microRNA 31 functions as an endometrial cancer oncogene by suppressing Hippo tumor suppressor pathway.
BACKGROUND
We aimed to investigate whether MIR31 is an oncogene in human endometrial cancer and identify the target molecules associated with the malignant phenotype.


METHODS
We investigated the growth potentials of MIR31-overexpressing HEC-50B cells in vitro and in vivo. In order to identify the target molecule of MIR31, a luciferase reporter assay was performed, and the corresponding downstream signaling pathway was examined using immunohistochemistry of human endometrial cancer tissues. We also investigated the MIR31 expression in 34 patients according to the postoperative risk of recurrence.


RESULTS
The overexpression of MIR31 significantly promoted anchorage-independent growth in vitro and significantly increased the tumor forming potential in vivo. MIR31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3'-UTR and consequently promoted the translocation of YAP1, a key molecule in the Hippo pathway, into the nucleus. Meanwhile, the nuclear localization of YAP1 increased the transcription of CCND1. Furthermore, the expression levels of MIR31 were significantly increased (10.7-fold) in the patients (n = 27) with a high risk of recurrence compared to that observed in the low-risk patients (n = 7), and this higher expression correlated with a poor survival.


CONCLUSIONS
MIR31 functions as an oncogene in endometrial cancer by repressing the Hippo pathway. MIR31 is a potential new molecular marker for predicting the risk of recurrence and prognosis of endometrial cancer.
Takashi
T
Mitamura
Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, N15, W7, Sapporo, Kita-ku 060-8638, Japan. watarih@med.hokudai.ac.jp.
Hidemichi
H
Watari
Lei
L
Wang
Hiromi
H
Kanno
Makiko
M
Kitagawa
Mohamed Kamel
MK
Hassan
Taichi
T
Kimura
Mishie
M
Tanino
Hiroshi
H
Nishihara
Shinya
S
Tanaka
Noriaki
N
Sakuragi
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D000368:Aged; D017209:Apoptosis; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D000090683:Hippo Signaling Pathway; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C530104:CCND1 protein, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D019938:Cyclin D1; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases