Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells

Kentaro Nasu, Kazunori Yamaguchi, Tomoka Takanashi, Keiichi Tamai, Ikuro Sato, Shoji Ine, Osamu Sasaki, Kennichi Satoh, Nobuyuki Tanaka, Yuetsu Tanaka, Takuya Fukushima, Hideo Harigae, Kazuo Sugamura

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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-CA9high and ST1-CA9low sublines. ST1-CA9high cells, like ST1-N6 cells, were more strongly tumorigenic than ST1-CA9low or parental ST1 cells when injected into NOG mice. Knockdown of CA9 with shRNAs suppressed the ability of ST1-CA9high cells 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.

Original languageEnglish
Pages (from-to)435-443
Number of pages9
JournalCancer science
Volume108
Issue number3
DOIs
Publication statusPublished - 2017 Mar 1

Keywords

  • Adult T-cell leukemia/lymphoma
  • carbonic anhydrase IX
  • human T-cell leukemia virus type 1
  • tumorigenicity
  • xenotransplantation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Nasu, K., Yamaguchi, K., Takanashi, T., Tamai, K., Sato, I., Ine, S., Sasaki, O., Satoh, K., Tanaka, N., Tanaka, Y., Fukushima, T., Harigae, H., & Sugamura, K. (2017). Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells. Cancer science, 108(3), 435-443. https://doi.org/10.1111/cas.13163