Abstract
Acquisition of resistance to cisplatin is a major impediment to the success of cisplatin-based combination therapies for cancer. Recent studies indicate that exosomal miRNAs derived from drug-resistant tumour cells can confer resistance properties to recipient cells by a horizontal transfer mechanism. Although the role of horizontal transfer of a few miRNAs has been described, little is known about the concerted action of horizontal transfer of miRNAs in conferring cisplatin resistance. The present study was designed to identify the role of miR-643, which is one of the most significantly increased miRNA in exosomes released from cisplatin-resistant Heptocarcinoma cells, in altering the cisplatin resistance properties of recipient cells. Drug-sensitivity assays involving miR-643 revealed that ectopic expression of miR-643 can desensitise the cells towards cisplatin. Furthermore, we identified APOL6 as a major target of miR-643. Further mechanistic studies showed that miR-643 can modulate APOL6 mRNA and protein levels, leading to a reversal of APOL6-mediated apoptosis. Altogether, our results suggest an APOL6-dependent mechanism for miR-643 mediated cisplatin resistance upon the horizontal transfer across cell types.
Highlights
Chemotherapy is one of the most commonly employed treatment methods for cancer management, which involves the use of cytotoxic agents [1]
The expression pattern of some candidate exosomal miRNAs such as miR-554, miR1258, miR-643, miR-1307, and miR-3194, which are scarcely reported in tumour progression and metastasis so far, and not yet reported in drug resistance was analysed by RT-PCR
In order to check the level of these candidate miRNAs in exosomes released from Cp-r HepG2 cells, exosomal miRNAs were isolated from cisplatin-resistant and -sensitive HepG2 cells followed by cDNA synthesis and real-time PCR analysis
Summary
Chemotherapy is one of the most commonly employed treatment methods for cancer management, which involves the use of cytotoxic agents [1]. Recent reports suggest that drug resistance is regulated by genetic or epigenetic changes, and by a class of regulatory RNA molecules known as microRNAs (miRNAs) [8]. MicroRNAs are a family of 21–25 nucleotide small non-coding RNA molecules that regulates gene expression by interacting with the 30 UTR of target mRNAs to induce mRNA degradation or translational repression [9], thereby regulating a vast variety of biological processes such as embryogenesis, cell growth, cellular migration, invasion, and apoptosis [10,11,12,13]. Cisplatin is one of the most commonly used chemotherapeutic agents to treat many types of cancers [14]
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