Xenotransplantation elicits salient tumorigenicity of adult T-cell leukemia-derived cells via aberrant AKT activation.
Xenotransplantation elicits salient tumorigenicity of adult T-cell leukemia-derived cells via aberrant AKT activation.
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DOI：
10.1111/cas.12921
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发表时间：
2016-05
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：
Yamaguchi K;Takanashi T;Nasu K;Tamai K;Mochizuki M;Satoh I;Ine S;Sasaki O;Satoh K;Tanaka N;Harigae H;Sugamura K
将人类癌细胞移植到免疫缺陷型NOD/SCID/IL-2 R γcnull（NOG）小鼠中通常会导致高度恶性的细胞群（如癌症干细胞）出现。在这里，通过在NOG小鼠中的连续移植，我们建立了两种高度致瘤性的成人T细胞白血病衍生细胞系ST 1-N6和TL-Om 1-N8。当皮下移植时，这些细胞形成肿瘤的时间比其亲本系ST 1和TL-Om 1显着更早，且初始细胞更少。我们发现，蛋白激酶B（AKT）信号在ST 1-N6和TL-Om 1-N8细胞中上调，这种上调是由于负调节因子INPP 5D的表达减少。此外，将组成型活性AKT突变体表达载体引入ST 1细胞增强了细胞的致瘤性，而用AKT抑制剂MK-2206治疗则减弱了ST 1-N6细胞诱导的肿瘤进展。总的来说，我们的研究结果表明，AKT信号通路在成人T细胞白血病衍生细胞的恶性肿瘤中起着关键作用。
The transplantation of human cancer cells into immunodeficient NOD/SCID/IL‐2Rγcnull (NOG) mice often causes highly malignant cell populations like cancer stem cells to emerge. Here, by serial transplantation in NOG mice, we established two highly tumorigenic adult T‐cell leukemia‐derived cell lines, ST1‐N6 and TL‐Om1‐N8. When transplanted s.c., these cells formed tumors significantly earlier and from fewer initial cells than their parental lines ST1 and TL‐Om1. We found that protein kinase B (AKT) signaling was upregulated in ST1‐N6 and TL‐Om1‐N8 cells, and that this upregulation was due to the decreased expression of a negative regulator, INPP5D. Furthermore, the introduction of a constitutively active AKT mutant expression vector into ST1 cells augmented the tumorigenicity of the cells, whereas treatment with the AKT inhibitor MK‐2206 attenuated the progression of tumors induced by ST1‐N6 cells. Collectively, our results reveal that the AKT signaling pathway plays a critical role in the malignancy of adult T‐cell leukemia‐derived cells.