Abstract 139: MicroRNA-375 and microRNA-221: Potential noncoding RNAs associated with antiproliferative activity of benzyl isothiocyanate in pancreatic cancer

Abstract

Abstract Large high-throughput studies in patients with pancreatic cancer revealed that oncogenic miR-221 is commonly upregulated microRNA whereas putative tumor suppressor miR-375 is generally down modulated when compared to adjacent benign pancreatic tissue or normal pancreas. In our laboratory, we observed that deregulated expression of miR-375 and miR-221 (as noted in pancreatic cancer patients) can be recapitulated in PDX1-Cre+; KRasG12D+ pancreatic cancer mouse model. Coherent data obtained from pancreatic cancer patient samples to preneoplastic lesions developed in preclinical mouse model tempted us to postulate that aberrant expression of these miRNAs (−375 and-221) might play significant role for the development of pancreatic cancer. Interestingly, ablation of miR-221 by ectopic expression of antagomir-221 in pancreatic ductal carcinoma cells can significantly exert antiproliferative effect with increased expression of p27kip1, a target of miR-221. To the other end, premiR-375 overexpression diminished cell proliferation with downmodulation of Insulin like growth factor binding protein 5 (IGFBP5) and Caveolin-1 (CAV-1 gene), which are of particular interest because of their potential link with pancreatic cancer cell growth and diagnosis. It is quite intriguing that the levels of both CAV-1 and IGFBP5 expression were elevated when miR-375 expression wanes in KRASG12D driven PanIN lesion in compound mutant mice. Previous studies in our laboratory demonstrate that benzyl isothiocyanate (BITC), a prototypical member of the isothiocyanate (ITC) family, inhibits proliferation of human pancreatic cancer cells by causing cell cycle arrest and inducing apoptosis. Interestingly, real time qRT-PCR analysis indicates that anticancer agent BITC can diminish oncogenic miR-221 expression and elevate the level of tumor suppressor miR-375 in pancreatic cancer cells. Besides, genetic manipulation studies revealed that enforced silencing of miR-221 or overexpression of miR-375 enhances the antiproliferative effect of BITC in pancreatic ductal carcinoma cells. Next we explored the efficacy of BITC to interfere with the development of mouse PanIN lesions. Results indicate that pancreata of BITC administered compound mutant mice exhibit reduced level of IGFBP5 protein. Histopathological analysis of the extent of PanINs as well as studies on the magnitude of expression of miR-221/miR-375 and other molecular mediators in these pancreata are in progress. Explicitly, our investigation might provide new insight into nonconventional microRNA replacement therapy against pancreatic cancer. 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 139. doi:10.1158/1538-7445.AM2011-139