Abstract LB-22: Gemcitabine resistance is associated with EMT phenotype along with expression of cancer stem cell markers and a specific miRNA profile in the human pancreatic cancer cell line BxPC3

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.LB-22-LB-22
• Main Authors: Bera, Alakesh, Freeman, James W., VenkataSubbaRao, Kolaparthi, Zhao, Shujie
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-LB-22

Despite new therapeutic strategies, human pancreatic ductal adenocarcinomas (PDAC) remain one of the greatest oncological challenges, as the rate of incidence almost equals the rate of mortality with a 5-year survival of less than 5%. Gemcitabine is the standard therapy for PDAC and is mostly used alone or in combination with an EGFR inhibitor. While tumors respond to Gemcitabine treatment initially, they generally develop chemoresistance. A thorough understanding of molecular events that promote resistance against Gemcitabine may identify pathways that can be efficiently targeted to reverse chemoresistance. A cell line model resistant to Gemcitabine was generated by transiently exposing BxPC3 cells to increasing concentrations of Gemcitabine. This Gemcitabine resistant cell line, BxPC3-GzR, was compared with untreated BxPC3 control cells. BxPC3-GzR cells showed properties of undergoing epithelial to mesenchymal transition (EMT) and these included a spindle shaped morphology, an increase in expression of vimentin and a decrease in expression of E-cadherin. BxPC3-GzR cells also showed an increase of expression of CD44 and in expression of phosphorylated STAT3TY705, which are characteristic of cancer stem cells. BxPC3 and BxPC3-GzR where further compared by microarray analyses for expression of micro-RNAs (miRNAs). BxPC3-GzR cells showed a specific miRNA expression profile (9 positively and 8 negatively regulated). Thus far seven of eight miRNAs identified as altered in BxPC3-GzR cells were validated by real-time RT-PCR (miR-15b, miR-21, miR-100, miRNA -125b, miRNA-155, miRNA-205 and miRNA-455-3p). These studies suggest that Gemcitabine treatment of PDAC selects for a resistant population of tumor cells that have a mesenchymal/stem cell-like phenotype and that express a distinct miRNA profile. Targeting these miRNAs may provide novel targets for restoring or enhancing anti-tumor response of Gemcitabine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-22. doi:1538-7445.AM2012-LB-22