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Background: Metformin is a biguanide, belonging to the oral hypoglycemic agents and is a widely used in the treatment of type 2 diabetes. Evidence indicate that Metformin inhibits cell proliferation in several human cancers and inhibits the Warburg phenomenon in tumor cells. Objective: The present study aims to explore the effects of Metformin in hypoxic conditions. Specifically, we focused on pyruvate dehydrogenase (PDH), (hypoxia-inducible factor 1α) HIF-1α levels and the oral squamous cell carcinoma (OSCC) cell phenotype. Additionally, we also investigated a theoretical consequence of Metformin treatment. Methods: PDH levels in patients with OSCC and oral dysplasia were evaluated. Metformin was administered in vitro to test the effect of Metformin under hypoxic conditions. The results were complemented by Bioinformatics analyses. Results: Low PDH levels were observed in OSCC, and Metformin promotes an increase in PDH levels in hypoxic conditions. Metformin also reduced HIF-1α mRNA and protein levels. Metformin demonstrated antiproliferative effects, inhibited migration, increased the number of apoptotic cells and increased the transcription of caspase 3. Conclusions: In conclusion, our current findings show that Metformin reduces HIF-1α gene expression and increases PDH expression. Metformin inhibits cell proliferation and migration in the OSCC cell line model. Additionally, Metformin enhances the number of apoptotic cells and caspase 3 levels. Interestingly enough, Metformin did not increase the mutant p53 levels under hypoxic conditions. Note: This abstract was not presented at the meeting. Citation Format: Talita Guimarães, Lucyana Farias, Carlos Fraga, Alfredo De Paula, Sergio Santos, Ricardo Gomez, Andre Guimaraes. Metformin increases PDH and suppresses HIF1A under hypoxic conditions and induces cell death in oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5424. doi:10.1158/1538-7445.AM2017-5424

induced by cobaltous chloride and the underlying mechanism. Methods and Results We first confirmed that Ang-(1-7) decreases HIF-1α signaling in a newly developed hydroxypropyl-β-cyclodextrin (HPBCD)-based Ang-(1-7) nano-formulation in a novel transgenic rat model of inducible insulin resistance and DM2. The chronic administration of this compound prevented the marked elevation of HIF-1α in diabetic rat kidney. Next, mouse embryonic fibroblasts (MEFs) and SCC-9 cells were incubated in a well humidified incubator with 5% CO2 and 95% air at 37 °C (normoxic condictions). For hypoxic cultures, cells were incubated 150 μM CoCl2 for 24 hours and maintained in a 5% CO2 atmosphere at 37°C. Then, we divided cells into 4 groups including control, CoCl2, Ang-(1-7) and CoCl2 + Ang-(1-7). HIF-1α protein expression and AKT phosphorylation were decreased in hypoxic cells after treatment with Ang-(1-7). Besides, Ang-(1-7) decreased SCC-9 cell migration in hypoxic condition. Conclusions In conclusion, our current findings suggest that Ang-(1-7) attenuates HIF-1 α protein stabilization via AKT and Mas receptor-dependent mechanism. In addition, we found that the Ang-(1-7)/Mas receptor inhibit oral cancer cell migration. Note: This abstract was not presented at the meeting. Citation Format: Andre Luiz Sena Guimaraes, Carlos Alberto de Carvalho Fraga, Lucyana Conceição Farias, Talita Antunes Guimarães, Alfredo Maurício Batista De Paula, Amanda Mota, Lais Santiago, Ricardo Santiago Gomez, Sergio Henrique Sousa Santos, Robson Augusto Souza dos Santos, Michael Bader. Ang-(1-7) decreases HIF-1α and migration of oral squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1148. doi:10.1158/1538-7445.AM2015-1148

Odontogenic keratocyst (OKC) is a benign destructive recurrent odontogenic cystic neoplasm. MicroRNAs (miRNAs) miR-15a and miR-16-1 are small non-protein coding RNAs that function as negative regulators of the anti-apoptotic gene BCL-2 at the post-transcriptional level. Increased immunoexpression of BCL-2 protein is reported in OKC. The purpose of the present study was to investigate whether miR-15a and miR-16-1 transcription is altered in OKC and if it is associated with BCL-2 expression in such lesions. Compared to dental follicles, we found higher BCL-2 mRNA expression and immunoreactivity in OKC. Our findings also showed that miR-15a and/or miR-16-1 are downregulated in the majority of OKC samples (24/28). Furthermore, in all five OKC paired samples (primary and marsupialized lesions) investigated there was an increase in the expression of miR-15a after marsupialization. Our results suggest that OKC neoplastic cells present an anti-apoptotic profile to which lower miR-16-15a expression might contribute. Additionally, our findings strongly suggest that marsupialization reduces BCL-2 expression in the OKC and this downregulation may result from microRNA post-transcriptional activity, even though this cause-effect relationship remains to be proved. This study was supported by FAPEMIG and CAPES, Brazil. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 153. doi:10.1158/1538-7445.AM2011-153