Up-regulation of genes involved in the insulin signalling pathway (IGF1, PTEN and IGFBP1) in the endometrium may link polycystic ovarian syndrome and endometrial cancer

Shafiee, Mohamad Nasir; Seedhouse, Claire; Mongan, Nigel P.; Chapman, Caroline; Deen, Suha; Abu, Jafaru; Atiomo, William

doi:10.1016/j.mce.2016.01.019

Cited by 67 publications

(59 citation statements)

References 26 publications

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“…Consistent with these, our results suggested that induction of IGFBP1 was required in stimulating the solamargine-inhibited NSCLC growth. However, opposite results were also observed in other cancer types, such as prostate cancer [33, 34] and endometrial cancer [35]. Thus, the true functions of IGFBP1 acting as a tumor suppressor or oncogene may depend upon the capacity of environmental context, and agents exposed, which required to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…We previously observed that ursolic acid, a natural pentacyclic triterpenoid, and emodin, one anthraquinones constituents derivative isolated from the roots of rheum palmatuma, inhibited growth of hepatocellular carcinoma and lung cancer cells through induction of IGFBP1 gene expression, suggesting tumor suppressing role of this molecule [31, 32]. However, conflicting results were observed in other cancer types, such as prostate [33, 34] and endometrial cancer [35] and others [36]. Thus, IGFBP1 may play dual roles depending upon the environmental content, cells examined, and agents exposed.…”

Section: Introductionmentioning

confidence: 99%

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Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1

Tang

Zheng

et al. 2017

Cell Physiol Biochem

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Background/Aims: Solamargine, one natural photochemical component from traditional plants, has been shown to have anti-cancers properties. We previously showed that solamargine inhibited the growth of non-small-cell lung cancer (NSCLC) cells through suppression of prostaglandin E2 (PGE₂) receptor EP4 gene and regulation of downstream signaling pathways. However, the detailed mechanism underlying this, especially in combination of metformin, a known AMPK activator, still remained to be determined. Methods: Cell viability was measured using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colorimetric 5-bromo-2-deoxyuridine (BrdU) ELISA methods, respectively. Western blot analysis and immunohistochemistry were performed to examine the phosphorylation and protein expressions of signal transducer and activator of transcription 3 (Stat3), SP1, forkhead box O3a (FOXO3a), and insulin-like growth factor (IGF)-IGF binding protein 1 (IGFBP1). The expression of IGFBP1 mRNA was measured by quantitative real time PCR (qRT-PCR). Silencing of FOXO3a and IGFBP1 were examined by siRNA procedures. Exogenously expression of SP1, FOXO3a, and IGFBP1 were carried out by transient transfection assays. The promoter activity of IGFBP1 was tested using Secrete-Pair^TM Dual Luminescence Assay Kit. A xenografted tumor model was used to further test the effect of solamargine in combining with metformin in vivo. Results: We further demonstrated that solamargine inhibited growth and induced cell cycle arrest in other NSCLC cell lines. Through mechanism-based approaches, we showed that solamargine decreased the phosphorylation of Stat3; In addition, solamargine induced FOXO3a, whereas reduced SP1 protein levels; all of which were abrogated in cells with overexpressed Stat3 gene. Interestingly, there is interaction between FOXO3a and SP1. Moreover, solamargine increased mRNA, protein expression and promoter activity of IGFBP1, which was not observed in cells with overexpressed SP1 or with silenced FOXO3a genes. Finally, ablation of IGFBP1 expression by siRNA blocked the effect of solamargine on cell growth inhibition. More importantly, there was a synergy of combination of solamargine and metformin. Similar findings were also observed in vivo. Conclusion: Our results show that solamargine increases IGFBP1 gene expression through inactivation of Stat3, followed by regulation and reciprocal interaction of FOXO3a and SP1 in vitro and in vivo. This ultimately leads to suppression of human lung cancer cell growth. Moreover, this is a synergy of solamargine in combination with metformin in this process. This study unravels a novel mechanism underlying the anti-lung cancer effects of solamargine in combination of metformin, and suggests a potential new lung cancer associated therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1

Tang

Zheng

et al. 2017

Cell Physiol Biochem

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“…As published , a total of 102 participants were recruited into three groups (women with PCOS, women with EC, and controls) with 34 participants in each group. Women with PCOS were diagnosed using the Rotterdam criteria and were aged between 18 and 45 years.…”

Section: Methodsmentioning

confidence: 96%

“…The life cycler 480 ® (CA, USA) machine was used to perform the qPCR analysis. The β‐actin gene was selected as a housekeeping gene to normalize differences in the quantity of RNA in each sample in comparison to the gene of interest ( SREBP1 ). To ensure a high degree of precision, every sample was made in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Sterol regulatory element binding protein‐1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer

Shafiee

Mongan

Seedhouse

et al. 2017

Acta Obstet Gynecol Scand

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Introduction Women with polycystic ovary syndrome have a three‐fold higher risk of endometrial cancer. Insulin resistance and hyperlipidemia may be pertinent factors in the pathogenesis of both conditions. The aim of this study was to investigate endometrial sterol regulatory element binding protein‐1 gene expression in polycystic ovary syndrome and endometrial cancer endometrium, and to correlate endometrial sterol regulatory element binding protein‐1 gene expression with serum lipid profiles. Material and methods A cross‐sectional study was performed at Nottingham University Hospital, UK. A total of 102 women (polycystic ovary syndrome, endometrial cancer and controls; 34 participants in each group) were recruited. Clinical and biochemical assessments were performed before endometrial biopsies were obtained from all participants. Taqman real‐time polymerase chain reaction for endometrial sterol regulatory element binding protein‐1 gene and its systemic protein expression were analyzed. Results The body mass indices of women with polycystic ovary syndrome (29.28 ± 2.91 kg/m2) and controls (28.58 ± 2.62 kg/m2) were not significantly different. Women with endometrial cancer had a higher mean body mass index (32.22 ± 5.70 kg/m2). Sterol regulatory element binding protein‐1 gene expression was significantly increased in polycystic ovary syndrome and endometrial cancer endometrium compared with controls (p < 0.0001). Sterol regulatory element binding protein‐1 gene expression was positively correlated with body mass index (r = 0.017, p = 0.921) and waist–hip ratio (r = 0.023, p = 0.544) in polycystic ovary syndrome, but this was not statistically significant. Similarly, statistically insignificant positive correlations were found between endometrial sterol regulatory element binding protein‐1 gene expression and body mass index in endometrial cancer (r = 0.643, p = 0.06) and waist–hip ratio (r = 0.096, p = 0.073). Sterol regulatory element binding protein‐1 gene expression was significantly positively correlated with triglyceride in both polycystic ovary syndrome and endometrial cancer (p = 0.028 and p = 0.027, respectively). Quantitative serum sterol regulatory element binding protein‐1 gene correlated with endometrial gene expression (p < 0.05). Conclusions Sterol regulatory element binding protein‐1 gene expression is significantly increased in the endometrium of women with polycystic ovary syndrome and women with endometrial cancer compared with controls and positively correlates with serum triglyceride in both polycystic ovary syndrome and endometrial cancer.

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“…PCOS is the commonest female endocrinopathy and women with PCOS have a 3 to 4 fold increased risk of EC. Pilot data from Nottingham suggests that this is possibly through elevated IGF1 levels [1]. However, the role of IGF1 in increasing EC risk in PCOS is yet to be firmly established as the competing roles of IGF-1 and PCOS on the risk of EC are unclear.…”

Section: Introductionmentioning

confidence: 99%

Investigating the Mechanisms of Endometrial Cancer Risk in Polycystic Ovary Syndrome: Can UK Biobank Help?

Atiomo¹,

Karanam²,

Sian³

et al. 2017

OGIJ

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Background: UK biobank was set up to investigate the respective contributions of genetic predisposition and environmental exposure to the development of disease and recruited participants between 2006 and 2010. Our aim was to investigate the feasibility of using UK biobank for exploring the association between polycystic ovarian syndrome (PCOS) and endometrial cancer, including the role played by serum IGF-1 levels. Methods:Publicly accessible and freely available online data in the resource section of the UK biobank website were used to determine the prevalence of selfreported PCOS and for assessing the quality of data on ovarian imaging and serum biomarkers. A literature review was conducted to compare rates of PCOS in UK Biobank with other populations.Results: UK biobank contains 273,469 women (age range 37-73 years) of whom 643 (0.23%) self-reported PCOS. This was compared with values ranging from 3.1 % to 19.9% obtained from 16 studies picked up by our systematic literature search. Conclusion:It is feasible to use UK biobank to conduct research into the role of IGF-1 in explaining the association between PCOS and endometrial cancer. More detailed phenotyping of women recruited into the diagnostic group of PCOS is, however, vital to underpin this research. The resulting resource would be excellent for researchers interested in exploring the long-term health risks associated with PCOS.

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Up-regulation of genes involved in the insulin signalling pathway (IGF1, PTEN and IGFBP1) in the endometrium may link polycystic ovarian syndrome and endometrial cancer

Cited by 67 publications

References 26 publications

Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1

Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1

Sterol regulatory element binding protein‐1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer

Investigating the Mechanisms of Endometrial Cancer Risk in Polycystic Ovary Syndrome: Can UK Biobank Help?

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