RT Journal Article
SR Electronic
T1 Neuroglobin, a Novel Intracellular Hexa-coordinated Globin, Functions as a Tumor Suppressor in Hepatocellular Carcinoma Via Raf/MAPK/Erk
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.083634
DO 10.1124/mol.112.083634
A1 Jun Zhang
A1 Shu Jue Lan
A1 Qian Rong Liu
A1 Ju Mei Liu
A1 Xiao Qian Chen
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/03/11/mol.112.083634.abstract
AB Hypoxia and oxidative stress are critical factors in carcinogenesis and exists throughout cancer development, however, the underlying mechanisms are far from clear. Here, for the first time, 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 as compared to 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, proliferation, G0/G1-S transition in vitro and tumor growth in vivo. On the contrary, overexpression of Ngb suppressed HepG2 cell growth, 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/Erk while knock-down of Ngb enhanced Raf/MEK/Erk activation in HepG2 cells in vitro and in vivo. GST 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-knock down 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/MAPK/Erk signaling. Our data suggest that neuroglobin could be a new target for cancer therapy.