Niemann-Pick type C2 protein regulates liver cancer progression via modulating ERK1/2 pathway

Clinicopathological correlations and therapeutical implications

Yi Jen Liao, Cheng Chieh Fang, Chia Hung Yen, Shih Ming Hsu, Chung Kwe Wang, Shiu Feng Huang, Yu Chih Liang, Ying Yu Lin, Yu Tseng Chu, Yi Ming Arthur Chen

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 α-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 markers - glypican 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.

Original languageEnglish
Pages (from-to)1341-1351
Number of pages11
JournalInternational Journal of Cancer
Volume137
Issue number6
DOIs
Publication statusPublished - Sep 1 2015

Fingerprint

MAP Kinase Signaling System
Liver Neoplasms
Hepatocellular Carcinoma
Proteins
Cholesterol
Cell Proliferation
Neoplasms
Carcinogenesis
Down-Regulation
Glypicans
Anticholesteremic Agents
Fetal Proteins
Dependovirus
Mitogen-Activated Protein Kinase Kinases
Therapeutics
Heterografts
Cell Movement
Blood Vessels
Early Diagnosis
Homeostasis

Keywords

  • Adeno-associated virus 8
  • ERK1/2
  • hepatocellular carcinoma
  • Niemann-Pick type C2
  • proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Niemann-Pick type C2 protein regulates liver cancer progression via modulating ERK1/2 pathway : Clinicopathological correlations and therapeutical implications. / Liao, Yi Jen; Fang, Cheng Chieh; Yen, Chia Hung; Hsu, Shih Ming; Wang, Chung Kwe; Huang, Shiu Feng; Liang, Yu Chih; Lin, Ying Yu; Chu, Yu Tseng; Chen, Yi Ming Arthur.

In: International Journal of Cancer, Vol. 137, No. 6, 01.09.2015, p. 1341-1351.

Research output: Contribution to journalArticle

Liao, Yi Jen ; Fang, Cheng Chieh ; Yen, Chia Hung ; Hsu, Shih Ming ; Wang, Chung Kwe ; Huang, Shiu Feng ; Liang, Yu Chih ; Lin, Ying Yu ; Chu, Yu Tseng ; Chen, Yi Ming Arthur. / Niemann-Pick type C2 protein regulates liver cancer progression via modulating ERK1/2 pathway : Clinicopathological correlations and therapeutical implications. In: International Journal of Cancer. 2015 ; Vol. 137, No. 6. pp. 1341-1351.
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AU - Huang, Shiu Feng

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AU - Lin, Ying Yu

AU - Chu, Yu Tseng

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AB - 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 α-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 markers - glypican 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.

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