Abstract
MicroRNAs function as oncomiRs and tumor suppressors in diverse cancers. However, the utility of specific microRNAs in predicting the clinical benefit of chemotherapy has not been well-established. Here, we investigated the correlation between microRNA-21 expression and hepatic arterial infusion chemotherapy with 5-fluorouracil and pirarubicin (HAIC) for hepatocellular carcinoma (HCC). We found that HCC patients with low microRNA-21 levels in tumors tended to have a longer time to recurrence and disease-free survival. We demonstrated that microRNA-21 suppression in combination with 5-fluorouracil and pirarubicin treatment inhibited tumor growth in subcutaneous xenograft mice models. Mechanistically, the AP-1 and microRNA-21-mediated axis was verified to be a therapeutic target of cytotoxic drugs and deregulation of this axis led to an enhanced cell growth in HCC. Taken together, our findings demonstrate that microRNA-21 is a chemotherapy responsive microRNA and can serve as a prognostic biomarker for HCC patients undergoing HAIC. Targeting microRNA-21 enhances the effect of chemotherapeutic drugs, thereby suggesting that microRNA-21 suppression in combination with HAIC may be a novel approach for HCC treatment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Blotting, Western
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Disease-Free Survival
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Doxorubicin / administration & dosage
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Doxorubicin / analogs & derivatives*
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Doxorubicin / pharmacology
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Female
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Fluorouracil / administration & dosage
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Fluorouracil / pharmacology*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Immunohistochemistry
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Immunosuppressive Agents / administration & dosage
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Immunosuppressive Agents / pharmacology
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / genetics
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Liver Neoplasms / pathology
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Male
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Mice, Inbred BALB C
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Mice, Nude
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MicroRNAs / genetics*
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Middle Aged
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Prognosis
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factor AP-1 / genetics*
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Transcription Factor AP-1 / metabolism
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Tumor Burden / drug effects
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Tumor Burden / genetics
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Xenograft Model Antitumor Assays
Substances
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Immunosuppressive Agents
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MIRN21 microRNA, human
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MicroRNAs
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Transcription Factor AP-1
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Doxorubicin
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pirarubicin
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Fluorouracil