MicroRNA miR-146a and further oncogenesis-related cellular microRNAs are dysregulated in HTLV-1-transformed T lymphocytes.
BACKGROUND
Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of a severe and fatal lymphoproliferative disease of mainly CD4+ T cell origin, adult T cell leukemia, which develops after prolonged viral persistence. Transformation of infected cells involves HTLV-1's oncoprotein Tax, which perturbs cell cycle regulation and modulates cellular gene expression. The latter function is also a hallmark of microRNAs, a rather new layer in the regulation of gene expression. Affecting e.g. proliferation, microRNAs constitute a potential target for viral interference on the way to persistence and transformation. Hence, we explored the interconnections between HTLV-1 and cellular microRNAs.


RESULTS
We report that several microRNAs--miRs 21, 24, 146a, 155 and 223--are deregulated in HTLV-1-transformed cells. They are all upregulated except for miR-223, which is downregulated. Each of those microRNAs has ties to cancer. Their expression pattern forms a uniform phenotype among HTLV-transformed cells when compared to HTLV-negative control cells. In particular, miR-146a expression was found to be directly stimulated by Tax via NF-kappaB-mediated transactivation of its promoter; a single NF-kappaB site proximal to the transcription start point was necessary and sufficient for this to happen. An in silico analysis of potential target genes revealed candidates that might be coregulated by two or more of the aforementioned overexpressed microRNAs.


CONCLUSIONS
These data demonstrate that cellular microRNAs are deregulated in HTLV-1-transformed T cells. In the case of miR-146a, this could be directly attributed to HTLV's oncoprotein Tax. Interference with cellular microRNAs may be crucial to maintaining persistence or may facilitate transformation of host cells.
Pichler
Klemens
K
Institute of Clinical and Molecular Virology, University Erlangen-Nuremberg, Schlossgarten 4, Erlangen, Germany. klemens.pichler@viro.med.uni-erlangen.de
Schneider
Grit
G
Grassmann
Ralph
R
D001665:Binding Sites; D002460:Cell Line; D002472:Cell Transformation, Viral; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D013601:T-Lymphocytes / Q000821:virology*
D016356:Gene Products, tax; D035683:MicroRNAs; D016328:NF-kappa B; C514970:tax protein, Human T-lymphotrophic virus 1