Receptor Isoforms in Cancer

Vella

Milluzzo

Scalisi

et al. 2018

IJMS

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“…Furthermore, either E 2 or P 4 showed an inhibitory effect on the uterine Ndrg1 mRNA and protein expression levels, whereas combined E 2 and P 4 inhibited only the protein expression level in ovariectomized mice (Figure b), which is consistent with the previously reported inhibitory effects of estrogen on NDRG1 expression in estrogen receptor alpha (ERα)‐positive human breast cancer cells (Fotovati et al, ). In the human menstrual cycle, the high levels of E 2 promote epithelial cell proliferation in the proliferation phase, and during the secretory phase, the increased levels of P 4 , together with E 2 , trigger stromal cell proliferation, and epithelial and stromal cell differentiation (Flannery et al, ). Because the endometrial NDRG1 expression level in the secretory phase was higher than it was in the proliferation phase (Malette et al, ), we hypothesized that, under the influence of combined E 2 and P 4 in the estrous phase in mice or the secretory phase in humans, uterine NDRG1 expression would increase to promote the differentiation of epithelial and/or stromal cells to prepare for embryo implantation.…”

Section: Discussionmentioning

confidence: 99%

Decreased NDRG1 expression is associated with pregnancy loss in mice and attenuates the in vitro decidualization of endometrial stromal cells

Meng

Yang

et al. 2019

Molecular Reproduction Devel

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Embryo implantation is an essential step for a successful pregnancy, and any defect in this process can lead to a range of pregnancy pathologies. The objective of this study was to explore the role of N‐myc downregulated gene 1 (NDRG1) in embryo implantation. It was found that uterine NDRG1 expression has a dynamic pattern during the estrous cycle in nonpregnant mice and that uterine NDRG1 expression was elevated during the implantation process in pregnant mice. The distinct accumulation of NDRG1 protein signals was observed in the primary decidual zone adjacent to the implanting embryo during early pregnancy. Furthermore, uterine NDRG1 expression could be induced by activated implantation or artificial decidualization in mice. Decreased uterine NDRG1 expression was associated with pregnancy loss in mice and was associated with recurrent miscarriages in humans. The in vitro decidualization of both mouse and human endometrial stromal cells (ESCs) was accompanied by increased NDRG1 expression and downregulated NDRG1 expression in ESCs effectively inhibited decidualization. Collectively, these data suggest that NDRG1 plays an important role in decidualization during the implantation process, and the abnormal expression of NDRG1 may be involved in pregnancy loss.

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“…However, no comparisons between clinical types I and II of EC, or between particular EC histotypes, were made, making the interpretation of these results somewhat difficult. On the contrary, Flannery et al found that INSR-B expression was increased in non-diabetic patients both in complex endometrial hyperplasia and EC, relative to normal tissue [54].…”

Section: Insulin Receptormentioning

confidence: 92%

Insulin Resistance and Endometrial Cancer: Emerging Role for microRNA

Sidorkiewicz

Jóźwik

Niemira

et al. 2020

Cancers

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Endometrial cancer (EC) remains one of the most common cancers of the female reproductive system. Epidemiological and clinical data implicate insulin resistance (IR) and its accompanying hyperinsulinemia as key factors in the development of EC. MicroRNAs (miRNAs) are short molecules of non-coding endogenous RNA that function as post-transcriptional regulators. Accumulating evidence has shown that the miRNA expression pattern is also likely to be associated with EC risk factors. The aim of this work was the verification of the relationships between IR, EC, and miRNA, and, as based on the literature data, elucidation of miRNA’s potential utility for EC prevention in IR patients. The pathways affected in IR relate to the insulin receptors, insulin-like growth factors and their receptors, insulin-like growth factor binding proteins, sex hormone-binding globulin, and estrogens. Herein, we present and discuss arguments for miRNAs as a plausible molecular link between IR and EC development. Specifically, our careful literature search indicated that dysregulation of at least 13 miRNAs has been ascribed to both conditions. We conclude that there is a reasonable possibility for miRNAs to become a predictive factor of future EC in IR patients.

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Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma

Cited by 28 publications

References 42 publications

Insulin Receptor Isoforms in Cancer

Insulin Receptor Isoforms in Cancer

Decreased NDRG1 expression is associated with pregnancy loss in mice and attenuates the in vitro decidualization of endometrial stromal cells

Insulin Resistance and Endometrial Cancer: Emerging Role for microRNA

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