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

// Jing Zhao 1, * , Qiong-Zhu Dong 1, 3, * , Fan Zhong 1, 2 , Li-Li Cai 1 , Zhao-Yu Qin 1 , Yang Liu 1 , Cheng-Zhao Lin 1 , Lun-Xiu Qin 1, 3 , Fu-Chu He 1, 4 1 Institutes of Biomedical Sciences, Fudan University, Shanghai, China 2 Department of Systems Biology for Medicine, Shanghai Medical College, Fudan University, Shanghai, China 3 Department of Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China 4 State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing, China * Co-first authors, these authors contributed equally to this work Correspondence to: Fu-Chu He, email: hefc@nic.bmi.ac.cn Lun-Xiu Qin, email: qinlx@fudan.edu.cn Keywords: liver cancer, N-myc (and STAT) interactor (NMI), metastasis Received: May 20, 2016     Accepted: November 24, 2016     Published: January 6, 2017 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.