Exosome-mediated delivery of miR-30a sensitize cisplatin-resistant variant of oral squamous carcinoma cells via modulating Beclin1 and Bcl2
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Bhagyashri Kulkarni1,*, Piyush Gondaliya1,*, Prathibha Kirave1,*, Rakesh Rawal2, Alok Jain1, Rachana Garg1 and Kiran Kalia1
1 Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
2 Department of Life Science, Gujarat University, Ahmedabad, Gujarat, India
* These authors contributed equally to this work
|Kiran Kalia,||email:||[email protected]|
|Rachana Garg,||email:||[email protected]|
Keywords: chemoresistance; miRNA30a-5p; exosomes; oral cancer; autophagy
Received: November 16, 2019 Accepted: March 19, 2020 Published: May 19, 2020
Exosomes facilitate cross-talk amongst tumor cells, and thus also possess the potential to influence tumor-microenvironment and chemo-resistance. miRNAs, the important constituent of exosomes, are often dysregulated in cancer. They have been shown to play an essential role in tumor progression, metastasis, invasion, and resistance developed against different therapies. Acquisition of cisplatin-chemoresistance remains a major hurdle in the effective treatment of oral squamous cell carcinoma (OSCC). In this study, we demonstrate the importance of exosome-mediated miR-30a transfer in conferring cisplatin sensitivity in the otherwise resistant OSCC cells. Notably, miR-30a was found to be significantly reduced in exosomes isolated from the serum of OSCC patients, especially those having disease-recurrence, post cisplatin treatment. In conjunction with the findings in clinical samples, decreased miR-30a expression was observed in vitro in the cisplatin-resistant cultured OSCC cells compared to the cisplatin-sensitive cells. Besides, we identified Beclin1, an autophagy-related marker, as a target of miR-30a and found it to be overexpressed in cisplatin-resistant OSCC cells, thus indicating at its possible negative-regulation by miR30a. Exosomes from the cisplatin-resistant cells that have been transfected with miR-30a mimics, when delivered to the naïve cisplatin-resistant cells, caused not only the significant enhancements in miR-30a expression but also a concomitant decrease in Beclin1 and Bcl2 expression (autophagic and anti-apoptotic marker). More importantly, this together resulted in the sensitization of cisplatin-resistant cells. Thus, our study highlighted the role of exosomal-mediated miR-30a transfer in regaining sensitivity of the cisplatin-resistant OSCC cells via Beclin1 and Bcl2 regulation and hence suggests at its potential therapeutic role.
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