Abstract 3338: DLK1 could be a potential target against the cancer stem/progenitor cells of hepatocellular carcinoma

Abstract

Abstract Introduction: DLK1 is considered to play a vital role in the development of liver, and the oncogenesis and progress of hepatocellular carcinoma (HCC). It has been reported that mouse DLK1(+) fetal hepatic cells are able to differentiate into hepatocytes and biliary epithelial cell lineages and exhibit more proliferative than DLK1(−) cells. Recently, some studies demonstrated that DLK1 was frequently up-regulated in HCC, concomitant with known potential cancer stem/progenitor markers, and ectopic DLK1 promoted the proliferation of HCC cells. However, the biological behaviors of DLK1(+) HCC cells remain largely unknown, and whether DLK1 as a membrane protein could serve as a potential therapeutic target for HCC need further investigation. Methods: The proportion of DLK1(+) cells in HCC cell lines was evaluated by flow cytometry. Both DLK1(+) and DLK1(−) cells were isolated by fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS), respectively. Self-renewal, chemoresistance, colony formation and spheroid colony formation ability of the two cell populations were evaluated. In vivo tumorigenicity experiment was performed in BALB/c nude mice or NOD/SCID mice. In addition, cell proliferation, colony formation, spheroid colony formation assays and tumorigenicity experiments were also employed to assess the effect of RNA interference against DLK1 on HCC cells. Results: DLK1(+) population was less than 10 percentage of all 10 HCC cell lines examined by flow cytometry analysis. Interestingly, DLK1(+) HCC cells sorted by FACS or MACS showed stronger ability of chemoresistance, colony formation and spheroid colony formation in vitro, and increased tumorigenicity ability in vivo, as compared with DLK1(−) cells. The DLK1(+) HCC cells with the property of self-renewal could generate differentiated progeny without DLK1 expression. Furthermore, DLK1 knockdown by adenovirus-mediated short hairpin RNA interference could significantly suppress the ability of proliferation, colony formation and spheroid colony formation, as well as in vivo tumorigenicity of HCC cells. Conclusion: DLK1(+) human HCC cells are endowed with characteristics similar to those of cancer stem/progenitor cells. RNA interference against DLK1 can suppress the tumorigenicity of HCC cells, possibly through inhibiting the malignant behaviors of cancer stem/progenitor cells, which suggested that DLK1 could be a potential therapeutic target against the HCC stem/progenitor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3338.