Abstract 1901: Leptin modulation of PCSC, HDAC, and microRNA in pancreatic adenocarcinoma

Abstract

Abstract Background: Obesity is an important risk factor of Pancreatic Adenocarcinoma (PA) and it is characterized by the accumulation of excessive body fat and a Body Mass Index (BMI) value greater than 30. Obesity is also characterized by high levels of leptin, which has been consistently associated with the development of many different cancer including PA. Leptin can induce the proliferation of Pancreatic Cancer Stem Cells (PCSC), which are responsible for chemoresistance, invasiveness and reoccurrence of PA. PCSC express specific cell markers and can form tumorspheres in vitro. Obesity can alter the DNA acetylation and microRNA activity which are also linked to PA progression. We hypothesized that high level of leptin could modulate Histone Deacetylase (HDAC) and microRNA activity in PA cells, which induce PCSC changes and tumor progression. Methods: The PA cell lines were cultured in mammocult media that contained heparin and hydrocortisone, which will allow the proliferation of tumorspheres enriched with PCSCs. The cells were cultured with leptin, chemotherapeutic drug, and leptin signaling inhibitor IONP-LPrA2. Tumorspheres formation (number and size) was determined after 1 week of treatment. Additionally, the levels of PCSC markers, HDAC1, HDAC2, HDAC3, and HDAC8 in tumorspheres were determined using flow cytometry, western blot, and RT-PCR. In addition, the effects of treatments on miR21 and miR200a/c levels were determined using RT-PCR. Results: Leptin induced PA tumorspheres formation and size, which was accompanied by higher level of PCSC markers (CD24, CD44, ESA, and ALDH1). Moreover, leptin affected the level of HDACs, miR21 and miR200a/c in PA tumorspheres. IONP-LPrA2 abrogated leptin effects and decreased PCSC which were spared by chemotherapeutics. Conclusion: Obesity signals via leptin could be involved in the increase PA aggressiveness and chemoresistance, which may be linked to the increase of PCSC. Leptin could induce PA progression and chemoresistance via modulation of HDAC and miRNA. Acknowledgement: This work was supported by the DOD W81XWH-13-1-0382; NIH/SBIR1R41CA183399-01A1; Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center Partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP; Calvin Johnson Jr. Foundation Pancreatic Cancer Research Scholarship to CITM, and facility and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR03034 and 1C06 RR18386). Citation Format: Cynthia M. Tchio, Adriana Harbuzariu, Tia Harmon, Derrick Beech, Ruben Gonzalez-Perez. Leptin modulation of PCSC, HDAC, and microRNA in pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1901.