Primary hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related death. Therefore, it is important to identify new targets for early diagnosis and treatment of HCC. Niemann-Pick Type C2 (NPC2) plays an important role in the regulation of intracellular cholesterol homeostasis via direct binding with free cholesterol. Previously, we reported that NPC2 acts coordinately with glycine N-methylatransferase to regulate hepatic cholesterol homeostasis and fatty liver disease progression. However, little is known about the significance of NPC2 in HCC tumorigenesis. Our preliminary data showed that NPC2 is abundantly expressed is normal liver, but is down-regulated in human HCC tissues. In addition, the patients with NPC2 down-regulation expressed much higher α-fetoprotein (p=0.03), multiple tumor type (p=0.02), vascular invasion (p=0.01), later pathological stage (p=0.03) and shorter survival rate (p=0.011). Since NPC2 knockdown fibroblast cells was shown to be a sustained phosphorylation of ERK1/2 mitogen activated protein kinase (MAPK), NPC2 may negatively regulate ERK1/2 MAPK activation. Therefore, we may predict a very broad and important NPC2 regulatory function in determine the tumor phenotype that are independent of NPC2 cholesterol binding ability. Accordingly, we hypothesizes that loss NPC2 expression will promote cell proliferation and liver cancer formation. In contrast, NPC2 administration may attenuate liver damage and delay or prevent liver cancer formation. The goals of this 3-year project are: a) to study the regulation mechanisms of NPC2 in cell proliferation and liver tumorigenesis; b) to identify novel pathways related to NPC2 down-regulation in HCC using microarray analysis; and c) to use a HCC animal model for Adeno-Associated Virus 8-NPC2 therapy. This study will elucidate the mechanisms of NPC2 in liver cancer progression and may shed light on the diagnosis and treatment modality for HCC in the future.
|Effective start/end date||8/1/13 → 7/31/14|
- Niemann-Pick Type C2 (NPC2)
- cell proliferation and tumorigenesis
- microarray analysis
- Adeno-Associated Virus 8 (AAV8)
- hepatocellular carcinoma (HCC)