| RRC ID |
65859
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| 著者 |
Ibrahim AA, Schmithals C, Kowarz E, Köberle V, Kakoschky B, Pleli T, Kollmar O, Nitsch S, Waidmann O, Finkelmeier F, Zeuzem S, Korf HW, Schmid T, Weigert A, Kronenberger B, Marschalek R, Piiper A.
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| タイトル |
Hypoxia Causes Downregulation of Dicer in Hepatocellular Carcinoma, Which Is Required for Upregulation of Hypoxia-Inducible Factor 1α and Epithelial-Mesenchymal Transition.
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| ジャーナル |
Clin Cancer Res
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| Abstract |
Purpose: A role of Dicer, which converts precursor miRNAs to mature miRNAs, in the tumor-promoting effect of hypoxia is currently emerging in some tumor entities. Its role in hepatocellular carcinoma (HCC) is unknown.Experimental Design: HepG2 and Huh-7 cells were stably transfected with an inducible Dicer expression vector and were exposed to hypoxia/normoxia. HepG2-Dicer xenografts were established in nude mice; hypoxic areas and Dicer were detected in HCC xenografts and HCCs from mice with endogenous hepatocarcinogenesis; and epithelial-mesenchymal transition (EMT) markers were analyzed by immunohistochemistry or by immunoblotting. The correlation between Dicer and carbonic anhydrase 9 (CA9), a marker of hypoxia, was investigated in resected human HCCs.Results: Hypoxia increased EMT markers in vitro and in vivo and led to a downregulation of Dicer in HCC cells. The levels of Dicer were downregulated in hypoxic tumor regions in mice with endogenous hepatocarcinogenesis and in HepG2 xenografts. In human HCCs, the levels of Dicer correlated inversely with those of CA9, indicating that the negative regulation of Dicer by hypoxia also applies to HCC patients. Forced expression of Dicer prevented the hypoxia-induced increase in hypoxia-inducible factor 1α (HIF1α), HIF2α, hypoxia-inducible genes (CA9, glucose transporter 1), EMT markers, and cell migration.Conclusions: We here identify downmodulation of Dicer as novel essential process in hypoxia-induced EMT in HCC and demonstrate that induced expression of Dicer counteracted hypoxia-induced EMT. Thus, targeting hypoxia-induced downmodulation of Dicer is a promising novel strategy to reduce HCC progression. Clin Cancer Res; 23(14); 3896-905. ©2017 AACR.
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| 巻・号 |
23(14)
|
| ページ |
3896-3905
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| 公開日 |
2017-7-15
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| DOI |
10.1158/1078-0432.CCR-16-1762
|
| PII |
1078-0432.CCR-16-1762
|
| PMID |
28167508
|
| MeSH |
Animals
Basic Helix-Loop-Helix Transcription Factors / genetics*
Carcinogenesis / genetics
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / pathology
Cell Proliferation / genetics
DEAD-box RNA Helicases / genetics*
Epithelial-Mesenchymal Transition / genetics
Gene Expression Regulation, Neoplastic
Hep G2 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
Liver Neoplasms / genetics*
Liver Neoplasms / pathology
Mice
Ribonuclease III / genetics*
Tumor Hypoxia / genetics
Xenograft Model Antitumor Assays
|
| IF |
10.107
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| リソース情報 |
| ヒト・動物細胞 |
HuH-7 |
