title: Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma.
abstract: The proto-oncogene BMI1 and its product, Bmi1, is overexpressed in various types of tumors, particularly in aggressive tumors and tumors resistant to conventional chemotherapy. BMI1/Bmi1 is also crucially involved in cancer-initiating cell maintenance, and is recurrently upregulated in mantle cell lymphoma (MCL), especially aggressive variants. Recently, side population (SP) cells were shown to exhibit tumor-initiating characteristics in various types of tumors. In this study, we show that recurrent MCL cases significantly exhibit upregulation of BMI1/Bmi1. We further demonstrate that clonogenic MCL SP shows such tumor-initiating characteristics as high tumorigenicity and self-renewal capability, and that BMI1 was upregulated in the SP from recurrent MCL cases and MCL cell lines. On screening for upstream regulators of BMI1, we found that expression of microRNA-16 (miR-16) was downregulated in MCL SP cells by regulating Bmi1 in the SPs, leading to reductions in tumor size following lymphoma xenografts. Moreover, to investigate downstream targets of BMI1 in MCL, we performed cross-linking/chromatin immunoprecipitation assay against MCL cell lines and demonstrated that Bmi1 directly regulated pro-apoptotic genes such as BCL2L11/Bim and PMAIP1/Noxa, leading to enhance anti-apoptotic potential of MCL. Finally, we found that a proteasome inhibitor bortezomib, which has been recently used for relapsed MCL, effectively induced apoptosis among MCL cells while reducing expression of Bmi1 and increasing miR-16 in MCL SP. These results suggest that upregulation of BMI1 and downregulation of miR-16 in MCL SP has a key role in the disease's progression by reducing MCL cell apoptosis. Our results provide important new insight into the pathogenesis of MCL and strongly suggest that targeting BMI1/Bmi1 might be an effective approach to treating MCL, particularly refractory and recurrent cases.
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Teshima
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nara
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Internal Medicine, Yamamoto Kumiai General Hospital, Noshiro, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hatano
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Department of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Seto
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tagawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D058985:Side-Population Cells / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C069077:BMI1 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001897:Boronic Acids; C000715470:MAS1 protein, human; C505362:MIRN16 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C498702:PMAIP1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D000069286:Bortezomib; D063150:Polycomb Repressive Complex 1