Abstract
Delta-like 1 homolog (DLK1; Drosophila) is a hepatic stem/progenitor cell marker in fetal livers that plays a vital role in oncogenesis of hepatocellular carcinoma (HCC). The aim of this study is to investigate whether DLK1 could serve as a potential therapeutic target against cancer stem/progenitor cells of HCC. DLK1(+) and DLK1(-) cells were sorted by fluorescence-activated cell sorting and magnetic-activated cell sorting, respectively, and then were evaluated by flow cytometry. The biological behaviors of these isolated cells and those with DLK1 knockdown were assessed by growth curve, colony formation assay, spheroid colony formation, chemoresistance, and in vivo tumorigenicity. Adenovirus-mediated RNA interference was used to knockdown the endogenous DLK1. We found that DLK1(+) population was less than 10% in almost all 17 HCC cell lines examined. DLK1(+) HCC cells showed stronger ability of chemoresistance, colony formation, spheroid colony formation, and in vivo tumorigenicity compared with DLK1(-) cells. The DLK1(+) HCC cells could generate the progeny without DLK1 expression. Furthermore, DLK1 knockdown could suppress the ability of proliferation, colony formation, spheroid colony formation, and in vivo tumorigenicity of Hep3B and Huh-7 HCC cells. Our data suggested that DLK1(+) HCC cells have characteristics similar to those of cancer stem/progenitor cells. RNA interference against DLK1 can suppress the malignant behaviors of HCC cells, possibly through directly disrupting cancer stem/progenitor cells, which suggested that DLK1 could be a potential therapeutic target against the HCC stem/progenitor cells.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and the second leading cause of cancer-related mortality worldwide [1]
More and more evidences have been reported that oncogenesis, development, and relapse of many cancers could be ascribed to cancer stem cells (CSC)
HCC, like other cancers, could be original from the malignant stem/ progenitor cells. Some membrane molecules such as CD90 were identified as the markers of liver CSCs [25], other membrane molecules relevant to hepatic development were proposed as markers of HCC stem/progenitor cells
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and the second leading cause of cancer-related mortality worldwide [1]. During the last few years, increasing evidences have been shown to support the hypothesis that, among a hierarchy of heterogeneous cell populations within a tumor, a small subpopulation called cancer stem cells (CSC) is responsible for the tumor initiation, growth, metastasis, and recurrence [3,4,5,6]. This cell subpopulation exhibits the stem/progenitor cell-like characteristics such as self-renewal and differentiation. Previous studies suggested that CSCs existed in leukemia [7, 8] and some solid tumors, including breast cancer [9, 10], glioblastoma [11, 12], prostate cancer [13,14,15,16], gastric carcinoma [17, 18], Authors' Affiliations: 1National Human Genome Center of Rui-Jin Hospital, Shanghai Jiaotong University School of Medicine; and 2ShanghaiMOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China
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