Niemann-Pick Type C2 Protein Regulates Liver Cancer Progression Via Modulating Erk1/2 Pathway: Clinicopathological Correlations And Therapeutical Implications

Primary hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related death. 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. However, little is known about the significance of NPC2 in HCC tumorigenesis. In this study, we showed that NPC2 is abundantly expressed in normal liver, but is downregulated in human HCC tissues. The patients with NPC2 downregulation expressed much higher -fetoprotein, multiple tumor type, vascular invasion, later pathological stage and shorter survival rate. Knockdown NPC2 in liver cancer cell lines promote cell proliferation, migration and xenograft tumorigenesis. In contrast, NPC2 overexpression inhibits HuH7 promoted tumor growth. Furthermore, administration of hepatotropic adeno-associated virus 8 (AAV8) delivered NPC2 decreased the inflammatory infiltration, the expression of two early HCC markersglypican 3 and survivin and suppressed the spontaneous HCC development in mice. To identify the NPC2-dependent mechanism, we emphasized on the status of MAPK/ERK signaling. MEK1/2 inhibitor treatment demonstrated that the expression of NPC2 affected the activation of ERK1/2 but not MEK1/2. In addition, cholesterol trafficking inhibitor treatment did not alter the cell proliferation and the activation of MEK/ERK. In conclusion, our study demonstrates that NPC2 may play an important role in negatively regulate cell proliferation and ERK1/2 activation that were independent of cholesterol accumulation. AAV-NPC2 may thus represent a new treatment strategy for liver cancer.What's new? The hunt for new markers and treatments in hepatocellular carcinoma (HCC) has opened the door to the development of novel strategies that promise to improve patient outcome. Here, that promise is highlighted by Niemann-Pick disease type C2 (NPC2), which is identified as a potential prognostic marker and therapeutic target in HCC. In liver cancer cells and in patients, NPC2 downregulation was associated with various clinicopathologic features, including vascular invasion, enhanced cell proliferation, and tumor growth. In patients, decreased NPC2 was associated with decreased survival. In mice, treatment with NPC2, delivered via adeno-associated virus 8, suppressed spontaneous HCC development.