Research Papers:

FOXO4 expression is related to stem cell-like properties and resistance to treatment in diffuse large B-cell lymphoma

Kyung Ju Ryu, Chaehwa Park, Mineui Hong, Young Hyeh Ko, Won Seog Kim and Seok Jin Kim _

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Oncotarget. 2017; 8:2466-2476. https://doi.org/10.18632/oncotarget.13690

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Kyung Ju Ryu1,*, Chaehwa Park2,*, Mineui Hong3, Young Hyeh Ko4, Won Seog Kim5, Seok Jin Kim1,5

1Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea

2Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea

3Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, Korea

4Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

5Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

*These authors contributed equally to this work

Correspondence to:

Seok Jin Kim, email: [email protected]

Keywords: stem cell, FOXO4, resistance, B-cell, lymphoma

Received: July 02, 2016     Accepted: November 22, 2016     Published: November 29, 2016


Cancer stem cells are proposed to be responsible for resistance to chemotherapeutic agents, including doxorubicin. As phenylbutyrate enhances cancer stem cell properties, we analyzed surviving lymphoma cells after treatment with doxorubicin and phenylbutyrate. Human B-cell lymphoma cell lines, including Toledo, BJAB, Daudi, and Raji were incubated with IC90 concentrations of doxorubicin (300 nM) or phenylbutyrate (8 mM). After 48 h, live cells were sorted and analyzed for their resistance to treatment by examining gene expression profiles using cDNA microarray and biological characteristics. A small fraction of lymphoma cells that survived after drug application showed higher expression of stem cell markers (NANOG, and SOX2) and superior ability of self-renewal and sphere formation, compared to untreated control cells (P < 0.05). Gene expression analysis disclosed elevated expression of 41 genes, including FOXO4, in the four lymphoma cell lines that survived drug treatment. Overexpression of FOXO4 was evident in lymphoma cells surviving after phenylbutyrate treatment and refractory patient-derived lymphoma cells. Induction of FOXO4 expression promoted self-renewal whereas its knockdown led to diminished expression of stem cell markers and colony-forming ability of lymphoma cells. Immunohistochemical staining for FOXO4 in tumor tissue of diffuse large B-cell lymphoma revealed nuclear localization and significant association with poor prognosis. In conclusion, lymphoma cells resistant to treatment exhibit stem cell-like properties and enhanced FOXO4 expression. The presence of FOXO4-expressing cells in tumor tissue and their association with poor survival supports a role of FOXO4 in promoting stem cell properties resulting in poor outcomes.

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