Mediator Complex Subunit 1 (MED1): A Common Molecular Participant in Pancreatic Carcinoma
Celina Villa, Jie Liao, Haonan Li, Wanying Zhang, Yuzhi Jia, Janardan K Reddy, Guang-Yu Yang. Northwestern University, Chicago, IL
Background: MED1 is a component of the Mediator complex that bridges GATA transcriptional activators and nuclear hormone receptors to the RNA polymerase II apparatus. Studies suggest that MED1 may be involved in organogenesis and carcinogenesis; however, the role of MED1 in the pancreas needs to be further elucidated.
Design: A total of 63 pancreatectomy specimens with 53 invasive carcinoma lesions queried from the Surgical Pathology department of Northwestern University were examined by immunohistochemistry for MED1 expression. The expression pattern of MED1 and its association with activation of mutant kras/p53 was determined immunohistochemically in the pancreata obtained from k-rasG12D/+/Trp53R172/+/Pdx-1-Cre mice and compared with wild type mice. MED1-positivity in ≥5% of the nuclei of carcinoma cells was considered positive staining. Focal positivity was defined as 5-50% of carcinoma cell nuclei and diffuse positivity as >50% of carcinoma cell nuclei. GST pull-down assay with S35-Labeled in vitro translated Pdx1 and GST-truncated MED1 was used to determine the interaction of MED1 and Pdx1.
Results: MED1 staining was confined to the nuclei of carcinoma cells as a dark brown staining pattern. MED1 expression was found in 50 of 53 (94%) human invasive pancreatic carcinomas, all exhibiting diffuse positivity; 100% (3/3) of invasive pancreatic adenocarcinomas in k-rasG12D/+/Trp53R172/+/Pdx-1-Cre mice showed diffusely positive nuclear staining, and 100% (2/2) early neoplastic foci with activated kras/p53 also showed diffuse positive nuclear staining.
All benign human pancreata (n=10) and benign epithelia adjacent to cancer (n=7) were MED1 negative. Negative staining was observed in benign pancreata of the wild type mice (n=3). GST pull-down assay identified Pdx1 binding sites in MED1 located in amino acid regions 440-740,740–1130 and 980–1370.
Conclusions: MED1 is over-expressed in human invasive pancreatic adenocarcinoma and murine invasive pancreatic carcinoma/early neoplastic foci with mutant activated kras/p53. MED1 expression was not observed in benign epithelium. These results imply that MED1 can be a useful malignant biomarker. Protein interaction between Pdx1 and MED1 indicates the potential role of MED1 in pancreatic linage differentiation/development and carcinogenesis.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 272, Wednesday Morning