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Analysis of the extracellular vesicles present in the plasma of head and neck squamous cell carcinomas patients to identify molecular markers for treatment response

Grant number: 17/24440-0
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): January 05, 2018
Effective date (End): April 04, 2018
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal researcher:Andre Luiz Vettore de Oliveira
Grantee:Dorival Mendes Rodrigues Junior
Supervisor abroad: N. Gopalakrishna Iyer
Home Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
Research place: National Cancer Centre of Singapore, Singapore  
Associated to the scholarship:15/21420-3 - Analysis content of the extracellular vesicles present in the plasma of head and neck squamous cell carcinoma patients for identification of molecular markers to treatment response, BP.DR

Abstract

Approximately 30% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) (stage III -IV) treated with cisplatin-based chemoradiotherapy (CRT) have incomplete response to the treatment and there is no biomarker able to prospectively segregate these patients from those who respond to the treatment. It had been shown that TGF² is a regulator of radiation therapy and promotes heterogeneity and drug resistance in squamous cell carcinoma. Since extracellular vesicles (EVs) are able to carry proteins in the plasma, Cholera toxin B chain (CTB) and Annexin V (AV), which respectively binds GM1 ganglioside and phosphatidylserine, were used to isolate EVs from cell lines and total plasma samples. HNSCC cell line HN120, which were inherently sensitive to cisplatin (WT), and their isogenic cisplatin-resistant (CR) counterpart were evaluated in this study. It was observed that TGF²3 expression was higher in the CTB-EVs in HN120 CR when compared to HN120 WT. TGF²3 expression was also examined in plasma samples from 38 HNSCC patients through ELISA sandwich. This assay revealed that TGF²3 in CTB and AV EVs was significantly lower in the patients presenting complete response to CRT compared to the patients with incomplete response. Based on the ROC curve of response to Induction Chemotherapy, a cut-off for TGF²3 expression level was established and this dichotomous variable was used for clinical association and final CRT response. The TGF²3 higher expression in AV EVs was associated to the worse progression-free survival, which was observed as an independent factor for final CRT response. Subsequently, we applyed the CRISPR-Cas9 methodology for TGF²3 gene silencing in the SCC25 cell line and we observed that, in the absence of this protein, this cell line become more sensitive to cisplatin treatment. Thus, to date, this study has observed that the high expression of TGF²3 in EVs present in circulating plasma can be used as a predictive factor for the response to CRT and that this protein plays a significant role for the cisplatin sensitivity in HNSCC. However, we still want to verify whether EVs can carry enough information to mediate the transformation of resistant cells into cisplatin sensitive (and vice versa). It is also intended to analyze the protein content of these EVs through proteomic assays in order to identify other possible markers contained in these EVs. (AU)

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