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

ABSTRACT: 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.

SUBMITTER: Kulkarni B

PROVIDER: S-EPMC7244014 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Kulkarni Bhagyashri B Gondaliya Piyush P Kirave Prathibha P Rawal Rakesh R Jain Alok A Garg Rachana R Kalia Kiran K

Oncotarget 20200519 20

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 ...[more]

PMID: 32499869

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Project description:Introduction:Curcumin has various biological properties including being anti-inflammatory and antidiabetic. Podocyte apoptosis and autophagy dysfunction have been found to be responsible for the development of diabetic nephropathy (DN). Thus, the aim of the study was to investigate the effects of curcumin on the podocyte apoptosis and autophagy in DN and clarify its potential mechanisms. Methods:The mice with DN induced by injection of streptozotocin were treated with curcumin by gavage at a dose of 200 mg/kg/day for 8 weeks. The serum lipid levels were detected by total cholesterol (TC) and triglyceride (TG) kits at different time points. Renal damage was assessed by detecting urine albumin, serum creatinine (Scr), HE staining and PAS staining. The renal impairment was detected by immunohistochemical staining and TUNEL staining. Western blot assay tested the expression of autophagy-related and apoptotic-related proteins in vivo and vitro. The viabilities and apoptosis of MPC5 cells exposed to high glucose (HG) or curcumin were respectively detected by CCK-8 assay and flow cytometry. Results:The results showed that curcumin significantly decreased the progress of DN possibly via increasing autophagy and inhibiting apoptosis of renal cell in DN mice. Besides, podocyte marker proteins (podocalyxin and nephrin) were markedly increased in DN mice by curcumin treatment. The autophagy-related proteins LC3, p62, Beclin1, UVRAG and ATG5 were significantly affected in DN mice by curcumin, along with reducing expression of pro-apoptotic protein Bax and caspase-3 and increasing anti-apoptotic protein Bcl-2. In vitro, curcumin increased the viabilities and inhibited apoptosis of MPC5 cells exposed to high glucose (HG). In addition, the podocyte autophagy was enhanced partly via regulating beclin1/UVRAG. Discussion:Together, the results showed that curcumin inhibited podocyte apoptosis and accelerated cell autophagy via regulating Beclin1/UVRAG/Bcl2. Thus, the study showed that curcumin exerted significantly protective effects in DN.

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

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

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