Study the Therapeutic Role of Niemann-Pick Type C2 Protein in Liver Cancer

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. Recently, we generated a series of anti-NPC2 monoclonal antibodies with the IgG2a isotype and verified in different cancers. Our preliminary data showed that NPC2 is abundantly expressed is normal liver, but is down-regulated in human HCC tissues. 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). In addition, knockdown NPC2 in liver cancer cell lines promote cell proliferation, migration and in-vivo tumorigenesis. To identify the NPC2-dependent mechanism, we emphasized on the status of MAPK signaling. Sustained phosphorylation of ERK1/2 has been observed in NPC2 knockdown cells. However, p38 and JNK did not activate in NPC2 knockdown cells. Therefore, NPC2 may negatively regulate ERK1/2 MAPK activation. Accordingly, we hypothesizes that NPC2 over-expression will inhibit cell proliferation and migration. In addition, NPC2 administration may attenuate liver damage and delay or prevent liver cancer formation in mouse model. 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 over-expression in HCC using microarray analysis; and c) to use a HCC animal model for hydrodynamic NPC2 injection. This study will elucidate the mechanisms of NPC2 in liver cancer progression and may shed light on the treatment modality for HCC in the future.