Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells.
Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells.
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DOI：
10.1111/cas.13163
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发表时间：
2017-03
期刊：
影响因子：
5.7
通讯作者：
Sugamura K
中科院分区：
文献类型：
--
作者：
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
碳酸酐酶IX（CA 9）是一种膜相关碳酸酐酶，可调节细胞pH值，在各种实体瘤中上调，被认为是治疗靶点。在这里，我们描述了CA 9在人成人T细胞白血病/淋巴瘤（ATL）细胞致瘤性中的重要作用。我们之前通过在NOG小鼠中进行连续异种移植，从ATL衍生的ST 1细胞系中建立了高度致瘤性的ST 1-N6亚系。在本研究中，我们首先表明，CA 9表达在ST 1-N6细胞中强烈增强。然后，我们通过高或低CA 9表达分选ST 1细胞，并建立ST 1-CA 9高和ST 1-CA 9低亚系。与ST 1-N6细胞一样，ST 1-CA 9 high细胞在注射到NOG小鼠中时比ST 1-CA 9 low或亲本ST 1细胞具有更强的致瘤性。用shRNA敲低CA 9抑制了ST 1-CA 9 high细胞引发肿瘤的能力，并且通过引入野生型CA 9或缺失胞质内结构域的CA 9突变体显著增强了ST 1细胞的致瘤性。然而，在催化位点具有点突变的CA 9并不增加ST 1细胞的致瘤性。此外，我们在ATL患者的淋巴结中检测到少量CA 9 + CD 25+细胞。这些发现表明，CA 9，特别是其碳酸酐酶活性，促进ATL衍生细胞的致瘤性，并可能参与淋巴瘤型ATL的恶性发展。
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.