An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis.

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Cell (Impact Factor: 33.12). 12/2011; 147(6):1233-47. DOI: 10.1016/j.cell.2011.10.043
Source: PubMed

ABSTRACT Hepatocyte nuclear factor 4α (HNF4α) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4α initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that, once this circuit is activated, it maintains suppression of HNF4α and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4α circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocellular carcinoma is a type of cancer characterized by significant morbidity and high mortality rates worldwide. Previous studies have revealed that alterations in microRNA (miRNA) expression are a common feature of cancer. Furthermore, as evolutionarily conserved, non-encoding RNAs, miRNAs have demonstrated fundamental roles in the various biological processes involved in cancer. Genome-wide miRNA expression profile studies and bioinformatic methods have provided comprehensive insight into the role of cancer-related miRNAs. In addition, investigation of the function and mechanisms of miRNAs has provided an understanding of the association with the pathogenesis of cancer. In the present review, the tumor-promoting or tumor-suppressive roles and underlying mechanisms of certain significant miRNAs at a single and integral level are summarized. Furthermore, the recognition of miRNA-gene networks and current advances in the potential use of miRNA-based diagnosis and therapy are discussed.
    Oncology letters 03/2015; 9(3):1027-1033. DOI:10.3892/ol.2014.2816 · 0.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidence has suggested that microRNAs (miRNAs) play an important role in the initiation and progression of hepatocellular carcinoma (HCC). Here, we identified a novel tumor suppressive miRNA, miR-377, and investigated its role in HCC. The expression of miR-377 in HCC tissues and cell lines was detected by real-time reverse-transcription PCR. The effects of miR-377 on HCC cell proliferation and invasion were also investigated. Western blot and luciferase reporter assay were used to identify the direct and functional target of miR-377. The expression of miR-377 was markedly downregulated in human HCC tissues and cell lines. MiR-377 can dramatically inhibit cell growth and invasion in HCC cells. Subsequent investigation revealed that T lymphoma invasion and metastasis 1 (TIAM1) was a direct and functional target of miR-377 in HCC cells. Overexpression of miR-377 impaired TIAM1-induced promotion of proliferation and invasion in HCC cells. Finally, miR-377 is inversely correlated with TIAM1 expression in human HCC tissues. These findings reveal that miR-377 functions as a tumor suppressor and inhibits the proliferation and invasion of HCC cells by targeting TIAM1, which may consequently serve as a therapeutic target for HCC patients.
    PLoS ONE 03/2015; 10(3):e0117714. DOI:10.1371/journal.pone.0117714 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Specific types of human papillomaviruses (HPVs) cause cervical cancer. Cervical cancers exhibit aberrant cellular microRNA (miRNA) expression patterns. By genome-wide analyses, we investigate whether the intracellular and exosomal miRNA compositions of HPV-positive cancer cells are dependent on endogenous E6/E7 oncogene expression. Deep sequencing studies combined with qRT-PCR analyses show that E6/E7 silencing significantly affects ten of the 52 most abundant intracellular miRNAs in HPV18-positive HeLa cells, downregulating miR-17-5p, miR-186-5p, miR-378a-3p, miR-378f, miR-629-5p and miR-7-5p, and upregulating miR-143-3p, miR-23a-3p, miR-23b-3p and miR-27b-3p. The effects of E6/E7 silencing on miRNA levels are mainly not dependent on p53 and similarly observed in HPV16-positive SiHa cells. The E6/E7-regulated miRNAs are enriched for species involved in the control of cell proliferation, senescence and apoptosis, suggesting that they contribute to the growth of HPV-positive cancer cells. Consistently, we show that sustained E6/E7 expression is required to maintain the intracellular levels of members of the miR-17~92 cluster, which reduce expression of the anti-proliferative p21 gene in HPV-positive cancer cells. In exosomes secreted by HeLa cells, a distinct seven-miRNA-signature was identified among the most abundant miRNAs, with significant downregulation of let-7d-5p, miR-20a-5p, miR-378a-3p, miR-423-3p, miR-7-5p, miR-92a-3p and upregulation of miR-21-5p, upon E6/E7 silencing. Several of the E6/E7-dependent exosomal miRNAs have also been linked to the control of cell proliferation and apoptosis. This study represents the first global analysis of intracellular and exosomal miRNAs and shows that viral oncogene expression affects the abundance of multiple miRNAs likely contributing to the E6/E7-dependent growth of HPV-positive cancer cells.
    PLoS Pathogens 03/2015; 11(3):e1004712. DOI:10.1371/journal.ppat.1004712 · 8.06 Impact Factor


Available from
Jun 6, 2014