SATB2 and NGR1: potential upstream regulatory factors in uterine leiomyomas
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We attempted to identify the genes involved in the pathogenesis of uterine leiomyomas, under a hypothesis that the aberrant expression of upstream regulatory genes caused by aberrant DNA methylation is involved in the onset and development of uterine leiomyomas.
To find such genes, we compared genome-wide mRNA expression and DNA methylation in uterine leiomyomas and adjacent normal myometrium. Analysis of the data by Ingenuity Pathway Analysis software identified SATB2 which is known to be an epigenetic regulator, and NRG1 as candidate upstream regulatory genes. To infer the functions of these genes, human uterine smooth muscle cell lines overexpressing SATB2 or NRG1 genes were established (SATB2 or NRG1 lines), and their transcriptomes and pathways were analyzed.
SATB2 and NRG1 were confirmed to be hypermethylated and upregulated in most uterine leiomyoma specimens (nine to 11 of the 11 cases). Among the established cell lines, morphological changes from spindle-like forms to fibroblast-like forms with elongated protrusions were observed in only the SATB2 line. Pathway analysis revealed that WNT/β-catenin and TGF-β signaling pathways which are related to the pathogenesis of uterine leiomyomas were activated in both SATB2 and NRG1 lines. In addition, signaling of growth factors including VEGF, PDGF, and IGF1, and retinoic acid signaling were activated in the SATB2 and NRG1 lines, respectively.
These results indicate that SATB2 and NRG1 overexpression induced many of the signaling pathways that are considered to be involved in the pathogenesis of uterine leiomyomas, suggesting that these genes have roles as upstream regulatory factors.
KeywordsUterine leiomyomas Upstream regulatory genes SATB2 NGR1
We would like to thank Drs. Ikuo Konishi and Noriomi Matsumura (Kyoto University, and Kindai University, respectively) for providing us human immortalized uterine smooth muscle cells (hTERT UtSMCs). This work was supported in part by JSPS KAKENHI Grants 15K10720, 16K11142, 16K20191, 17K11240, 17K11239, and 16K11091 for Scientific Research from the Ministry of Education, Science, and Culture, Japan.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study was approved by the Institutional Review Board of Yamaguchi University Graduate School of Medicine. Informed consent was obtained from the patients before the collection of any samples. All of the experiments handling human tissues were performed in accordance with Tenets of the Declaration of Helsinki.
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