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J Clin Endocrinol Metab. 2017 May 1;102(5):1588-1595. doi: 10.1210/jc.2016-3497.
2
Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo.表达CD34和CD49b的人子宫平滑肌瘤干/祖细胞在体内引发肿瘤。
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Activation of protein kinase B by WNT4 as a regulator of uterine leiomyoma stem cell function.WNT4激活蛋白激酶B作为子宫平滑肌瘤干细胞功能的调节剂。
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本文引用的文献

1
Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo.表达CD34和CD49b的人子宫平滑肌瘤干/祖细胞在体内引发肿瘤。
J Clin Endocrinol Metab. 2015 Apr;100(4):E601-6. doi: 10.1210/jc.2014-2134. Epub 2015 Feb 6.
2
Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications.卵巢类固醇、干细胞与子宫平滑肌瘤：治疗意义
Hum Reprod Update. 2015 Jan-Feb;21(1):1-12. doi: 10.1093/humupd/dmu048. Epub 2014 Sep 8.
3
Missense mutations in exon 2 of the MED12 gene are involved in IGF-2 overexpression in uterine leiomyoma.MED12基因外显子2中的错义突变与子宫平滑肌瘤中IGF-2的过表达有关。
Mol Hum Reprod. 2014 Oct;20(10):1009-15. doi: 10.1093/molehr/gau055. Epub 2014 Jul 11.
4
Uterine fibroids.子宫肌瘤
N Engl J Med. 2013 Oct 3;369(14):1344-55. doi: 10.1056/NEJMra1209993.
5
Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth.子宫平滑肌瘤干细胞中旁分泌激活的 WNT/β-连环蛋白通路促进肿瘤生长。
Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17053-8. doi: 10.1073/pnas.1313650110. Epub 2013 Sep 30.
6
IGF2 and cancer.IGF2 与癌症。
Endocr Relat Cancer. 2013 Oct 24;20(6):R321-39. doi: 10.1530/ERC-13-0231. Print 2013 Dec.
7
Increased AKT or MEK1/2 activity influences progesterone receptor levels and localization in endometriosis.AKT 或 MEK1/2 活性的增加会影响子宫内膜异位症中孕激素受体的水平和定位。
J Clin Endocrinol Metab. 2013 Dec;98(12):E1871-9. doi: 10.1210/jc.2013-1661. Epub 2013 Sep 24.
8
Identification and characterization of the human leiomyoma side population as putative tumor-initiating cells.鉴定和表征人类平滑肌瘤侧群作为肿瘤起始细胞。
Fertil Steril. 2012 Sep;98(3):741-751.e6. doi: 10.1016/j.fertnstert.2012.04.044. Epub 2012 May 23.
9
IGF-II promotes stemness of neural restricted precursors.IGF-II 促进神经限制前体细胞的干性。
Stem Cells. 2012 Jun;30(6):1265-76. doi: 10.1002/stem.1095.
10
Role of stem cells in human uterine leiomyoma growth.干细胞在人子宫肌瘤生长中的作用。
PLoS One. 2012;7(5):e36935. doi: 10.1371/journal.pone.0036935. Epub 2012 May 3.

子宫平滑肌瘤干细胞中的旁分泌途径涉及胰岛素样生长因子2和胰岛素受体A。

Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A.

作者信息

Moravek Molly B, Yin Ping, Coon John S, Ono Masanori, Druschitz Stacy A, Malpani Saurabh S, Dyson Matthew T, Rademaker Alfred W, Robins Jared C, Wei Jian-Jun, Kim J Julie, Bulun Serdar E

机构信息

Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.

Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.

出版信息

J Clin Endocrinol Metab. 2017 May 1;102(5):1588-1595. doi: 10.1210/jc.2016-3497.

DOI:10.1210/jc.2016-3497
PMID:28324020
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5443334/
Abstract

CONTEXT

Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown.

OBJECTIVE

To define differential gene expression and signaling pathways in leiomyoma cell populations.

DESIGN

Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b-, and CD34-/CD49b-. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, real-time quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-2'-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma.

SETTING

Research laboratory.

PATIENTS

Eight African American women.

INTERVENTIONS

None.

MAIN OUTCOMES MEASURES

Gene expression patterns, cell proliferation, and differentiation.

RESULTS

A total of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b- intermediary cells, which then terminally differentiate to CD34-/CD49b- cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b- vs CD34-/CD49b- cells (83-fold; P < 0.05). Insulin receptor A (IR-A) expression was higher and IGF1 receptor lower in CD34+/CD49b+ vs CD34-/CD49b- cells (15-fold and 0.35-fold, respectively; P < 0.05). IGF2 significantly increased cell number (1.4-fold; P < 0.001), proliferation indices, and extracellular signal-regulated kinase (ERK) phosphorylation. ERK inhibition decreased IGF2-stimulated cell proliferation.

CONCLUSIONS

IGF2 and IR-A are important for leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas.

摘要

背景

子宫平滑肌瘤（纤维瘤）是女性最常见的良性肿瘤。最近，基于CD34和CD49b表达发现了三类平滑肌瘤细胞，但这些细胞群体之间的分子差异仍不清楚。

目的

确定平滑肌瘤细胞群体中的差异基因表达和信号通路。

设计

通过流式细胞术将人平滑肌瘤组织中的细胞分为三类：CD34+/CD49b+、CD34+/CD49b-和CD34-/CD49b-。进行微阵列基因表达谱分析和通路分析。为研究胰岛素样生长因子（IGF）通路，对从新鲜平滑肌瘤中分离出的细胞进行实时定量聚合酶链反应、免疫印迹和5-乙炔基-2'-脱氧尿苷掺入研究。

地点

研究实验室。

患者

8名非裔美国女性。

干预措施

无。

主要观察指标

基因表达模式、细胞增殖和分化。

结果

在三类平滑肌瘤细胞群体中共有1164个基因差异表达，提示存在一种分级分化顺序，即CD34+/CD49b+干细胞分化为CD34+/CD49b-中间细胞，后者再终末分化为CD34-/CD49b-细胞。通路分析显示几种IGF信号通路基因存在差异表达。与CD34-/CD49b-细胞相比，IGF2在CD34+/CD49b-细胞中过表达（83倍；P<0.05）。与CD34-/CD49b-细胞相比，胰岛素受体A（IR-A）在CD34+/CD49b+细胞中的表达更高，而IGF1受体更低（分别为15倍和0.35倍；P<0.05）。IGF2显著增加细胞数量（1.4倍；P<0.001）、增殖指数和细胞外信号调节激酶（ERK）磷酸化。ERK抑制降低了IGF2刺激的细胞增殖。

结论

IGF2和IR-A对平滑肌瘤干细胞增殖很重要，可能代表平滑肌瘤细胞类型之间的旁分泌信号。针对IGF通路的治疗方法应进行研究，用于平滑肌瘤的治疗和预防。