Abstract 3296: The loss of miR-34a and activation of Notch-1 leads to aggressiveness of pancreatic cancer cells, which could be attenuated by CDF.

Abstract

Abstract Studies have shown that Notch-1 plays key roles in early development and also becomes activated during the development and progression of a variety of tumors including pancreatic cancer (PC), one of the most lethal malignant diseases, which is in part due to its potential for rapid growth, drug resistance, and metastasis. The expression of microRNA (miRNA) miR-34a, a potential tumor suppressor, has been reported to be decreased in many human tumors including PC, suggesting that miR-34a is a critical during tumor development and progression. Several recent experimental studies have shown an inhibitory role of miR-34a in tumor cell growth by targeting Notch-1 in various tumor cells lines derived from prostate cancer, colorectal cancer and pancreatic cancer. However, the mechanistic interrelationship between the loss of miR-34a and activation of Notch-1 has not been fully elucidated. Here, we show that the expression of miR-34a is significantly reduced in a number of PC cell line. Forced over-expression of Notch-1 by Notch-1 cDNA transfection led to decreased expression of miR-34a in AsPC-1 PC cells, which was consistent with increased tumor cell aggressiveness such as increased cell migration and sphere formation (pancreatospheres). Conversely, knock-down of Notch-1 by Notch-1 specific siRNA decreased the formation of pancreatospheres in AsPC-1 cells and cancer stem like cells (CSLCs) such as those which formed spheres. Re-expression of miR-34a by the transfection of its precursor decreased the expression of Notch-1 protein in Notch-1 over-expressing PC cells, which was consistent with a decrease in the formation of pancreatospheres. Moreover, re-expression of miR-34a also decreased angiogenesis in vitro, the production of VEGF as well as mRNA levels of Notch-1 and other CSC markers (Nanog, Oct4, and EZH2) in pancreatic CSLCs (sphere cells). Finally, we found that CDF, a novel synthetic analogue of natural compound Curcumin, could decrease cell growth, cell migration, angiogenesis in vitro, and the formation of pancreatospheres, consistent with decreased expression of Notch-1 and VEGF, and increased expression of miR-34a in PC cells and in mouse xenograft tumor model of PC. In conclusion, our findings suggest that the inhibitory effect of CDF on PC tumor growth in vitro and in vivo is in part mediated through deregulations of Notch-1 and miR-34a in PC, suggesting that further in-depth investigations are warranted. Citation Format: Bin Bao, Shadan S. Ali, Asfar Azmi, Aamir Ahmad, Dejuan Kong, Yiwei Li, Sanjeev Banerjee, Amro Aboukameel, Subhash Padhye, Fazlul Sarkar. The loss of miR-34a and activation of Notch-1 leads to aggressiveness of pancreatic cancer cells, which could be attenuated by CDF. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3296. doi:10.1158/1538-7445.AM2013-3296