Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells

Abstract 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...

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Autores principales:	Kazumi Nakano, Yohei Chihara, Seiichiro Kobayashi, Masako Iwanaga, Atae Utsunomiya, Toshiki Watanabe, Kaoru Uchimaru
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d53aaa65846e42c9b243a01280f115e1
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spelling	oai:doaj.org-article:d53aaa65846e42c9b243a01280f115e12021-12-02T10:54:30ZOverexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells10.1038/s41598-021-83613-22045-2322https://doaj.org/article/d53aaa65846e42c9b243a01280f115e12021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83613-2https://doaj.org/toc/2045-2322Abstract 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.Kazumi NakanoYohei ChiharaSeiichiro KobayashiMasako IwanagaAtae UtsunomiyaToshiki WatanabeKaoru UchimaruNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kazumi Nakano Yohei Chihara Seiichiro Kobayashi Masako Iwanaga Atae Utsunomiya Toshiki Watanabe Kaoru Uchimaru Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells
description	Abstract 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.
format	article
author	Kazumi Nakano Yohei Chihara Seiichiro Kobayashi Masako Iwanaga Atae Utsunomiya Toshiki Watanabe Kaoru Uchimaru
author_facet	Kazumi Nakano Yohei Chihara Seiichiro Kobayashi Masako Iwanaga Atae Utsunomiya Toshiki Watanabe Kaoru Uchimaru
author_sort	Kazumi Nakano
title	Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells
title_short	Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells
title_full	Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells
title_fullStr	Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells
title_full_unstemmed	Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells
title_sort	overexpression of aberrant wnt5a and its effect on acquisition of malignant phenotypes in adult t-cell leukemia/lymphoma (atl) cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d53aaa65846e42c9b243a01280f115e1
work_keys_str_mv	AT kazuminakano overexpressionofaberrantwnt5aanditseffectonacquisitionofmalignantphenotypesinadulttcellleukemialymphomaatlcells AT yoheichihara overexpressionofaberrantwnt5aanditseffectonacquisitionofmalignantphenotypesinadulttcellleukemialymphomaatlcells AT seiichirokobayashi overexpressionofaberrantwnt5aanditseffectonacquisitionofmalignantphenotypesinadulttcellleukemialymphomaatlcells AT masakoiwanaga overexpressionofaberrantwnt5aanditseffectonacquisitionofmalignantphenotypesinadulttcellleukemialymphomaatlcells AT ataeutsunomiya overexpressionofaberrantwnt5aanditseffectonacquisitionofmalignantphenotypesinadulttcellleukemialymphomaatlcells AT toshikiwatanabe overexpressionofaberrantwnt5aanditseffectonacquisitionofmalignantphenotypesinadulttcellleukemialymphomaatlcells AT kaoruuchimaru overexpressionofaberrantwnt5aanditseffectonacquisitionofmalignantphenotypesinadulttcellleukemialymphomaatlcells
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Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells

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