Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor in the world. Sorafenib is the first-line drug for patients with advanced HCC. However, long-term treatment with sorafenib often results in reduced sensitivity of tumor cells to the drug, leading to acquired resistance. Identifying biomarkers which can predict the response to sorafenib treatment may represent a clinical challenge in the personalized treatment era. Niemann-Pick type C2 (NPC2), a secretory glycoprotein, plays an important role in regulating intracellular free cholesterol homeostasis. In HCC patients, downregulation of hepatic NPC2 is correlated with poor clinical pathological features through regulating mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) activation. This study aimed to investigate the roles of secretory NPC2-mediated free cholesterol levels as biomarkers when undergoing sorafenib treatment and evaluate its impact on acquired sorafenib resistance in HCC cells. Herein, we showed that NPC2 downregulation and free cholesterol accumulation weakened sorafenib’s efficacy through enhancing MAPK/AKT signaling in HCC cells. Meanwhile, NPC2 overexpression slightly enhanced the sorafenib-induced cytotoxic effect. Compared to normal diet feeding, mice fed a high-cholesterol diet had much higher tumor growth rates, whereas treatment with the free cholesterol-lowering agent, hydroxypropyl-β-cyclodextrin, enhanced sorafenib’s tumor-inhibiting ability. In addition, sorafenib treatment induced higher NPC2 secretion, which was mediated by inhibition of the Ras/Raf/MAPK kinase (MEK)/ERK signaling pathway in HCC cells. In both acquired sorafenib-resistant cell and xenograft models, NPC2 and free cholesterol secretion were increased in culture supernatant and serum samples. In conclusion, NPC2-mediated free cholesterol secretion may represent a candidate biomarker for the likelihood of HCC cells developing resistance to sorafenib.
Highlights
Liver cancer was the fourth leading cause of cancer deaths worldwide in 2018
Niemann-Pick type C2 (NPC2) Downregulation Facilitates Free Cholesterol Accumulation which Weakened Sorafenib Efficacy through Enhancing mitogen-activated protein kinase (MAPK)/AKT Signaling in Hepatocellular carcinoma (HCC) Cells
We showed that NPC2 downregulation is related to the development of nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma [21,23,24] the effects of NPC2 expression and intracellular free cholesterol homeostasis on sorafenib sensitivity have not been explored in detail
Summary
Liver cancer was the fourth leading cause of cancer deaths worldwide in 2018. It was estimated that about 841,000 new cases are diagnosed and 782,000 deaths occur annually [1]. Primary liver cancer includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, and other rare types. HCC is the most common primary liver malignancy, comprising 75%~85% of all cases [2]. Chronic liver disease and cirrhosis remain the main risk factors for developing HCC [3]. Major risk factors include chronic infection with hepatitis B or C virus, heavy alcohol consumption, obesity, and type 2 diabetes [3]. It was reported that only about 30% of patients are responsive to sorafenib treatment [7], and about 70% of patients develop acquired resistance within 6 months [8]. Since sorafenib treatment only prolongs survival for a few months and sorafenib resistance develops in most patients, identifying novel biomarkers that can reflect the sorafenib response is urgently needed
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