Mutual suppression between BHLHE40/BHLHE41 and the MIR301B-MIR130B cluster is involved in epithelial-to-mesenchymal transition of endometrial cancer cells
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Kazuo Asanoma1, Emiko Hori1, Sachiko Yoshida1, Hiroshi Yagi1, Ichiro Onoyama1, Keisuke Kodama1, Masafumi Yasunaga1, Tatsuhiro Ohgami1, Eisuke Kaneki1, Kaoru Okugawa1, Hideaki Yahata1 and Kiyoko Kato1
1 Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
|Kazuo Asanoma,||email:||[email protected]|
Keywords: microRNA; transcription factor; epithelial-to-mesenchymal transition; cell invasion; endometrial cancer
Received: April 24, 2019 Accepted: June 19, 2019 Published: July 23, 2019
BHLHE40 and BHLHE41 (BHLHE40/41) are basic helix-loop-helix type transcription factors involved in multiple cell activities including epithelial-to-mesenchymal transition (EMT). However, the expression mechanism of BHLHE40/41 in EMT remains unclear. In the present study, we showed that the expression levels of BHLHE40/41 were negatively correlated with those of the microRNA (MIR) 130 family in endometrial cancer (EC) specimens. Our in vitro assays indicated that the expression of BHLHE40/41 was suppressed directly by the MIR130 family in a 3’-untranslated region-mediated manner. In EC cells, the MIR130 family promoted EMT and tumor cell invasion by suppressing the expression of BHLHE40/41. We identified the critical promoter region of the MIR301B-MIR130B cluster for its basal transcription by the transcription factor, SP1. We also found that BHLHE40/41 suppressed the expression of MIR301B and MIR130B, and we identified a binding site in the promoter region for BHLHE40/41. This study is the first to report that BHLHE40/41 and the MIR301B-MIR130B cluster suppressed each other to regulate EMT and invasion of EC cells. We propose that BHLHE40/41 and the MIR130 family are excellent markers to predict the progression of EC cases, and that molecular therapy targeting the MIR130 family-BHLHE40/41 axis may effectively control EC extension.
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