Abstract
BackgroundSeveral markers have been reported to be specific for hepatic cancer stem cells (HCSCs), which is usually thought to be highly associated with poor clinical outcomes. Tumor-infiltrating immune cells act as an important factor for oncogenesis. Little is known about the correlation of HCSC markers to prognosis and immune infiltrates.MethodsExpression of HCSC markers was analyzed through Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA) and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), respectively. The prognostic effect of HCSC markers was evaluated using Kaplan-Meier plotter in association with different tumor stages, risk factors, and gender. The correlation of HCSC markers to tumor-infiltrating immune cells was tested by Tumor Immune Estimation Resource (TIMER). HCSC markers related gene sets were investigated by GEPIA, with their biological functions being analyzed by Cytoscape software.ResultsThe expression level of 10 HCSC markers in HCC was higher than that in normal tissues in at least one database. Among them, high expression of CD24, SOX9, and SOX12 was positively correlated with poor prognosis (CD24: OS P = 0.0012, PFS P = 7.9E–05. SOX9: OS P = 0.012. SOX12: OS P = 0.0004, PFS P = 0.0013, respectively). However, the expression of CD13, CD34 and ALDH1A1 was associated with prolonged OS and PFS. SOX12 was significantly upregulated in poor prognosis of HCC patients with different conditions. Besides, total nine HCSC markers were identified to be positively associated with immune infiltration, including SOX12. Furthermore, Toll-like receptor signaling pathway was found to be one major pathway of these HCSC markers related gene networks.ConclusionOur results suggest that seven upregulated HCSC markers (CD90, EpCAM, CD133, CD24, SOX9, CK19, and SOX12) are related with poor prognosis and immune infiltration in HCC. In addition, we find that high SOX12 expression remarkably affect prognosis in male HCC patients but not in female. HCC patients under viral infection or alcohol intake with increased SOX12 expression had poorer prognosis. Therefore, HCSCs markers likely play an important role in tumor related immune infiltration and SOX12 might be a potential therapeutic target in patients with HCC.
Highlights
Liver cancer is the second leading cause of worldwide cancer death in men, and sixth in women (Torre et al, 2015; Ferlay et al, 2019), and it accounts approximately 50% of the total number of cancer cases and deaths in China (Torre et al, 2015)
To determine the differences between expression level of hepatic cancer stem cells (HCSCs) markers in hepatocellular carcinoma (HCC) and normal tissues, the mRNA levels of CD90, epithelial cell adhesion molecules (EpCAM), CD133, CD24, CD13, CD34, sex determining region Y-box 9 (SOX9), ABCG2, CD44, ALDH1A1, ALDH3A1, CK19, sex determining region Y-box 12 (SOX12), and CD47 in HCC and normal tissues were analyzed based on Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA) and HCCDB database, respectively
The mRNA expression levels of nine HCSC markers were up-regulated in patients with HCC in Oncomine database, while seven and six were up-regulated in GEPIA database and HCCDB, respectively (Figures 1A–C)
Summary
Liver cancer is the second leading cause of worldwide cancer death in men, and sixth in women (Torre et al, 2015; Ferlay et al, 2019), and it accounts approximately 50% of the total number of cancer cases and deaths in China (Torre et al, 2015). It has been known that the tumor-infiltrating immune cells play a key role in tumor microenvironment of HCC, such as tumor-associated macrophages (TAMs) (Werb and Coussens, 2002) and tumor-infiltrating lymphocytes (TILs) (Chen and Mellman, 2013). TAMs produce factors that maintain cancerrelated inflammation and potentiate tumor progression (Schoppmann et al, 2002), whereas some TILs may control cancer outcome (Gao et al, 2007). Emerging immunotherapies of immune checkpoint blockade for HCC, like programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen 4 (CTLA-4), are still in the start-up stage compared to other tumors. Several markers have been reported to be specific for hepatic cancer stem cells (HCSCs), which is usually thought to be highly associated with poor clinical outcomes. Little is known about the correlation of HCSC markers to prognosis and immune infiltrates
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