Research Papers:

Mutual suppression between BHLHE40/BHLHE41 and the MIR301B-MIR130B cluster is involved in epithelial-to-mesenchymal transition of endometrial cancer cells

Kazuo Asanoma, Emiko Hori, Sachiko Yoshida, Hiroshi Yagi, Ichiro Onoyama, Keisuke Kodama, Masafumi Yasunaga, Tatsuhiro Ohgami, Eisuke Kaneki, Kaoru Okugawa, Hideaki Yahata and Kiyoko Kato

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Oncotarget. 2019; 10:4640-4654. https://doi.org/10.18632/oncotarget.27061

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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

Correspondence to:

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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