RRC ID 65859
Author 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.
Title Hypoxia Causes Downregulation of Dicer in Hepatocellular Carcinoma, Which Is Required for Upregulation of Hypoxia-Inducible Factor 1α and Epithelial-Mesenchymal Transition.
Journal Clin Cancer Res
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.
Volume 23(14)
Pages 3896-3905
Published 2017-7-15
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
Human and Animal Cells HuH-7