Abstract 4065: Mechanistic role of heavy metal cadmium exposure in the etiology of pancreatic cancer

Persistent and cumulative human exposures to toxic metals lead to various health concerns and chronic illnesses. Cadmium is a heavy metal of considerable occupational and environmental concern, and has been shown to have an epidemiological association with pancreatic cancer. In this pursuit we have demonstrated that cadmium metal is carcinogenic and can induce transformation and reprogramming of normal pancreatic epithelial cells. In this study we have shown that exposure of normal pancreatic ductal epithelial HPNE cells to low levels of Cd+2 induce cellular transformation and also induce the expression of a transcription factor SATB2 which is oncogenic in pancreatic cancer. During cadmium-induced cellular transformation, cells gain the phenotype of cancer stem cells (CSCs) / progenitor cells and express pluripotency maintaining factors. SATB2 is a transcription factor and its role in cadmium-induced cellular transformation in pancreas has never been examined. SATB2 (special AT-rich binding protein-2), a transcription factor and epigenetic regulator that binds DNA in nuclear matrix attachment regions influences gene expression both by orchestrating chromatin structure and by functioning as a transcriptional co-factor. Our data have demonstrated that human pancreatic normal ductal epithelial (HPNE) cells do not express SATB2, whereas it is highly expressed in pancreatic cancer cell lines and cancer stem cells (CSCs). The CSCs / tumor initiating cells are believed to be the cause of cancer initiation, progression, and metastasis. During cadmium-induced cell transformation, cells gain the phenotype of cancer stem cells (CSCs) / progenitor cells and express pluripotency maintaining factors. This suggests that overexpression of SATB2 may induce cellular transformation. Interestingly, our data also reveal that chronic exposure of HPNE cells to low levels of cadmium results in SATB2 induction and cellular transformation. Using ChIP assay, we have demonstrated that SATB2 can directly bind to Bcl-2, Nanog, Bsp, Klf4, Myc, Xiap, and Hoxa2, and regulate the expression of EMT genes, pluripotency maintaining factors and drug resistance genes. Based on these observations, we conclude that the SATB2, induced by cadmium exposure or through over-expression studies, play a role in cell transformation of human pancreatic normal ductal epithelial cells. It can thus serve as a potential novel target for treatment of pancreatic cancer. To evaluate the human health risks associated with chronic exposure to cadmium we develop a mechanistic understanding of the cadmium induced human pancreatic normal ductal epithelial cell transformation. The results shown set the stage that cadmium toxicity enhances pancreatic carcinogenesis by up-regulating SATB2 which may thus be a potential target for development of targeted therapeutic interventions. Citation Format: Wei Yu, Yiming Ma, Rakesh Srivastava, Sharmila Shankar. Mechanistic role of heavy metal cadmium exposure in the etiology of pancreatic cancer. [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 4065.