title: Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells.
abstract: Carbonic anhydrase IX (CA9) is a membrane-associated carbonic anhydrase that regulates cellular pH, is upregulated in various solid tumors, and is considered to be a therapeutic target. Here, we describe the essential role of CA9 in the tumorigenicity of cells derived from human adult T-cell leukemia/lymphoma (ATL). We previously established the highly tumorigenic ST1-N6 subline from the ATL-derived ST1 cell line by serial xenotransplantation in NOG mice. In the present study, we first show that CA9 expression is strongly enhanced in ST1-N6 cells. We then sorted ST1 cells by high or low CA9 expression and established ST1-CA9highand ST1-CA9lowsublines. ST1-CA9highcells, like ST1-N6 cells, were more strongly tumorigenic than ST1-CA9lowor parental ST1 cells when injected into NOG mice. Knockdown of CA9 with shRNAs suppressed the ability of ST1-CA9highcells to initiate tumors, and the tumorigenicity of ST1 cells was significantly enhanced by introducing wild-type CA9 or a CA9 mutant with deletion of an intracytoplasmic domain. However, a CA9 with point mutations in the catalytic site did not increase the tumorigenicity of ST1 cells. Furthermore, we detected a small population of CA9+CD25+cells in lymph nodes of ATL patients. These findings suggest that CA9, and particularly its carbonic anhydrase activity, promotes the tumorigenicity of ATL-derived cells and may be involved in malignant development of lymphoma-type ATL.
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.|Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nasu
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.|Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Takanashi
authors.affiliation: Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.|Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tamai
authors.affiliation: Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.|Division of Pathology, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Ikuro
authors.initials: I
authors.lastname: Sato
authors.affiliation: Division of Hematology, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Ine
authors.affiliation: Division of Hematology, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sasaki
authors.affiliation: Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.|Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Kennichi
authors.initials: K
authors.lastname: Satoh
authors.affiliation: Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.|Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Laboratory of Hemato-Immunology, Faculty of Medicine, School of Health Sciences, University of the Ryukyus, Okinawa, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX / Q000235:genetics* / Q000378:metabolism*; D020134:Catalytic Domain / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D000951:Antigens, Neoplasm; D034741:RNA, Small Interfering; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX
keywords: Adult T-cell leukemia/lymphoma; carbonic anhydrase IX; human T-cell leukemia virus type 1; tumorigenicity; xenotransplantation