Abstract
Global dysregulation of microRNAs (miRNAs), a class of non-coding RNAs that regulate genes expression, is a common feature of human tumors. Profiling of cellular miRNAs on Adult T cell Leukemia (ATL) cells by Yamagishi et al. showed a strong decrease in expression for 96.7% of cellular miRNAs in ATL cells. However, the mechanisms that regulate the expression of miRNAs in ATL cells are still largely unknown. In this study, we compared the expression of 12 miRs previously described for being overexpress by Tax and the expression of several key components of the miRNAs biogenesis pathways in different HBZ expressing cell lines as well as in primary CD4 (+) cells from acute ATL patients. We showed that the expression of miRNAs and Dicer1 were downregulated in cells lines expressing HBZ as well as in fresh CD4 (+) cells from acute ATL patients. Using qRT-PCR, western blotting analysis and Chromatin Immunoprecipitation, we showed that dicer transcription was regulated by c-Jun and JunD, two AP-1 transcription factors. We also demonstrated that HBZ affects the expression of Dicer by removing JunD from the proximal promoter. Furthermore, we showed that at therapeutic concentration of 1mM, Valproate (VPA) an HDAC inhibitors often used in cancer treatment, rescue Dicer expression and miRNAs maturation. These results might offer a rationale for clinical studies of new combined therapy in an effort to improve the outcome of patients with acute ATL.
Highlights
Adult T-cell leukemia (ATL) is an aggressive human malignancy with a rapid and lethal clinical course [1, 2]
In order to assess the effect of HTLV-1 bZIP factor (HBZ) on miRNA expression, we compared the abundance of miRlet7-a, 16, 20, 21, 31, 93, 125a, 132, 143, 155, 200 and 873 in two uninfected T-cell lines (CEM and Jurkat), one HTLV-1 T-cell line with low HBZ-expression (Hut-102), and two HTLV-1 T-cell lines with high HBZ-expression (C81-66 and ATL-2) (Figure 1) and in HTLV-1 infected cells from asymptomatic carries (AC) and from ATL patients (ATL) (Figure 2)
These findings suggest that expression of HBZ is associated with decrease of miRNAs abundance previously observed in fresh ATL cells by Yamagishi et al [13]
Summary
Adult T-cell leukemia (ATL) is an aggressive human malignancy with a rapid and lethal clinical course [1, 2]. Current findings suggest that HTLV-I induced oncogenesis is due to the action of the two viral proteins Tax and HTLV-1 bZIP factor (HBZ). The viral transactivator protein regulates viral transcription, but interferes with most DNA repair mechanisms, preventing cell cycle arrest and inducing cellular senescence [1, 2]. HBZ which is encoded by the minus strand of the HTLV-1 provirus, promotes proliferation of ATL cells and is consistently expressed in all ATL cells [1,2,3,4]. Treatments of patients with ATL include chemotherapy and allogeneic hematopoietic stem-cell transplantation [1, 2]. As far as chemotherapy against ATL is concerned, inhibitors of the topoisomerase II, doxorubicin and etoposide, are frequently used. None of the drugs used seems to alter the fatal outcome of the disease; new therapeutic approaches are needed
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