HTLV-1 bZIP Factor HBZ Promotes Cell Proliferation and Genetic Instability by Activating OncomiRs
- 30 October 2014
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 74 (21), 6082-6093
- https://doi.org/10.1158/0008-5472.can-13-3564
Abstract
Viruses disrupt the host cell microRNA (miRNA) network to facilitate their replication. Human T-cell leukemia virus type I (HTLV-1) replication relies on the clonal expansion of its host CD4+ and CD8+ T cells, yet this virus causes adult T-cell leukemia/lymphoma (ATLL) that typically has a CD4+ phenotype. The viral oncoprotein Tax, which is rarely expressed in ATLL cells, has long been recognized for its involvement in tumor initiation by promoting cell proliferation, genetic instability, and miRNA dysregulation. Meanwhile, HBZ is expressed in both untransformed infected cells and ATLL cells and is involved in sustaining cell proliferation and silencing virus expression. Here, we show that an HBZ–miRNA axis promotes cell proliferation and genetic instability, as indicated by comet assays that showed increased numbers of DNA-strand breaks. Expression profiling of miRNA revealed that infected CD4+ cells, but not CD8+ T cells, overexpressed oncogenic miRNAs, including miR17 and miR21. HBZ activated these miRNAs via a posttranscriptional mechanism. These effects were alleviated by knocking down miR21 or miR17 and by ectopic expression of OBFC2A, a DNA-damage factor that is downregulated by miR17 and miR21 in HTLV-1–infected CD4+ T cells. These findings extend the oncogenic potential of HBZ and suggest that viral expression might be involved in the remarkable genetic instability of ATLL cells. Cancer Res; 74(21); 6082–93. ©2014 AACR.Other Versions
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