ABSTRACT
Primary hepatocellular carcinoma as the main pathological type of liver cancer is one of the common malignant tumors in our country. Liver cancer stem cells (LCSCs) have the characteristics of multidrug resistance, anti-radiotherapy and high tumorigenicity in addition to the characteristics of stem cells, namely, self-renewal, multi-directional differentiation and unlimited proliferation. Based on the above features, relapse and metastasis often occur after the patients being treated with conventional methods, which results in poor prognosis. Effective treatment targeting LCSCs has the potential to cure hepatocellular carcinoma (HCC) completely. This article reviews the common biomarkers used in identification of LCSCs and development of stem cell-targeted therapy for HCC.
ABSTRACT
Liver cancer stem cells have the abilities of infinite proliferation,self-renewal,chemoradiation tolerance,high tumorigenicity and stem cell characteristics.The proportion of liver cancer stem cells is positively correlated with the malignancy of the tumor.MicroRNAs (miRNA) can regulate the expression of many genes by degrading mRNA or inhibiting mRNA translation.MicroRNAs also play an important role in a series of life activities such as embryogenesis,tissue and organ development,cell growth and differentiation,apoptosis,disease development.In-depth study of specific miRNA in the occurrence and development of liver cancer and its role in LCSCs,it may provide a new target for prevention and treatment of recurrence and metastasis of liver cancer.
ABSTRACT
Objective To study the effect of radiofrequency ablation (RFA) with sublethal temperature on the production of liver cancer stem cells (LCSCs) and on the expression of LCSCs-related transcriptional factors.Methods Mouse hepl-6 hepatoma cell line and clinical samples of patients with hepatocellular carcinoma (HCC) were used to test the expressions of LCSCs-related markers and transcriptional factors.Results Different temperatures were used to stimulate Hep1-6 cells,and it was proved that the temperature of 45℃ was a sublethal temperature that could not induce cell death.Flow cytometry testing showed that treatment with 45℃ could obviously increase CD13+,CD44+,CD90 and CD133+ Hep1-6 cells,suggesting that treatment with 45℃ could increase the production of above mentioned types of LCSCs in hep1-6 cells.Real-time quantitative polymerase chain reaction (RT-qPCR) assay indicated that the temperature of 45℃could cause significant increase in CD13,CD90 and CD133 mRNA.In all 5 HCC patients,CD13 mRNA in the recurrent HCC lesions was remarkably increased,CD133 mRNA was increased in 4 patients with recurrent HCC,and CD90 mRNA was increased in only one patient with recurrent HCC.Flow cytometry testing revealed that CD13+ LCSCs were strikingly increased in 4 recurrent HCC patients,while CD133+LCSC was increased in only one patient,suggesting that more close correlation existed between the increase of CD13+ LCSCs and the temperature of 45℃.RT-qPCR assay showed that in 4 recurrent HCC patients with increased CD13+ LCSC,the Sox2 and Stat2 among 13 LCSCs-related transcriptional factors were obviously increased.Flow cytometry testing showed that 45℃ treatment also increased the expression of Sox2 and Stat1 mRNA in Hep1-6 cells.Finally,Sox2 and Stat1 could be knockdown by siRNAs,indicating that both Sox2 and Stat1 transcriptional factors were involved in 45℃-induced production of CD13+ LCSCs in Hep1-6 cells.Conclusion In RFA therapy,the use of sublethal temperature of 45℃ can increase CD13+LCSCs,which is related to the promotion of Sox2 and Stat1 expression.The results of this study can be used for reference in the research of liver cancer recurrence.
ABSTRACT
Accumulating evidence has indicated the importance of cancer stem cells in carcinogenesis. The goal of the present study was to determine the effect of low-dose cisplatin on enriched liver cancer stem cells (LCSCs). Human hepatoblastoma HepG2 cells were treated with concentrations of cisplatin ranging from 1 to 5 μg/mL. Cell survival and proliferation were evaluated using a tetrazolium dye (MTT) assay. LCSCs were identified using specific markers, namely aldehyde dehydrogenase-1 (ALDH1) and CD133. The percentage of ALDH1+ or CD133+ cells was examined by flow cytometric analysis. The expression of ALDH1 and/or CD133 in HepG2 cells was determined by immunocytochemical analysis. Low-dose cisplatin treatment significantly decreased cell survival in HepG2 cells after 24 or 72 h. However, the percentage of LCSCs in the surviving cells was greatly increased. The percentage of ALDH1+ or CD133+ cells was increased in a time- and dose-dependent manner after treatment with 1-4 μg/mL cisplatin, whereas 5 μg/mL cisplatin exposure slightly reduced the number of positive cells. These findings indicate that low-dose cisplatin treatment may efficiently enrich the LCSC population in HepG2 cells.