Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells.
Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells.
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DOI：
10.1038/s41598-021-83613-2
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发表时间：
2021-02-18
影响因子：
4.6
通讯作者：
Uchimaru K
中科院分区：
文献类型：
--
作者：
Nakano K;Chihara Y;Kobayashi S;Iwanaga M;Utsunomiya A;Watanabe T;Uchimaru K
Wnt 5a是参与细胞分化、运动和炎症反应的非经典Wnt信号传导途径的配体。成人T细胞白血病/淋巴瘤（ATL）是由人T细胞白血病病毒1型（HTLV-1）感染引起的最具侵袭性的T细胞恶性肿瘤之一。在ATL的亚型中，急性型ATL细胞对目前的多药化疗特别耐药，并显示出显著高的细胞增殖和侵袭表型。在这里，我们显示了一个显着增加的WNT 5A基因表达在急性型ATL细胞与惰性型ATL细胞相比。用IWP-2或Wnt 5a特异性敲低处理显著抑制ATL衍生的T细胞系的细胞生长。我们证明了c-Myb和FoxM 1的过表达是WNT 5A启动子协同激活的原因。此外，在急性型ATL细胞中，编码Δ C-Wnt 5（380个氨基酸中的1- 136个氨基酸）的不含外显子4的WNT 5A转录变体（ΔE4-WNT 5A mRNA）过表达。与野生型（WT）-Wnt 5a相比，Δ C-Wnt 5a在细胞外分泌并在更大程度上增强细胞迁移/侵袭。此外，Δ C-Wnt 5a的分泌不受IWP-2的抑制，表明该突变体Wnt 5a通过与WT-Wnt 5a不同的途径分泌。总之，c-Myb和FoxM 1协同过表达Δ C-Wnt 5a可能是急性型ATL细胞恶性表型的原因。
Wnt5a is a ligand of the non-canonical Wnt signaling pathway involved in cell differentiation, motility, and inflammatory response. Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive T-cell malignancies caused by infection of human T-cell leukemia virus type1 (HTLV-1). Among subtypes of ATL, acute-type ATL cells are particularly resistant to current multidrug chemotherapies and show remarkably high cell-proliferative and invasive phenotypes. Here we show a dramatic increase of WNT5A gene expression in acute-type ATL cells compared with those of indolent-type ATL cells. Treatment with IWP-2 or Wnt5a-specific knockdown significantly suppressed cell growth of ATL-derived T-cell lines. We demonstrated that the overexpression of c-Myb and FoxM1 was responsible for the synergistic activation of the WNT5A promoter. Also, a WNT5A transcript variant without the exon4 (the ΔE4-WNT5A mRNA), encoding ΔC-Wnt5 (1-136aa of 380aa), is overexpressed in acute-type ATL cells. The ΔC-Wnt5a is secreted extracellularly and enhances cellular migration/invasion to a greater extent compared with wildtype (WT)-Wnt5a. Moreover, the ΔC-Wnt5a secretion was not suppressed by IWP-2, indicating that this mutant Wnt5a is secreted via a different pathway from the WT-Wnt5a. Taken together, synergistic overexpression of the ΔC-Wnt5a by c-Myb and FoxM1 may be responsible for the malignant phenotype of acute-type ATL cells.
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影响因子：
12.3
作者：
Firouzi S;López Y;Suzuki Y;Nakai K;Sugano S;Yamochi T;Watanabe T
通讯作者：
Watanabe T
用于定量细胞迁移，突起和荧光强度的开源软件。
DOI：
10.1083/jcb.201501081
发表时间：
2015-04-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Barry DJ;Durkin CH;Abella JV;Way M
通讯作者：
Way M
影响因子：
4.4
作者：
Kim, Jungtae;Kim, Dong Wook;Lee, Inchul
通讯作者：
Lee, Inchul
影响因子：
11.4
作者：
Gu C;Yang Y;Sompallae R;Xu H;Tompkins VS;Holman C;Hose D;Goldschmidt H;Tricot G;Zhan F;Janz S
通讯作者：
Janz S
影响因子：
11.2
作者：
Gartel AL
通讯作者：
Gartel AL