Laboratory of Molecular Virology, Department of Biological Sciences, and The Dedman College Center for Drug Discovery, Design & Delivery, Southern Methodist University, 6501 Airline Drive, 334-DLS, Dallas, TX 75275-0376, United States.
Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, United States.
Virology. 2018 Jul;520:39-58. doi: 10.1016/j.virol.2018.05.007. Epub 2018 May 26.
The human T-cell leukemia virus type-1 (HTLV-1) is an oncoretrovirus that infects and transforms CD4+ T-cells and causes adult T-cell leukemia/lymphoma (ATLL) -an aggressive lymphoproliferative disease that is highly refractive to most anticancer therapies. The HTLV-1 proviral genome encodes several regulatory products within a conserved 3' nucleotide sequence, known as pX; however, it remains unclear how these factors might cooperate or dynamically interact in virus-infected cells. Here we demonstrate that the HTLV-1 latency-maintenance factor p30 induces the TP53-induced glycolysis and apoptosis regulator (TIGAR) and counters the oxidative stress, mitochondrial damage, and cytotoxicity caused by the viral oncoproteins Tax and HBZ. The p30 protein cooperates with Tax and HBZ and enhances their oncogenic potential in colony transformation/foci-formation assays. Further, we have shown that TIGAR is highly expressed in HTLV-1-induced tumors associated with oncogene dysregulation and increased angiogenesis in an in vivo xenograft model of HTLV-1-induced T-cell lymphoma. These findings provide the first evidence that p30 likely collaborates as an ancillary factor for the major oncoproteins Tax and HBZ during retroviral carcinogenesis.
人类 T 细胞白血病病毒 1 型（HTLV-1）是一种逆转录病毒，可感染和转化 CD4+T 细胞，并导致成人 T 细胞白血病/淋巴瘤（ATLL）-一种高度侵袭性的淋巴增生性疾病，对大多数抗癌疗法高度耐药。HTLV-1 前病毒基因组在保守的 3'核苷酸序列内编码几个调节产物，称为 pX；然而，这些因素如何可能在病毒感染的细胞中合作或动态相互作用仍然不清楚。在这里，我们证明 HTLV-1 潜伏维持因子 p30 诱导 TP53 诱导的糖酵解和凋亡调节剂（TIGAR），并抵抗病毒癌蛋白 Tax 和 HBZ 引起的氧化应激、线粒体损伤和细胞毒性。p30 蛋白与 Tax 和 HBZ 合作，并增强它们在集落转化/焦点形成测定中的致癌潜能。此外，我们已经表明，TIGAR 在 HTLV-1 诱导的肿瘤中高度表达，与癌基因失调和 HTLV-1 诱导的 T 细胞淋巴瘤体内异种移植模型中的血管生成增加有关。这些发现提供了第一个证据，表明 p30 可能作为辅助因子与主要癌蛋白 Tax 和 HBZ 合作，参与逆转录病毒致癌作用。
