LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Dermatology. 2021;237(2):283-290. doi: 10.1159/000509159. Epub 2020 Aug 14.
The thioredoxin-interacting protein (TXNIP) is involved in cellular metabolism and cell proliferation, and recently, deficient expression of TXNIP has been associated with progression and poor outcome for cancer patients.
To assess TXNIP expression and function in malignant T cells from cutaneous T-cell lymphoma (CTCL).
CTCL-derived malignant (MyLa2059, PB2B) and non-malignant (MyLa1850) cell lines were analysed by Western blotting and qPCR for TXNIP expression. Subsequently, the malignant CTCL cell lines were treated with GSK126 - an inhibitor of enhancer of zeste homolog 2 (EZH2) methyltransferase activity or assessed by bisulphite sequencing for TXNIP promoter methylation. Methylation was also assessed with the demethylating agent 5-azacytidine (5AZA). Finally, TXNIP was overexpressed in the malignant PB2B cell line via plasmid transduction, and the effect of TXNIP was further analysed by flow cytometry.
We report on low expression of TXNIP protein in all cell lines representing different subtypes and stages of CTCL when compared to non-malignant T cells. Epigenetic silencing and other mechanisms were involved in the repression of TXNIP whereas forced expression of TXNIP strongly inhibited proliferation of malignant T cells.
Epigenetic silencing and other as yet unknown mechanisms repress TXNIP expression in malignant T cells. As forced expression of TXNIP inhibits malignant proliferation, we propose that TXNIP is a putative tumour suppressor in CTCL.
硫氧还蛋白相互作用蛋白（TXNIP）参与细胞代谢和细胞增殖，最近，TXNIP 表达不足与癌症患者的进展和预后不良有关。
评估皮肤 T 细胞淋巴瘤（CTCL）恶性 T 细胞中 TXNIP 的表达和功能。
通过 Western blot 和 qPCR 分析 CTCL 来源的恶性（MyLa2059、PB2B）和非恶性（MyLa1850）细胞系中 TXNIP 的表达。随后，用增强子结合抑制因子 2（EZH2）甲基转移酶活性抑制剂 GSK126 处理恶性 CTCL 细胞系或进行亚硫酸氢盐测序以评估 TXNIP 启动子甲基化。用去甲基化剂 5-氮杂胞苷（5AZA）也评估了甲基化。最后，通过质粒转导在恶性 PB2B 细胞系中过表达 TXNIP，并通过流式细胞术进一步分析 TXNIP 的作用。
与非恶性 T 细胞相比，我们报告了所有代表 CTCL 不同亚型和阶段的细胞系中 TXNIP 蛋白表达水平较低。TXNIP 的抑制涉及表观遗传沉默和其他机制，而强制表达 TXNIP 则强烈抑制恶性 T 细胞的增殖。
恶性 T 细胞中 TXNIP 的表达受表观遗传沉默和其他未知机制的抑制。由于强制表达 TXNIP 抑制恶性增殖，我们提出 TXNIP 是 CTCL 中的潜在肿瘤抑制因子。
