title: iNOS promotes HBx-induced hepatocellular carcinoma via upregulation of JNK activation.
abstract: Inducible nitric oxide (iNOS) is closely correlated with chronic inflammation in hepatitis B virus X protein (HBx)-induced hepatocellular carcinoma (HCC). However, the molecular mechanisms through which iNOS contribute to hepatocarcinogenesis remain poorly understood. Therefore, we investigated the role of iNOS in signaling pathways underlying HBx-induced liver tumorigenesis. iNOS deletion showed a marked decrease in the hepatic tumor size and stage of HBx transgenic (Tg) mice, indicating a strong contribution of iNOS signaling pathways to hepatocarcinogenesis. In addition, we found that nitric oxide (NO) increased HBx mRNA by recruiting CREB to the CRE site of HBV enhancer in HepG2 cells, suggesting a positive feedback loop between HBx and iNOS signaling pathway. Moreover, iNOS-modulated JNK activation was associated with sustained upregulation of Cyclin D1 in HBxTg mice and HepG2-HBx cells. These results imply that iNOS may play a key role in HBx-associated HCC development. Taken together, our findings demonstrate that iNOS aligns with HBx to promote tumor progression. These findings provide a better understating of the mechanism involving HBx-mediated hepatic tumorigenesis and selective inhibition of iNOS may have therapeutic applications in HBx-associated HCC.
authors: Disease Model Research Laboratory, Aging Research Center, Daejeon, Republic of Korea.
authors: Young-Ho
authors: YH
authors: Park
authors: Hye-Jun
authors: HJ
authors: Shin
authors: Sun-Uk
authors: SU
authors: Kim
authors: Jin-Man
authors: JM
authors: Kim
authors: Joo-Hyun
authors: JH
authors: Kim
authors: Dong-Ho
authors: DH
authors: Bang
authors: Kyu-Tae
authors: KT
authors: Chang
authors: Bo-Yeon
authors: BY
authors: Kim
authors: Dae-Yeul
authors: DY
authors: Yu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D015854:Up-Regulation / Q000187:drug effects; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048670:MAP Kinase Kinase 4