Abstract 4002: Alternations in microRNA expression profiles during the pancreatic multistep carcinogenesis
Authors: Kishikawa Takahiro , Otsuka Motoyuki , Yoshikawa Takeshi , Ohno Motoko , Koike Kazuhiko 
Published: August 2015

Introduction: While the process of carcinogenesis is generally a multistep with accumulation of mutations in oncogenes and tumor-suppressor genes, pancreatic cancers have frequent mutations relatively in limited genes, such as KRAS, TP53 (p53), CDKN2A (p16), and SMAD4. Then, series of mouse models have been generated to target these genes in the pancreas, and pancreatic cancers or pre-cancerous tumors have been successfully observed in such gene-modified mice. These mouse models are advantageous compared to human samples in genetic simplicity and little influence of environmental factors. During the steps of carcinogenesis, microRNAs (miRNAs), regulators of gene expression, may also be dysregulated. Although many studies have already been performed to determine the dysregulated miRNAs in pancreatic cancers, consistent results have not always been obtained so far, probably due to the complexity of the samples tested. Then, in this study, we examined comprehensive expression profiles of miRNAs in the pancreatic tissues in two kinds of gene-modified mice, which develop pre-cancerous tumor or progressive pancreatic cancer, to obtain an information about the expression changes of miRNA levels during the pancreatic multistep carcinogenesis. Methods: We used two mouse models: Ptf1a cre/+; LSL-Kras G12D/+ which induced constitutively active Kras mutation specifically in the pancreas and develop focal premalignant ductal tumors similar to human pancreatic intraepithelial neoplasia (PanINs). Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox, which induced Tgfbr2 knockout with active Kras expression in the pancreas and promoted aggressive pancreatic carcinoma with similar histology to human pancreatic ductal adenocarcinoma (PDAC). We performed miRNA microarrays (3D-GENE mouse miRNA Oligo chip, Toray) using total RNAs from pancreatic tumors of these mouse models and from wild type pancreas tissues. Results; MiRNAs, such as miR-21, miR-125b-5p, miR-31, and miR-192, were upregulated in PDAC compared to normal tissues. Interestingly, the expression levels of the majority of these miRNAs already increased from the stage of pre-cancerous PanINs in Kras-mutated mice. However, some miRNAs, such as miR-669p* and miR-200b/c, were increased at the stage between PDAC and PanINs, while no changes were observed at the stage of PanINs. In contrast, miR-148a and miR-802 were downregulated from the stage of PanINs, and miR-187* decreased during the stages of between PDAC and PanINs. Discussion; We showed using genetically-simple mouse models that the changes of miRNA expression levels occur at specific stages during the course of pancreatic carcinogenesis. Although validation of these results is required in human samples, the stage-specific expression profiles of miRNAs may provide with the insights regarding the pathogenesis of pancreatic multistep-carcinogenesis, and the information may also be useful as novel diagnostic biomarkers.

Citation Format: Takahiro Kishikawa, Motoyuki Otsuka, Takeshi Yoshikawa, Motoko Ohno, Kazuhiko Koike. Alternations in microRNA expression profiles during the pancreatic multistep carcinogenesis. [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 4002. doi:10.1158/1538-7445.AM2015-4002