Abstract
Most hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage; however, the effect of systemic therapy on advanced HCC remains undetermined. Therefore, new treatment targets must be identified. We analyzed Gene Expression Omnibus datasets from two HCC patient cohorts and found that NT5DC2 was associated with vascular invasion and poor survival. In two hepatoma cell lines, NT5DC2 overexpression promoted HCC cell proliferation and clone formation in vitro and promoted tumor growth in vivo. Coimmunoprecipitation assays and liquid chromatography with tandem mass spectrometry analysis revealed that NT5DC2 bound directly to epidermal growth factor receptor (EGFR). NT5DC2 upregulated EGFR expression by downregulating EGFR ubiquitination and preventing its degradation via the ubiquitin-proteasome pathway but did not upregulate its transcription. EGFR upregulation activated downstream signal transduction, which played a critical role in the protumor effects of NT5DC2. Erlotinib, a small-molecule inhibitor of EGFR, blocked the effect of NT5DC2 in promoting HCC cell proliferation. In a cohort of 79 patients who underwent curative resection for HCC, NT5DC2 expression in the tumors was associated with larger tumors and microvascular invasion. NT5DC2 expression was also independently associated with recurrence-free survival. The present study demonstrated for the first time that NT5DC2 promotes tumor cell proliferation in HCC and may serve as a potential molecular target for treating HCC. EGFR blockage could be used to treat selected patients with NT5DC2 upregulation.
Highlights
Liver cancer ranks sixth in incidence and fourth in mortality globally among all malignant tumors[1]
The expression profiles of normal liver tissue, low-risk metastatic (LRM) Hepatocellular carcinoma (HCC), which refers to primary HCC without venous metastases and no recurrence within 2 years after liver resection, and high-risk metastatic (HRM) HCC, which refers to primary HCC with macroscopic tumor thrombus in the major branch of the portal vein or inferior vena cava at diagnosis, were compared to identify genes associated with early recurrence in the GSE54238 dataset[24]
Venous metastasis and early recurrence are associated with poor outcomes for HCC patients[22,24]
Summary
Liver cancer ranks sixth in incidence and fourth in mortality globally among all malignant tumors[1]. According to the Global Burden of Disease Cancer Collaboration, liver cancer was the second leading cause of absolute years of life lost among both sexes in 20172. Hepatocellular carcinoma (HCC) is the primary pathological type of liver cancer. The treatment regimen for hepatocellular carcinoma includes surgery, liver transplantation, patients because most patients are diagnosed at advanced stages and have lost the window for surgical treatment and must receive systemic therapy[4]. Molecular targeted therapy is a promising area that has shown progress in treating malignant tumors[5,6]. Few molecular targeted drugs have been approved by the Food and Drug
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