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Goicoechea SM , Bednarski B , Stack C , Cowan DW , Volmar K , Thorne L , Cukierman E , Rustgi AK , Brentnall T , Hwang RF , McCulloch CAG , Yeh JJ , Bentrem DJ , Hochwald SN , Hingorani SR , Kim HJ , Otey CA
Isoform-Specific Upregulation of Palladin in Human and Murine Pancreas Tumors
Plos One. 2010 Apr;5(4)
PMID: ISI:000277079500017    PMCID: PMCID: PMC2859948    
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Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a characteristic pattern of early metastasis, which is driving a search for biomarkers that can be used to detect the cancer at an early stage. Recently, the actin-associated protein palladin was identified as a candidate biomarker when it was shown that palladin is mutated in a rare inherited form of PDA, and overexpressed in many sporadic pancreas tumors and premalignant precursors. In this study, we analyzed the expression of palladin isoforms in murine and human PDA and explored palladin's potential use in diagnosing PDA. We performed immunohistochemistry and immunoblot analyses on patient samples and tumor-derived cells using an isoform-selective monoclonal antibody and a pan-palladin polyclonal antibody. Immunoblot and real-time quantitative reverse transcription-PCR were used to quantify palladin mRNA levels in human samples. We show that there are two major palladin isoforms expressed in pancreas: 65 and 85-90 kDa. The 65 kDa isoform is expressed in both normal and neoplastic ductal epithelial cells. The 85-90 kDa palladin isoform is highly overexpressed in tumor-associated fibroblasts (TAFs) in both primary and metastatic tumors compared to normal pancreas, in samples obtained from either human patients or genetically engineered mice. In tumor-derived cultured cells, expression of palladin isoforms follows cell-type specific patterns, with the 85-90 kDa isoform in TAFs, and the 65 kDa isoform predominating in normal and neoplastic epithelial cells. These results suggest that upregulation of 85-90 kDa palladin isoform may play a role in the establishment of the TAF phenotype, and thus in the formation of a desmoplastic tumor microenvironment. Thus, palladin may have a potential use in the early diagnosis of PDA and may have much broader significance in understanding metastatic behavior.
Notes
Goicoechea, Silvia M. Bednarski, Brian Stack, Christianna Cowan, David W. Volmar, Keith Thorne, Leigh Cukierman, Edna Rustgi, Anil K. Brentnall, Teresa Hwang, Rosa F. McCulloch, Christopher A. G. Yeh, Jen Jen Bentrem, David J. Hochwald, Steven N. Hingorani, Sunil R. Kim, Hong Jin Otey, Carol A. Elsa U. Pardee Foundation ; UNC Center for Gastrointestinal Biology and Disease ; National Institutes of Health (NIH) [R01-GM081505, CA113451, K08-CA098240, T32-CA09688, CA15704, CA114028, CA129357, DK0606994]; Fox Chase Cancer Center's (FCCC) Kidney Keystone Program ; Mead Foundation ; Rosenzweig Foundation ; PanCAN ; CIHR [MOP-36332]; UNC SPORE in Gastrointestinal Cancers [P50-CA10699]; National Cancer Institute (NCI) [P50-CA106991] Elsa U. Pardee Foundation, http://www.pardeefoundation.org/ (C. A. Otey and H.J. Kim), UNC Center for Gastrointestinal Biology and Disease, https://cgibd.med.unc.edu/index. php (C. A. Otey), National Institutes of Health (NIH) R01-GM081505 (C. A. Otey), National Cancer Institute (NCI)/NIH CA113451 and Fox Chase Cancer Center's (FCCC) Kidney Keystone Program Grant (E. Cukierman). Mead Foundation, http://gileswmeadfoundation.org/; Rosenzweig Foundation, http://jrpancan.org/; and PanCAN, http://www.pancan.org/ (S. Hingorani), NIH, http://www.nih.gov/ to H.J. Kim (K08-CA098240), B. Bednarski (T32-CA09688), S. Hingorani (CA15704, CA114028, CA129357) and A. Rustigi (DK0606994). CIHR, http://www.cihr-irsc.gc.ca/ operating grant MOP-36332 (C. A. G. McCulloch). UNC SPORE in Gastrointestinal Cancers, http://cancer.med.unc.edu/patient/programs/gi. asp P50-CA10699 (H.J. Kim). NCI SPORE in Gastrointestinal Cancers, http://spores.nci.nih.gov/current/gi/index. htm P50-CA106991 (Jen Jjen Yeh). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 34 Public library science; 185 berry st, ste 1300, san francisco, ca 94107 usa 588nw