Neuroglobin, a Novel Intracellular Hexa-Coordinated Globin, Functions as a Tumor Suppressor in Hepatocellular Carcinoma via Raf/MAPK/Erk

	Neuroglobin, a Novel Intracellular Hexa-Coordinated Globin, Functions as a Tumor Suppressor in Hepatocellular Carcinoma via Raf/MAPK/Erk
	Zhang, J; Lan, SJ; Liu, QR; Liu, JM; Chen, XQ
刊名	MOLECULAR PHARMACOLOGY
	2013
卷号	83 期号:5 页码:1109-1119
通讯作者	Chen, XQ (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Pathophysiol, Hangkong Rd 13, Wuhan 430032, Peoples R China.,chenxiaoqian66@gmail.com
英文摘要	Hypoxia and oxidative stress are critical factors in carcinogenesis and exist throughout cancer development; however, the underlying mechanisms are far from clear. Here, for the first time to our knowledge, we reported that neuroglobin (Ngb), an intracellular hexa-coordinated globin serving as an oxygen/reactive oxygen species (ROS) sensor, functions as a tumor suppressor in hepatocelluar carcinoma (HCC). Ngb protein and mRNA expression were significantly down-regulated in tumor tissues, compared with its adjacent non-tumor tissues of human HCC samples and normal liver tissues. Knock-down of Ngb by RNA interference promoted human HCC cell line (HepG2) growth and proliferation, G0/G1-S transition in vitro, and tumor growth in vivo. On the contrary, overexpression of Ngb suppressed HepG2 cell growth and proliferation, G0/G1-S transition, colony formation in vitro, and tumorigenicity in vivo. These results established a tumor suppressor function of Ngb in HCC. The underlying mechanisms were further investigated. Overexpression of Ngb suppressed Raf/MEK/extracellular signal-regulated kinase (Erk), whereas knockdown of Ngb enhanced Raf/MEK/Erk activation in HepG2 cells in vitro and in vivo. Glutathione S-transferase pull-down showed that Ngb interacted with c-Raf-1 in HepG2 cells. Overexpression of Ngb suppressed serum-and H2O2-stimulated Erk activation in HepG2 cells. Pharmacological inhibition of Erk activation abolished the proliferative effect of Ngb knockdown in HepG2 cells. Mutation of Ngb at its oxygen-binding site (H64L) abolished the inhibitory effects of Ngb on Erk activation and HepG2 cell proliferation. Therefore, we propose that Ngb controls HCC development by linking oxygen/ROS signals to oncogenic Raf/mitogen-activated protein kinase (MAPK)/Erk signaling. Our data suggest that neuroglobin could be a new target for cancer therapy.
学科主题	Pharmacology & Pharmacy
类目[WOS]	Pharmacology & Pharmacy
关键词[WOS]	THERAPEUTIC TARGETS ; MURINE NEUROGLOBIN ; OXIDATIVE STRESS ; NITRIC-OXIDE ; EXPRESSION ; PATHWAYS ; BINDING ; INJURY ; OXYGEN ; PHOSPHORYLATION
收录类别	SCI
语种	英语
WOS记录号	WOS:000317575500019
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/390]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Zhang, J,Lan, SJ,Liu, QR,et al. Neuroglobin, a Novel Intracellular Hexa-Coordinated Globin, Functions as a Tumor Suppressor in Hepatocellular Carcinoma via Raf/MAPK/Erk[J]. MOLECULAR PHARMACOLOGY,2013,83(5):1109-1119.
APA	Zhang, J,Lan, SJ,Liu, QR,Liu, JM,&Chen, XQ.(2013).Neuroglobin, a Novel Intracellular Hexa-Coordinated Globin, Functions as a Tumor Suppressor in Hepatocellular Carcinoma via Raf/MAPK/Erk.MOLECULAR PHARMACOLOGY,83(5),1109-1119.
MLA	Zhang, J,et al."Neuroglobin, a Novel Intracellular Hexa-Coordinated Globin, Functions as a Tumor Suppressor in Hepatocellular Carcinoma via Raf/MAPK/Erk".MOLECULAR PHARMACOLOGY 83.5(2013):1109-1119.