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

Autor: Soheil Akbari, Zeynep Firtina Karagonlar, Neşe Atabey, Kivilcim Eren Ates, Mustafa Karabicici, Kubra Nur Kaplan, Eren Şahin, Esra Erdal, Tuğsan Ballı, Canan Celiker, Bilge Karacicek, Sanem Tercan Avci, Nevin Ersoy
Rok vydání: 2020
Předmět:
0301 basic medicine
Carcinoma
Hepatocellular
Transcription
Genetic
Carcinogenesis
Kruppel-Like Transcription Factors
Mice
SCID
Article
hepatocellular carcinoma (HCC)
Kruppel-Like Factor 4
03 medical and health sciences
0302 clinical medicine
Mice
Inbred NOD
Cancer stem cell
Cell Line
Tumor
Animals
Humans
AC133 Antigen
Progenitor cell
lcsh:QH301-705.5
beta Catenin
Chemistry
tumor plasticity
Cell Membrane
Liver Neoplasms
LGR5
reprogramming
Cell migration
General Medicine
Cell Dedifferentiation
Cadherins
Epithelial Cell Adhesion Molecule
KLF4
Phenotype
030104 developmental biology
lcsh:Biology (General)
liver cancer stem cells
Cell culture
EpCAM
030220 oncology & carcinogenesis
embryonic structures
Neoplastic Stem Cells
Cancer research
biological phenomena
cell phenomena
and immunity
Stem cell
Reprogramming
Zdroj: Cells
Cells, Vol 9, Iss 1198, p 1198 (2020)
Volume 9
Issue 5
ISSN: 2073-4409
Popis: 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 &beta
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.
Databáze: OpenAIRE
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