title: FOXO4 expression is related to stem cell-like properties and resistance to treatment in diffuse large B-cell lymphoma.
abstract: 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.
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Kyung Ju
authors.initials: KJ
authors.lastname: Ryu
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Chaehwa
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, Korea.
authors.forename: Mineui
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Young Hyeh
authors.initials: YH
authors.lastname: Ko
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Seok Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D051858:Forkhead Transcription Factors; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010654:Phenylbutyrates / Q000494:pharmacology; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D010654:Phenylbutyrates; D014157:Transcription Factors; D004317:Doxorubicin
keywords: B-cell; FOXO4; lymphoma; resistance; stem cell