Zhao Jing, Dong Qiong-Zhu, Zhong Fan, Cai Li-Li, Qin Zhao-Yu, Liu Yang, Lin Cheng-Zhao, Qin Lun-Xiu, He Fu-Chu
Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Department of Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.
Oncotarget. 2017 Feb 14;8(7):12174-12185. doi: 10.18632/oncotarget.14556.
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.
肝细胞癌（HCC）是最常见且侵袭性最强的恶性肿瘤之一。N-myc（和STAT）相互作用分子（NMI）在HCC进展中的作用及其可能的功能机制仍有待阐明。在本研究中，我们发现与非转移性HCC细胞系相比，NMI在转移性HCC细胞系中过表达；并且在有转移的HCC样本中NMI的表达水平高于无转移的样本。此外，在体外，NMI缺失显著降低了HCC细胞的增殖和侵袭能力，在体内，在携带人HCC的裸鼠模型中也抑制了肿瘤生长和肺转移。相反，NMI稳定过表达可明显增强恶性行为。此外，根据体内或体外HCC中NMI表达的双向扰动，我们进一步证实NMI促进BDKRB2的表达并介导MAPK/ERK信号通路的激活。综上所述，NMI是一种促转移分子，部分负责HCC的肿瘤生长和运动。NMI可提高其下游靶点BDKRB2的表达以诱导ERK1/2激活，从而进一步引发HCC的恶性进展。
