NMI promotes hepatocellular carcinoma progression via BDKRB2 and MAPK/ERK pathway.

Jing Zhao,Qiong-Zhu Dong,Yang Liu,Li-Li Cai,Zhao-Yu Qin,Cheng-Zhao Lin,Fu-Chu He,Fan Zhong,Lun-Xiu Qin

doi:10.18632/oncotarget.14556

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive malignant tumors. The involvement of N-myc (and STAT) interactor (NMI) and its possible functional mechanisms in HCC progression still remain to be elucidated. In this study, we found that NMI was overexpressed in metastatic HCC cell lines compared with non-metastatic ones; and the expression levels of NMI in the HCC samples with metastasis were higher than that in the non-metastatic specimens. Furthermore, NMI depletion significantly decreased HCC cell proliferation and invasiveness in vitro, and also inhibited tumor growth and lung metastasis in vivo in nude mice models bearing human HCC. By contrast, NMI stable overexpression can enhance the malignant behaviors obviously. Moreover, we further verified that NMI promotes the expression of BDKRB2 and mediates the activation of MAPK/ERK signaling pathway according to the bidirectional perturbations of NMI expression in vivo or in vitro of HCC. Taken together, NMI is a pro-metastatic molecule and partially responsible for HCC tumor growth and motility. NMI could improve its downstream target BDKRB2 expression to induce ERK1/2 activation, and thereby further evoke malignant progression of HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive malignant tumors worldwide [1]
We found that N-myc (and STAT) interactor (NMI) was overexpressed in metastatic HCC cell lines compared with non-metastatic ones; and the expression levels of NMI in the HCC samples with metastasis were higher than that in the non-metastatic specimens
To further evaluation the relationship between NMI expression and metastatic potential of HCC, we analyzed the mRNA expression of NMI in 20 metastatic primary HCC tissues and 17 non-metastatic HCCs by qRT-PCR (Table 1)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive malignant tumors worldwide [1]. The molecular pathogenesis and complicated signal transduction pathways implicated in HCC progression and metastasis are not fully understood, with currently only a few effectual diagnostic biomarkers and therapeutic targets [4]. Screening of independent biomarkers or pathways of metastatic HCC by using omics studies have become more popular due to technological advances in cell function monitoring from a holistic perspective [5]. To better understand the metastatic drivers triggering HCC dissemination, we previously carried out an integrated transcriptomic and proteomic inspect among metastatic HCC cell lines, and identified 7 up-regulated significant genes including NMI [10]

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Results

Conclusion