Abstract
BackgroundmicroRNAs have been shown to regulate the chemosensitivity of cancer cells. The aim of this study is to investigate the role and mechanism of mir-23a in enhancing the anti-tumor effect of topoisomerase 2A (TOP2A) poison etoposide in human hepatocellular carcinoma (HCC).MethodsThe anti-tumor effect of chemotherapeutic agents in HCC cells were examined in vitro and in vivo xenograft model. Expression of mRNA and miRNAs were determined by quantitative real-time PCR. Protein expression was analyzed by immunoblotting.ResultsOverexpression of mir-23a could significantly potentiate the in vitro and in vivo anti-tumor effect of etoposide; however, ectopic expression of miR-23a fails to sensitize HCC cells to 5-fluorouracil treatment, indicating the miR-23a-induced cancer cell hypersensitivity in chemotherapy is TOP2A-specific though miR-23a overexpression could not directly up-regulate TOP2A expression. Topoisomerase 1(TOP1) is down-regulated in miR-23a-overexpressed HCC cells. MiR-23a could directly bind to 3′untranslated region of TOP1 mRNA, and suppress the corresponding protein expression and inhibition of miR-23a further arguments the expression of TOP1. MiR-23a was up-regulated during DNA damage in cancer cells in line with the p53 expression. Up-regulation of p53 induces mir-23a expression, while suppression of p53 inhibits miR-23a in HCC cells.ConclusionOur study sheds light on the role of miR-23a as a potential target in regulating chemosensitivity of HCC cells.
Highlights
MicroRNAs are small non-coding RNAs with an average length of 20–22 nucleotides
It was found the expression of miR-23a is slightly increased in hepatocellular carcinoma (HCC) as evidenced by literature [15] and our own study (Additional file 1: Figure S1), we found that overexpression of miR-23a could potentiate the response of HCC to topoisomerase 2A (TOP2A) poison etoposide (Figure 1A)
This was further evidenced by the fact that HCC cells with ectopic miR-23a are vulnerable to another TOP2A poison doxorubicin (Figure 1B)
Summary
MicroRNAs (miRNAs) are small non-coding RNAs with an average length of 20–22 nucleotides. Previous studies have shown that the expression profile of miRNAs in chemoresistant human cancer cell lines varies from chemo-responsive tumor cells [6]. TOP2A is one of cellular topoisomerases that determines tumor cell response to chemotherapeutics. A recent study found that chemosensitivity of tumor cells could be determined by intracellular topoisomerase level [8], which provides a novel strategy in enhancing drug response in cancer therapy. Discovered as a Topoisomerase 2A (TOP2A) poison, etoposide is a frontline chemotherapeutics in treating various human cancers [9]. The aim of this study is to investigate the role and mechanism of mir-23a in enhancing the anti-tumor effect of topoisomerase 2A (TOP2A) poison etoposide in human hepatocellular carcinoma (HCC)
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