A Novel Function for KLF4 in Modulating the De-differentiation of EpCAM-/CD133- nonStem Cells into EpCAM+/CD133+ Liver Cancer Stem Cells in HCC Cell Line HuH7

Cells

Esra Erdal¹  Eren Sahin¹  Sanem Tercan Avci¹  Soheil Akbari¹  Kıvılcım Eren Ates²  Tugsan Balli³  Zeynep Firtina Karagonlar⁴  Bilge Karacicek⁵  Nese Atabey⁵  Mustafa Karabicici⁵  Kubra Nur Kaplan⁵  Nevin Ersoy⁵  Canan Celiker⁵ 

[1] Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey;Department of Pathology, Faculty of Medicine, Cukurova University, 01260 Adana, Turkey;Department of Radiology, Faculty of Medicine, Cukurova University, 01260 Adana, Turkey;Genetics and Bioengineering Department, Izmir University of Economics, 35330 Izmir, Turkey;Izmir Biomedicine and Genome Center, 35340 Izmir, Turkey;

关键词: hepatocellular carcinoma (HCC);    liver cancer stem cells;    tumor plasticity;    KLF4;    reprogramming;    EpCAM;   

DOI  :  10.3390/cells9051198

来源: DOAJ

【 摘 要 】

The complex and heterogeneous nature of hepatocellular carcinoma (HCC) hampers the identification of effective therapeutic strategies. Cancer stem cells (CSCs) represent a fraction of cells within tumors with the ability to self-renew and differentiate, and thus significantly contribute to the formation and maintenance of heterogeneous tumor mass. Increasing evidence indicates high plasticity in tumor cells, suggesting that non-CSCs could acquire stem cell properties through de-differentiation or reprogramming processes. In this paper, we reveal KLF4 as a transcription factor that can induce a CSC-like phenotype in non-CSCs through upregulating the EpCAM and E-CAD expression. Our studies indicated that KLF4 could directly bind to the promoter of EpCAM and increase the number of EpCAM⁺/CD133⁺ liver cancer stem cells (LCSCs) in the HuH7 HCC cell line. When KLF4 was overexpressed in EpCAM^-/CD133^- non-stem cells, the expressions of hepatic stem/progenitor cell genes such as CK19, EpCAM and LGR5 were significantly increased. KLF4 overexpressing non-stem cells exhibited greater cell viability upon sorafenib treatment, while the cell migration and invasion capabilities of these cells were suppressed. Importantly, we detected an increased membranous expression and colocalization of β-CAT, E-CAD and EpCAM in the KLF4-overexpressing EpCAM^-/CD133^- non-stem cells, suggesting that this complex might be required for the cancer stem cell phenotype. Moreover, our in vivo xenograft studies demonstrated that with a KLF4 overexpression, EpCAM^-/CD133^- non-stem cells attained an in vivo tumor forming ability comparable to EpCAM⁺/CD133⁺ LCSCs, and the tumor specimens from KLF4-overexpressing xenografts had increased levels of both the KLF4 and EpCAM proteins. Additionally, we identified a correlation between the KLF4 and EpCAM protein expressions in human HCC tissues independent of the tumor stage and differentiation status. Collectively, our data suggest a novel function for KLF4 in modulating the de-differentiation of tumor cells and the induction of EpCAM⁺/CD133⁺ LCSCs in HuH7 HCC cells.

【 授权许可】

Unknown