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      Inhibition of microRNA-19b promotes ovarian granulosa cell proliferation by targeting IGF-1 in polycystic ovary syndrome

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          Abstract

          The purpose of the present study was to investigate the functional role of microRNA (miR)-19b in polycystic ovary syndrome (PCOS) and try to elucidate its underlying mechanisms. Expression of miR-19b and insulin-like growth factor 1 (IGF-1) was examined in ovarian cortexes [(from 18 women with PCOS and 10 who did not have PCOS (non-PCOS)] and KGN cells. Cell proliferation assays (cell viability and colony formation assay) were performed following overexpression or inhibition of miR-19b and IGF-1 or following insulin treatment in KGN cells. Expression levels of the cell cycle-associated protein cyclin D1 and cyclin-dependent kinase (CDK) 1 were analyzed following overexpression or inhibition of miR-19b and IGF-1. Potential miR-19b targets were identified by bioinformatics. Luciferase assay, reverse transcription-quantitative polymerase chain reaction and western blotting were performed to determine whether IGF-1 was a target of miR-19b. miR-19b expression was significantly decreased in the PCOS ovarian cortex and KGN cells and its identified target, IGF-1, was upregulated. miR-19b overexpression inhibited cell proliferation at G 2/M phrase. Overexpression of IGF-1 promoted cell viability and colony formation ability in KGN cells. The expression of cyclin D1 and CDK1 was statistically increased by inhibition of miR-19b and overexpression of IGF-1. High concentrations of insulin decreased levels of miR-19b, stimulated KGN cell proliferation, and elevated IGF-1 levels. Inhibition of miR-19b promoted ovarian granulosa cell proliferation by targeting IGF-1 in PCOS. Insulin decreased the expression levels of miR-19b and stimulated cell proliferation. The present study suggested that overexpression of miR-19b may be a potential therapeutic approach for PCOS.

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          Most cited references 24

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          Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling.

          Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non-small cell lung cancer (NSCLC) samples for ALDH1A1, ALDH3A1, and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed that most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH(+) lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared with their ALDH(-) counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH(+) cells. Suppression of the Notch pathway by treatment with either a γ-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH(+) lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH(+) component, implicating Notch signaling in lung cancer stem cell maintenance.
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            Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.

            Women with polycystic ovary syndrome (PCOS) are insulin resistant, have insulin secretory defects, and are at high risk for glucose intolerance. We performed this study to determine the prevalence of glucose intolerance and parameters associated with risk for this in PCOS women. Two-hundred and fifty-four PCOS women, aged 14-44 yr, were prospectively evaluated at 2 centers, 1 urban and ethnically diverse (n = 110) and 1 rural and ethnically homogeneous (n = 144). The rural PCOS women were compared to 80 control women of similar weight, ethnicity, and age. A 75-g oral glucose challenge was administered after a 3-day 300-g carbohydrate diet and an overnight fast with 0 and 2 h blood samples for glucose levels. Diabetes was categorized according to WHO criteria. The prevalence of glucose intolerance was 31.1% impaired glucose intolerance (IGT) and 7.5% diabetes. In nonobese PCOS women (body mass index, <27 kg/m2), 10.3% IGT and 1.5% diabetes were found. The prevalence of glucose intolerance was significantly higher in PCOS vs. control women (chi2 = 7.0; P = 0.01; odds ratio = 2.76; 95% confidence interval = 1.23-6.57). Variables most associated with postchallenge glucose levels were fasting glucose levels (P < 0.0001), PCOS status (P = 0.002), waist/hip ratio (P = 0.01), and body mass index (P = 0.021). The American Diabetes Association criteria applied to fasting glucose significantly underdiagnosed diabetes compared to the WHO criteria (3.2% vs. 7.5%; chi2 = 4.7; P = 0.046; odds ratio = 2.48; 95% confidence interval = 1.01-6.69). We conclude that 1) PCOS women are at significantly increased risk for IGT and type 2 diabetes mellitus at all weights and at a young age; 2) these prevalence rates are similar in 2 different populations of PCOS women, suggesting that PCOS may be a more important risk factor than ethnicity or race for glucose intolerance in young women; and 3) the American Diabetes Association diabetes diagnostic criteria failed to detect a significant number of PCOS women with diabetes by postchallenge glucose values.
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              Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis

               A Dunaif (1997)
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                April 2018
                22 January 2018
                22 January 2018
                : 17
                : 4
                : 4889-4898
                Affiliations
                [1 ]Department of General Gynaecology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
                [2 ]Department of Obstetrics and Gynecology, Eighth People's Hospital of Guangzhou, Guangzhou, Guangdong 510060, P.R. China
                Author notes
                Correspondence to: Professor Qing Xiao, Department of General Gynaecology, Guangzhou Women and Children's Medical Center, 9 Jinsui Road, Tianhe, Guangzhou, Guangdong 510623, P.R. China, E-mail: qingxiao68@ 123456126.com
                [*]

                Contributed equally

                Article
                mmr-17-04-4889
                10.3892/mmr.2018.8463
                5865948
                29363717
                Copyright: © Zhong et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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