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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.

ABSTRACT: 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 ?-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.

SUBMITTER: Karagonlar ZF

PROVIDER: S-EPMC7290717 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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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.

Karagonlar Zeynep Firtina ZF Akbari Soheil S Karabicici Mustafa M Sahin Eren E Avci Sanem Tercan ST Ersoy Nevin N Ates Kıvılcım Eren KE Balli Tugsan T Karacicek Bilge B Kaplan Kubra Nur KN Celiker Canan C Atabey Nese N Erdal Esra E

Cells 20200512 5

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 o ...[more]

PMID: 32408542

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Project description:The therapeutic induction of senescence is a potential means to treat cancer, primarily acting through the induction of a persistent growth-arrested state in tumors. However, recent studies have indicated that therapy-induced senescence (TIS) in tumor cells allows for the prolonged survival of a subgroup of cells in a dormant state, with the potential to re-enter the cell cycle along with an increased stemness gene expression. Residual cells after TIS with increased cancer stem cell phenotype may have profound implications for tumor aggressiveness and disease recurrence. Herein, we investigated senescence-associated stemness in EpCAM+/CD133+ liver cancer stem cell and EpCAM-/CD133- nonstem cell populations in HuH7 cell line. We demonstrated that treatment with doxorubicin induces senescence in both cell populations, accompanied by a significant increase in the expression of reprogramming genes SOX2, KLF4, and c-MYC as well as liver stemness-related genes EpCAM, CK19, and ANXA3 and the multidrug resistance-related gene ABCG2. Moreover, doxorubicin treatment significantly increased EpCAM + population in nonstem cells indicating senescence-associated reprogramming of nonstem cell population. Also, Wnt/β-catenin target genes were increased in these cells, while inhibition of this signaling pathway decreased stem cell gene expression. Importantly, Dox-treated EpCAM-/CD133- nonstem cells had increased in vivo tumor-forming ability. In addition, when SASP-CM from Dox-treated cells were applied onto hİPSC-derived hepatocytes, senescence was induced in hepatocytes along with an increased expression of TGF-β, KLF4, and AXIN2. Importantly, SASP-CM was not able to induce senescence in Hep3B-TR cells, a derivative line rendered resistant to TGF-β signaling. Furthermore, ELISA experiments revealed that the SASP-CM of Dox-treated cells contain inflammatory cytokines IL8 and IP10. In summary, our findings further emphasize the importance of carefully dissecting the beneficial and detrimental aspects of prosenescence therapy in HCC and support the potential use of senolytic drugs in HCC treatment in order to eliminate adverse effects of TIS.

Dataset Information

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.

Publications

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

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