Exosome mediated miR-155 delivery confers cisplatin chemoresistance in oral cancer cells via epithelial-mesenchymal transition

// Prathibha Kirave 1 , * , Piyush Gondaliya 1 , * , Bhagyashri Kulkarni 1 , * , Rakesh Rawal 2 , Rachana Garg 1 , Alok Jain 1 and Kiran Kalia 1 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 and are first authors Correspondence to: Kiran Kalia, email: director@niperahm.ac.in Rachana Garg, email: rachanag@niperahm.ac.in Alok Jain, email: alokjain@niperahm.ac.in Keywords: cisplatin chemoresistance; miRNA155; exosomes; oral cancer; apoptosis Received: November 15, 2019 Accepted: March 03, 2020 Published: March 31, 2020 ABSTRACT Cisplatin is used as chemotherapeutic drug for oral squamous cell carcinoma (OSCC). However, OSCC cells develop resistance following long-term cisplatin exposure. Resistance against cisplatin chemo-therapy is accredited to the process of epithelial-to-mesenchymal transition, which in-turn has been linked to tumor-recurrence. miRNA deregulation, a common event in cancer, plays contributory role in chemo-resistance. Exosomes acts as the natural cargo for miRNA and facilitates inter-cell communication in the tumor micro-environment. Hence, exosomal-mediated miRNA transference may play essential role in drug resistance and serve as a target for cancer-therapy. miR-155 upregulation in OSCC has been described, however, its relevance in the observed chemo-resistance is unclear and also, if exosomes have any role in miR-155 regulation remain elusive. In the present study, we document for the first time the critical role of exosomes in mediating increments in miR-155 expression in OSCC cells that have acquired cisplatin resistance (cis Res cells). Importantly, exosomal transfer from cis Res to the cisplatin sensitive (cis Sens ) cells was found to confer significant miR-155 induction in the recipient cis Sens cells. Restoration of miR-155 expression in cis Sens cells following miR-155 mimics treatment led to epithelial to mesenchymal transition, enhancements in their migratory potential as well as acquisition of resistant phenotype. Notably, similar augmentations in the migratory and chemo-resistant traits were seen upon delivery of exosomes from cis Res to the recipient cis Sens cells. Overall, our findings establish the significance of exosomal-mediated miR-155 shuttling in the cisplatin-chemoresistance, commonly observed in OSCC cells, thereby providing rationale for targeting miR-155 signalling for oral cancer therapy.