Exosome-mediated delivery of mi R-30a sensitize cisplatin-resistant variant of oral squamous carcinoma cells via modulating Beclin1 and Bcl2

Volume 11, Issue 20 of @Oncotarget reported that in conjunction with the findings in clinical samples, decreased mi R-30a expression was observed in vitro in the cisplatin-resistant cultured OSCC cells compared to the cisplatin-sensitive cells.

Besides, the authors identified Beclin1, an autophagy-related marker, as a target of mi R-30a and found it to be overexpressed in cisplatin-resistant OSCC cells, thus indicating at its possible negative-regulation by mi R30a.

Exosomes from the cisplatin-resistant cells that have been transfected with mi R-30a mimics, when delivered to the naive cisplatin-resistant cells, caused not only the significant enhancements in mi R-30a expression but also a concomitant decrease in Beclin1 and Bcl2 expression.

Dr. Kiran Kalia and Dr. Rachana Garg from The Department of Biotechnology at The National Institute of Pharmaceutical Education and Research in Ahmedabad, Gujarat India said, "Oral squamous cell carcinoma (OSCC) is the sixth most frequent cancer that affects the human population worldwide."

"Oral squamous cell carcinoma (OSCC) is the sixth most frequent cancer that affects the human population worldwide."

- Dr. Kiran Kalia and Dr. Rachana Garg, The Department of Biotechnology at The National Institute of Pharmaceutical Education and Research

Emerging studies have shown that cancer cells release exosomes at a higher rate compared to the normal cells, and contribute significantly in instituting a milieu that supports neoplastic proliferation, angiogenesis, invasion, and metastasis.

This showed a significant reduction in mi R-30a expression in He La, MCF7, and Hep G2 cancer cells following cisplatin treatment, whilst the forced expression of mi R-30a sensitizes them to cisplatin via blocking beclin 1-mediated autophagy.

Notably, reduced expression of mi R-30a has recently been reported in OSCC, and it has also been associated with decreased cell proliferation, migration, and invasion.

Hence, it is worth determining if exogenously increasing mi R-30a in OSCC has any role in combating cisplatin chemoresistance, regulating autophagy, a process known to influence chemoresistance, and if exosomal-mediated mi R30a delivery can be exploited as an approach to enhance the therapeutic efficacy.

Figure 1: (A) Binding position prediction of miR-30a with Beclin1 using TargetScan web-based tool. (B) Binding position prediction of miR-30a with Beclin1 using the DIANA microT-CDS tool. (C) Binding energy prediction of miR-30a with Beclin1 by RNAhybrid. (D) BECN1 luciferase activity in cis^Res cells co-transfected with either empty vector or pmirGLO-Becn1 vector having miR-30a target sequence and either NTC or miR30a mimics. Data are expressed as the mean +/– SD. ^***P < 0.001, significant difference vs. control group (n = 3). Two independent experiments gave similar results.

In the present study, the authors show significantly decreased expression of mi R-30a in oral cancer patients with disease recurrence post cisplatin treatment and OSCC cultured cells having cisplatin resistance.

Herein, they present the first evidence that exosomal-mediated mi R-30a delivery in the cisplatin-resistant OSCC cells led to decreased autophagic response via Beclin1 while it augments apoptosis by inhibiting Bcl2, hence mediating reversal of cisplatin sensitivity.

The Research Team concluded in their Oncotarget Research Article, "we identified Beclin1 as the miR-30a target in oral cancer, and present here first evidence of the essential role of exosomal-miR-30a in reducing acquired chemo-resistance in OSCC via regulation of autophagic and apoptotic markers (Figure 7).

Our study thus provides a strong rationale for employing exosomal-mediated miR-30a delivery as an effective therapeutic approach and also highlights its importance in retrieving sensitivity against cisplatin resistance, a major hurdle in conventional current approaches."

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DOI - https://doi.org/10.18632/oncotarget.27557

Full text - https://www.oncotarget.com/article/27557/text/

Correspondence to - Kiran Kalia - director@niperahm.ac.in and Rachana Garg - rachanag@niperahm.ac.in

Keywords - chemoresistance, miRNA30a-5p, exosomes, oral cancer, autophagy

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