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MicroRNA-31-5p regulates chemosensitivity by preventing the nuclear location of PARP1 in hepatocellular carcinoma.

Abstract：

BACKGROUND:MicroRNAs (miRNAs) posttranscriptionally regulate gene expression and thereby contribute to the modulation of numerous complex and disease-relevant cellular processes, including cell proliferation, cell motility, apoptosis and stress response. miRNA-31-5p is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many hepatocellular carcinoma (HCC) tumors. Based on previous findings, we hypothesized that miR-31-5p alters chemosensitivity and that miR-31-5p mimics may influence sensitivity to chemotherapeutics in HCC as well as in a variety of other cancers. METHODS:MiR-31-5p and PARP1 in HCC tissues were tested by RT-PCR and histological analysis, respectively. Next, clonogenic assay and western blot were used to detect miR-31-5p and PARP1 to modulate sensitivity to OXA-based chemotherapy. The distribution of OXA in the nuclear and intracellular was detected by ICP-MS. Coimmunoprecipitation was used to characterize the protein-protein interaction between PARP1 and ABCB9. A xenograft nude mouse model was used to examine the in vivo effects of miR-31-5p. RESULTS:Reintroduction of miR-31-5p into miR-31-5p-null Hep3B cells significantly enhanced clonogenic resistance to oxaliplatin. Although miR-31-5p re-expression increased chemoresistance, it paradoxically increased the relative intracellular accumulation of oxaliplatin. This effect was coupled with a significantly decreased intranuclear concentration of oxaliplatin by ICP-MS. miR-31-5p prevents the nuclear location of PARP1 detected by immunofluorescence, histological analysis and Western blotting analysis. We subsequently identified an indirect miR-31-5p-mediated upregulation of ABCB9, which is a transporter associated with drug accumulation in lysosomes, along with an increased uptake of oxaliplatin to lysosomes; these phenomena were associated with a downregulation of PARP1, a bipotential transcriptional regulator with multiple miR-31-5p binding sites. However, the indirect overexpression of ABCB9 promoted cellular chemosensitivity, suggesting that miR-31-5p promotes chemoresistance largely via an ABCB9-independent mechanism. CONCLUSIONS:Overall, our data suggest that the loss of miR-31-5p from HCC tumors promotes chemosensitivity, and this knowledge may be prognostically beneficial in the context of therapeutic sensitivity.

journal_name

J Exp Clin Cancer Res

journal_title

Journal of experimental & clinical cancer research : CR

authors

Que KT,Zhou Y,You Y,Zhang Z,Zhao XP,Gong JP,Liu ZJ

doi

10.1186/s13046-018-0930-0

subject

Has Abstract

pub_date

2018-11-06 00:00:00

pages

268

issue

eissn

0392-9078

issn

1756-9966

pii

10.1186/s13046-018-0930-0

journal_volume

pub_type

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MicroRNA-31-5p regulates chemosensitivity by preventing the nuclear location of PARP1 in hepatocellular carcinoma.