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2015 ; 16
(1
): 365
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Integrated microRNA, mRNA, and protein expression profiling reveals microRNA
regulatory networks in rat kidney treated with a carcinogenic dose of
aristolochic acid
#MMPMID25952319
Li Z
; Qin T
; Wang K
; Hackenberg M
; Yan J
; Gao Y
; Yu LR
; Shi L
; Su Z
; Chen T
BMC Genomics
2015[May]; 16
(1
): 365
PMID25952319
show ga
BACKGROUND: Aristolochic Acid (AA), a natural component of Aristolochia plants
that is found in a variety of herbal remedies and health supplements, is
classified as a Group 1 carcinogen by the International Agency for Research on
Cancer. Given that microRNAs (miRNAs) are involved in cancer initiation and
progression and their role remains unknown in AA-induced carcinogenesis, we
examined genome-wide AA-induced dysregulation of miRNAs as well as the regulation
of miRNAs on their target gene expression in rat kidney. RESULTS: We treated rats
with 10 mg/kg AA and vehicle control for 12 weeks and eight kidney samples (4 for
the treatment and 4 for the control) were used for examining miRNA and mRNA
expression by deep sequencing, and protein expression by proteomics. AA treatment
resulted in significant differential expression of miRNAs, mRNAs and proteins as
measured by both principal component analysis (PCA) and hierarchical clustering
analysis (HCA). Specially, 63 miRNAs (adjusted p value < 0.05 and fold change >
1.5), 6,794 mRNAs (adjusted p value < 0.05 and fold change > 2.0), and 800
proteins (fold change > 2.0) were significantly altered by AA treatment. The
expression of 6 selected miRNAs was validated by quantitative real-time PCR
analysis. Ingenuity Pathways Analysis (IPA) showed that cancer is the top network
and disease associated with those dysregulated miRNAs. To further investigate the
influence of miRNAs on kidney mRNA and protein expression, we combined proteomic
and transcriptomic data in conjunction with miRNA target selection as confirmed
and reported in miRTarBase. In addition to translational repression and
transcriptional destabilization, we also found that miRNAs and their target genes
were expressed in the same direction at levels of transcription (169) or
translation (227). Furthermore, we identified that up-regulation of 13 oncogenic
miRNAs was associated with translational activation of 45 out of 54
cancer-related targets. CONCLUSIONS: Our findings suggest that dysregulated miRNA
expression plays an important role in AA-induced carcinogenesis in rat kidney,
and that the integrated approach of multiple profiling provides a new insight
into a post-transcriptional regulation of miRNAs on their target repression and
activation in a genome-wide scale.