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LINC01234/MicroRNA-31-5p/MAGEA3 Axis Mediates the Proliferation and Chemoresistance of Hepatocellular Carcinoma Cells.

ABSTRACT: Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by aggressiveness and poor prognosis; however, the molecular mechanism remains to be fully identified. Based on the analysis of The Cancer Genome Atlas (TCGA) database, melanoma-associated antigen A3 (MAGEA3) and long non-coding RNA (lncRNA) LINC01234 were upregulated in HCC and associated with poor prognosis of HCC. We investigated the mechanism of how MAGEA3 and LINC01234 influenced HCC cellular functions and cisplatin resistance. MAGEA3 depletion inhibited proliferation, invasion, and cisplatin resistance of HepG2 cells and Huh7 cells in vitro, reduced resistance-associated protein 2 (MRP2), MRP3, and multidrug resistance protein 1 (MDR-1) expression, and elevated ALB expression. RNA pull-down and RIP assays identified the binding of LINC01234 and MAGEA3 to microRNA-31-5p (miR-31-5p). LINC01234 could restore MAGEA3 expression by binding to miR-31-5p. Furthermore, we delivered plasmids into HepG2 cells and Huh7 cells to alter the expression of LINC01234 and miR-31-5p. When miR-31-5p was downregulated, the proliferation and invasion of HepG2 cells and Huh7 cells were enhanced and the cisplatin-induced apoptosis was inhibited, while LINC01234 knockdown could diminish the effects caused by miR-31-5p depletion. In summary, these data highlight the vital role of MAGEA3/LINC01234/miR-31-5p axis in the HCC progression and chemoresistance of HCC cells.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6926330 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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LINC01234/MicroRNA-31-5p/MAGEA3 Axis Mediates the Proliferation and Chemoresistance of Hepatocellular Carcinoma Cells.

Chen Yunhao Y Zhao Hui H Li Haibo H Feng Xiao X Tang Hui H Qiu Chunhui C Zhang Jianwen J Fu Binsheng B

Molecular therapy. Nucleic acids 20191113

Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by aggressiveness and poor prognosis; however, the molecular mechanism remains to be fully identified. Based on the analysis of The Cancer Genome Atlas (TCGA) database, melanoma-associated antigen A3 (MAGEA3) and long non-coding RNA (lncRNA) LINC01234 were upregulated in HCC and associated with poor prognosis of HCC. We investigated the mechanism of how MAGEA3 and LINC01234 influenced HCC cellular functions and cisplatin resi ...[more]

PMID: 31838274

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Project description:BackgroundMicroRNAs (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.MethodsMiR-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.ResultsReintroduction 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.ConclusionsOverall, 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.

Dataset Information

LINC01234/MicroRNA-31-5p/MAGEA3 Axis Mediates the Proliferation and Chemoresistance of Hepatocellular Carcinoma Cells.

Publications

LINC01234/MicroRNA-31-5p/MAGEA3 Axis Mediates the Proliferation and Chemoresistance of Hepatocellular Carcinoma Cells.

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