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 (cisRes cells). Importantly, exosomal transfer from cisRes to the cisplatin sensitive (cisSens) cells was found to confer significant miR-155 induction in the recipient cisSens cells. Restoration of miR-155 expression in cisSens 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 cisRes to the recipient cisSens 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.
Highlights
Oral squamous cell carcinoma (OSCC) ranks sixth amongst all cancers worldwide, and one of the most predominant and leading cancer found in Indian subcontinent [1, 2]
Several factors including epithelial to mesenchymal transition (EMT), drug efflux, DNA damage repair, cell-death inhibition, drug-target alteration, drug-inactivation, epigenetics are some of the chief causes that contribute to chemoresistance [32]
Pioneering studies have highlighted the key role of growth factors, cytokines, www.oncotarget.com www.oncotarget.com www.oncotarget.com www.oncotarget.com transcription factors, non-coding RNAs, and tumor microenvironment in triggering EMT and acquisition of drug resistance [3]
Summary
Oral squamous cell carcinoma (OSCC) ranks sixth amongst all cancers worldwide, and one of the most predominant and leading cancer found in Indian subcontinent [1, 2]. Despite substantial developments in current treatment strategies, OSCC remains one of the most common cause of cancer related deaths and there are not much improvements in the 5-year survival rate over the last two decades. Recent studies have identified several contributory reason for this: lack of targeted therapy, tolerance of drug in the body, limited treatment options and a poor understanding of OSCC biology [3, 4]. There are multiple etiological factors that are responsible for oral cancer development; smoking being the primary risk factor with others including the use of alcohol, betal leaf, www.oncotarget.com areca nut and, human papillomavirus (HPV) infection [5]. Though there are different options (surgery, chemotherapy and radiotherapy) available for OSCC patients, every therapy possesses advantages as well as limitations. Owing to the developing chemoresistance, significant changes occur in the tumor microenvironment of which exosomes are an important component [6]
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