Reciprocal Regulation of MicroRNA-122 and c-Myc in Hepatocellular Cancer: Role of E2F1 and Transcription Factor Dimerization Partner 2
Mice, Knockout
0301 basic medicine
Carcinoma, Hepatocellular
Liver Neoplasms
Down-Regulation
Mice, Transgenic
Up-Regulation
3. Good health
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Proto-Oncogene Proteins c-myc
Disease Models, Animal
Mice
MicroRNAs
03 medical and health sciences
Cell Line, Tumor
Hepatocytes
Animals
Humans
E2F1 Transcription Factor
Transcription Factors
DOI:
10.1002/hep.26712
Publication Date:
2013-08-28T16:17:41Z
AUTHORS (10)
ABSTRACT
c-Myc
is a well-known oncogene frequently up-regulated in different malignancies, whereas liver-specific microRNA (miR)-122, a
bona fide
tumor suppressor, is down-regulated in hepatocellular cancer (HCC). Here we explored the underlying mechanism of reciprocal regulation of these two genes. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and northern blot analysis demonstrated reduced expression of the primary, precursor, and mature miR-122 in
c-MYC
-induced HCCs compared to the benign livers, indicating transcriptional suppression of
miR-122
upon MYC overexpression. Indeed, chromatin immunoprecipitation (ChIP) assay showed significantly reduced association of RNA polymerase II and histone H3K9Ac, markers of active chromatin, with the
miR-122
promoter in tumors relative to the c-MYC-uninduced livers, indicating transcriptional repression of
miR-122
in c-MYC-overexpressing tumors. The ChIP assay also demonstrated a significant increase in c-Myc association with the
miR-122
promoter region that harbors a conserved noncanonical c-Myc binding site in tumors compared to the livers. Ectopic expression and knockdown studies showed that c-Myc indeed suppresses expression of primary and mature miR-122 in hepatic cells. Additionally, Hnf-3β, a liver enriched transcription factor that activates
miR-122
gene, was suppressed in c-MYC-induced tumors. Notably, miR-122 also repressed
c-Myc
transcription by targeting transcriptional activator E2f1 and coactivator Tfdp2, as evident from ectopic expression and knockdown studies and luciferase reporter assays in mouse and human hepatic cells.
Conclusion
: c-Myc represses
miR-122
gene expression by associating with its promoter and by down-regulating Hnf-3β expression, whereas miR-122 indirectly inhibits
c-Myc
transcription by targeting Tfdp2 and E2f1. In essence, these results suggest a double-negative feedback loop between a tumor suppressor (
miR-122
) and an oncogene (
c-Myc
). (Hepatology 2014;59:555–566)
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