HEY2, a target of miR-137, indicates poor outcomes and promotes cell proliferation and migration in hepatocellular carcinoma.

Dan-Chun Wu,Mei-Fang Zhang,Shu-Guang Su,Heng-Ying Fang,Dan He,Xue-Hua Wang,Xu-Hui Liu,Yuan-Yuan Xie

doi:10.18632/oncotarget.9343

Abstract

HEY2, a bHLH transcription factor, has been implicated in the progression of human cancers. Here, we showed that HEY2 expression was markedly increased in HCC, compared with the adjacent nontumorous tissues. High HEY2 expression was closely correlated with tumor multiplicity, tumor differentiation and TNM stage. Kaplan-Meier analyses revealed that HEY2 expression was significantly associated with poor overall and disease-free survival in a training cohort of 361 patients with HCC. The prognostic implication of HEY2 was validated in another cohort of 169 HCC patients. Multivariate Cox regression model indicated HEY2 as an independent factor for overall survival in HCC (Hazard ratio = 1.645, 95% confident interval: 1.309-2.067, P<0.001). We also demonstrated that HEY2 expression was inhibited by miR-137. In clinical samples, HEY2 expression was reversely associated to miR-137 expression. Furthermore, overexpression of HEY2 increased cell viabilities, colony formation and cell migration, whereas knockdown of HEY2 resulted in the opposite phenotypes. Collectively, our data suggest HEY2 as a promising biomarker for unfavorable outcomes and a novel therapeutic target for the clinical management of HCC.

Highlights

The incidence and mortality of hepatocellular carcinoma (HCC) has not been improved in the last decade worldwide [1]
We demonstrated that HEY2 expression was inhibited by miR-137
HEY2 expression is increased in HCC tissues

Summary

Introduction

The incidence and mortality of hepatocellular carcinoma (HCC) has not been improved in the last decade worldwide [1]. Due to the intrahepatic metastases and high-risk recurrence, mortality of HCC is the second most common cause of cancer-related death in men and the sixth in women [3]. Accumulating interests are focus on developing advanced strategies for HCC diagnosis and clinical treatment. Wittmann et al showed that HEY2 expression was deregulated in high-risk tumors and associated with tumor relapse in Wilms tumor [13]. High expression of HEY2 in prostate cancer was associated with poor survival and served as an independent prognostic factor [10]. The role of HEY2 and its clinical significance in HCC remain elusive

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Conclusion