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

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 tumorrecurrence. 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 exosomalmediated miR-155 shuttling in the cisplatin-chemoresistance, commonly observed in OSCC cells, thereby providing rationale for targeting miR-155 signalling for oral cancer therapy.

Exosomal cargoes in OSCC: current findings and potential functions

“…Exosomes isolated from CIS-resistant cell lines contained a higher concentration of miR-21 in accordance with the parental cells' increased cisplatin resistance, which indicates that miR-21 may be a potential target against chemoresistance (Liu et al, 2017). The underlying mechanism is considered related to EMT and decreased DNA damage in cancer cells (Cui et al, 2020;Kirave et al, 2020). Some miRNAs were downregulated during chemoresistance.…”

Peer Review #1 of "Exosomal cargoes in OSCC: current findings and potential functions (v0.1)"

“…Exosomes isolated from CIS-resistant cell lines contained a higher concentration of miR-21 in accordance with the parental cells' increased cisplatin resistance, which indicates that miR-21 may be a potential target against chemoresistance (Liu et al 2017). The underlying mechanism is considered related to EMT and decreased DNA damage in cancer cells (Cui et al 2020b;Kirave et al 2020). Some miRNAs were downregulated during chemoresistance.…”

“…However, Chemoresistance is a significant challenge for OSCC treatment with no clear mechanism. Several studies have shown that miRNAs in exosomes of both healthy and tumor cells can manipulate this phenomenon (Cui et al 2020b;Kirave et al 2020;Qin et al 2019). Some miRNAs are upregulated during chemotherapy, which can enhance chemoresistance against antitumor drugs such as cisplatin (CIS) and docetaxel (DTX).…”

“…Some miRNAs are upregulated during chemotherapy, which can enhance chemoresistance against antitumor drugs such as cisplatin (CIS) and docetaxel (DTX). Kirave et al found that when transferring exosomes from CISresistant to CIS-sensitive cells, miR-155 was significantly upregulated in the recipient CISsensitive cells (Kirave et al 2020). Exosomes isolated from CIS-resistant cell lines contained a higher concentration of miR-21 in accordance with the parental cells' increased cisplatin resistance, which indicates that miR-21 may be a potential target against chemoresistance (Liu et al 2017).…”

Emerging role of FBXO22 in carcinogenesis

“…In addition, miR-155 inhibited proliferation, migration, invasion and triggered cell cycle arrest and apoptosis via regulating the expression of collagen triple repeat containing 1 (CTHRC1) in human melanoma 27 . Moreover, exosome-mediated miR-155 delivery led to cisplatin resistance of oral squamous cell carcinoma (OSCC) cells via induction of EMT 28 . However, it is unclear whether miR-155 targets FBXO22 in human cancer cells, which is required to further determine.…”