Abstract
Background Primary hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related deaths. Therefore, it is important to identify new targets for the treatment of HCC. Niemann-pick type C2 (NPC2) plays an important part in the regulation of intracellular cholesterol homeostasis via direct binding with free cholesterol. However, little is known about the significance of NPC2 in HCC tumourigenesis. Methods To identify the NPC2-dependent mechanism, we examined the status of MAPK signalling. Findings In this study, we showed that NPC2 is abundantly expressed in normal liver, but is downregulated in human HCC tissues. Patients with NPC2 downregulation expressed much higher α-fetoprotein, multiple tumour types, vascular invasion, later pathological stage, and shorter survival. NPC2 overexpression inhibited HuH7 cells proliferation, migration, and xenograft tumourigenesis. Furthermore, administration of hepatotropic adeno-associated virus 8 delivered NPC2 significantly suppressed the spontaneous HCC development in mice. NPC2 overexpression decreases phosphorylation of ERK1/2. Interpretation Our study demonstrates that NPC2 may play an important part in negatively regulating ERK1/2 activation in liver cancer. Thus, NPC2 may represent a new treatment strategy for liver cancer.
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