Abstract
Abstract Pancreatic cancer is the 4th leading cause of cancer-related mortality in the United States. Despite these statistics, progress in therapy of pancreatic cancer has been slow. p53 tumor suppressor pathway is altered in 50-75% of pancreatic cancer tumors. However, the role of p53 homologs p63 and p73 has not been well studied. We previously reported that p63 is expressed in pancreatic cancer cell lines and contributes to their motility and invasion. Here we tested expression of p63 in resected tumors and investigated its role as a transcription factor in pancreatic cancer. Expression of p63 was determined by immunohistochemistry in 20 resected tumor samples (15 - adenocarcinoma, 5 - squamous) using pan-p63 (clone 4A4) and ΔNp63-specific antibodies; and by immunoblotting, real-time quantitative and semi-quantitative PCR in 5 pancreatic cancer cell lines. p63 levels were manipulated employing transient overexpression and lentiviral approaches. We studied cell doubling times, motility in a wound assay and invasiveness in Matrigel chambers in the presence or absence of epidermal growth factor (EGF). Functional reporter and chromatin immunoprecipitation assays were performed to study the effects of p63 on selected promoters. We found that the p53 homolog p63 was expressed in resected pancreatic cancer samples. Pancreatic tumors with squamous differentiation showed strong diffuse expression of p63, whereas adenocarcinomas without squamous component had a focal expression of p63 (ΔNp63). In pancreatic cancer cell lines, p63 protein levels were high in 3/5 tested cell lines and ΔNp63α was the predominantly expressed variant. By contrast, TAp63 was not detected while p73 was barely detectable in 2/5 cell lines. Ectopic expression of ΔNp63α in PANC-1 cells (which had low endogenous p63) and shRNA-mediated knockdown in T3M4 cells (with high endogenous p63) indicated that ΔNp63α promoted anchorage-dependent and independent growth, motility and invasion, and enhanced resistance to cisplatin-induced apoptosis. Motogenic effects of ΔNp63α were augmented in presence of EGF. ΔNp63α augmented the EGF receptor expression in pancreatic cancer cells via transcriptional regulation and potentiated EGF-mediated activation of ERK, Akt and JNK signaling. 14-3-3α transcription was also positively regulated by ΔNp63α and we have previously shown that 14-3-3α contributes to chemoresistance in pancreatic cancer. Thus, p53 homolog ΔNp63α is expressed in pancreatic cancer, where it enhances tumor progression and chemoresistance via trans-activation of EGF receptor and 14-3-3α. 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 3076. doi:1538-7445.AM2012-3076
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