Niemann-Pick type C2 protein regulates liver cancer progression<i>via</i>modulating ERK1/2 pathway: Clinicopathological correlations and therapeutical implications

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

doi:10.1002/ijc.29507

Cited by 27 publications

(28 citation statements)

References 47 publications

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“…As for invasion assay, we found that knockdown of survivin protein inhibited the invasive abilities of BGC823 cells into Matrigel compared with control. Consistent with our findings, recent articles also reported the silencing of survivin also affected the capacity of migration and invasion of a variety of cancers, such as breast cancer [13] and liver cancer [18].…”

Section: Discussionsupporting

confidence: 92%

The involvement of survivin in insulin-like growth factor 1-induced epithelial-mesenchymal transition in gastric cancer

Liu

Li²,

Wu³

et al. 2015

Tumor Biol.

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It has been identified that insulin-like growth factor 1 (IGF-1) activated various pathways of the epithelial-mesenchymal transition (EMT) in a couple of tumors. At the same time, survivin is implicated in EMT of gastric cancer (GC). To date, the impact of survivin on IGF-1-mediated EMT of GC has not been featured. In this work, we used the immunohistochemistry and molecular and cellular experiments to investigate the existence and significance of IGF-1 and survivin. Our findings revealed that survivin protein can be observed in majority of samples in all GC samples. Importantly, survivin expression has an obvious association with GC stage, and metastasis. In vitro, GC cell line BGC823 was treated with different concentrations of IGF-1, resulting in the activation of p-ERK, p-AKT, survivin, and the expression of EMT biomarkers, including N-cadherin, MMP2, and Snail. However, the silencing of survivin eradicated the expression IGF-1-induced EMT biomarkers and affected the migration and invasion of BGC823 cells. In conclusion, IGF-1 signaling activated survivin expression and controlled the expression of EMT biomarkers in the development of GC. This study lays a new stage for the molecular therapy of GC patients in the clinical treatment.

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Section: Discussionsupporting

confidence: 92%

The involvement of survivin in insulin-like growth factor 1-induced epithelial-mesenchymal transition in gastric cancer

Liu

Li²,

Wu³

et al. 2015

Tumor Biol.

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“…Hep3B (purchased from BCRC, No. 60434) and Huh-7 [55] cells were infected with lentivirus in medium containing polybrene (8 µg/mL) for the generation of stable cell lines. After 24 h of infection, 1 µg/mL puromycin was added to select the stable cells.…”

Section: Cell Culture Plasmids and Lentivirus Infectionmentioning

confidence: 99%

HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma

Wang

Liu

Chiu

et al. 2019

Cancers

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Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide; however, the traditional therapeutic approaches and survival rates are still limited. To improve current therapies, it is necessary to investigate the molecular mechanisms underlying liver cancer and to identify potential therapeutic targets. The aims of this study were to verify the mechanisms and therapeutic potential of the ketogenesis rate-limiting enzyme 3-Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in HCC. Immunohistochemical staining of human liver disease tissue arrays showed that HMGCS2 is abundantly expressed in normal liver tissues but is downregulated in cirrhosis and HCC tissues. In HCC patients, lower HMGCS2 expression was correlated with higher pathological grades and clinical stages. In our investigation of the molecular mechanisms of HMGCS2 in HCC, we showed that knockdown of HMGCS2 decreased ketone production, which promoted cell proliferation, cell migration, and xenograft tumorigenesis by enhancing c-Myc/cyclinD1 and EMT signaling and by suppressing the caspase-dependent apoptosis pathway. Ketone body treatment reduced the proliferation- and migration-promoting effects of HMGCS2 knockdown in cells. In contrast, HMGCS2 overexpression increased the intracellular ketone level and inhibited cell proliferation, cell migration, and xenograft tumorigenesis. Finally, ketogenic diet administration significantly inhibited liver cancer cell growth in mice. Our studies highlight the potential therapeutic strategy of targeting HMGCS2-mediated ketogenesis in liver cancer.

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“…We recently reported that NPC2 down-regulation is correlated with the α-fetoprotein level, tumor type, vascular invasion, and pathology stages of HCC patients. In-vitro and in vivo xenograft data demonstrated that the expression of NPC2 regulates cell proliferation, migration, and tumorigenesis by regulating ERK1/2 activation [ 21 ]. Previously, we conducted an immunohistochemical-based study to examine the expression of NPC2 in a variety of different human cancers, and meanwhile NPC2 was found to be down-regulated in human liver cirrhosis and hepatoma tissues [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Niemann-Pick Type C2 Protein Mediates Hepatic Stellate Cells Activation by Regulating Free Cholesterol Accumulation

Twu¹,

Lee²,

Lin

et al. 2016

IJMS

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In chronic liver diseases, regardless of their etiology, the development of fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. Hepatic stellate cells (HSCs) are the main profibrogenic cells that promote the pathogenesis of liver fibrosis, and so it is important to identify the molecules that regulate HSCs activation and liver fibrosis. Niemann-Pick type C2 (NPC2) protein plays an important role in the regulation of intracellular cholesterol homeostasis by directly binding with free cholesterol. However, the roles of NPC2 in HSCs activation and liver fibrosis have not been explored in detail. Since a high-cholesterol diet exacerbates liver fibrosis progression in both rodents and humans, we propose that the expression of NPC2 affects free cholesterol metabolism and regulates HSCs activation. In this study, we found that NPC2 is decreased in both thioacetamide- and carbon tetrachloride-induced liver fibrosis tissues. In addition, NPC2 is expressed in quiescent HSCs, but its activation status is down-regulated. Knockdown of NPC2 in HSC-T6 cells resulted in marked increases in transforming growth factor-β1 (TGF-β1)-induced collagen type 1 α1 (Col1a1), α-smooth muscle actin (α-SMA) expression, and Smad2 phosphorylation. In contrast, NPC2 overexpression decreased TGF-β1-induced HSCs activation. We further demonstrated that NPC2 deficiency significantly increased the accumulation of free cholesterol in HSCs, increasing Col1a1 and α-SMA expression and activating Smad2, and leading to sensitization of HSCs to TGF-β1 activation. In contrast, overexpression of NPC2 decreased U18666A-induced free cholesterol accumulation and inhibited the subsequent HSCs activation. In conclusion, our study has demonstrated that NPC2 plays an important role in HSCs activation by regulating the accumulation of free cholesterol. NPC2 overexpression may thus represent a new treatment strategy for liver fibrosis.

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Niemann-Pick type C2 protein regulates liver cancer progressionviamodulating ERK1/2 pathway: Clinicopathological correlations and therapeutical implications

Cited by 27 publications

References 47 publications

The involvement of survivin in insulin-like growth factor 1-induced epithelial-mesenchymal transition in gastric cancer

The involvement of survivin in insulin-like growth factor 1-induced epithelial-mesenchymal transition in gastric cancer

HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma

Niemann-Pick Type C2 Protein Mediates Hepatic Stellate Cells Activation by Regulating Free Cholesterol Accumulation

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