Abstract
Multidrug resistance-associated protein 4 (MRP4), a member of the adenosine triphosphate (ATP) binding cassette transporter family, pumps various molecules out of the cell and is involved in cell communication and drug distribution. Several studies have reported the role of miRNAs in downregulating the expression of MRP4. However, regulation of MRP4 by circular RNA (circRNA) is yet to be elucidated. In this study, MRP4 was significantly upregulated in hepatocellular carcinoma (HCC) tissues compared to the adjacent noncancerous tissues. Computational prediction, luciferase reporter assay and miRNA transfection were used to investigate the interaction between miRNAs and MRP4. miR-124-3p and miR-4524-5p reduced the expression of MRP4 at the protein but not mRNA level. Circular RNA in vivo precipitation and luciferase reporter assays demonstrated that circHIPK3, as a competitive endogenous RNA, binds with miR-124-3p and miR-4524-5p. Further, knockdown of circHIPK3 resulted in downregulation of MRP4 protein, whereas cotransfection of circHIPK3-siRNA and miR-124-3p or miR-4524-5p inhibitors restored its expression. In conclusion, we report that miR-4524-5p downregulates the expression of MRP4 and circHIPK3 regulates MRP4 expression by sponging miR-124-3p and miR-4524-5p for the first time. Our results may provide novel insights into the prevention of MRP4-related proliferation and multiple drug resistance in HCC.
Highlights
Introduction published maps and institutional affilHepatocellular carcinoma (HCC) is estimated to be the sixth leading cause of cancer incidences and fourth leading cause of cancer-related deaths worldwide [1]
Multidrug resistance-associated protein 4 (MRP4) with 1325 amino acids is the shortest member of the adenosine triphosphate binding cassette subfamily C, which is encoded by the ABCC4 gene
The RT-qPCR results showed significant upregulation of MRP4/ABCC4 mRNA in hepatocellular carcinoma (HCC) tissues compared to the adjacent noncancerous tissues (Figure 1A), which was in agreement with the expression patterns retrieved from the The Cancer Genome Atlas Program (TCGA) (Figure 1B)
Summary
Hepatocellular carcinoma (HCC) is estimated to be the sixth leading cause of cancer incidences and fourth leading cause of cancer-related deaths worldwide [1]. Radical resection and transplantation of liver are the first line of preferred treatments for HCC. Not every HCC patient is suitable for surgery. Chemotherapy is one of the primary treatment options for HCC. Multiple drug resistance (MDR) in HCC is believed to be a major clinical obstacle to effective chemotherapy [2]. Drug resistance can be classified into two categories: inherent resistance and acquired resistance; HCCs with the latter type are the most difficult to treat. MDR in the majority of the cases can be attributed to the dysregulation of genes coding for drug transporters. Overexpression of the efflux transporters leads to reduction in uptake of anticancer drugs, such as adriamycin [4] and 5-fluorouracil (5-FU) [5]
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