MED29 Possesses a Complex Role in Pancreatic Cancer
Acta Universitatis Tamperensis, No 1574
By Riina Kuuselo
Tampere University Press
Distributed by Coronet Books Inc.
$84.50 Paper Original
Pancreatic cancer is one of the most aggressive malignancies with high mortality. It affects about approximately 900 people annually in Finland and nearly the same number of people die of it. The current treatment strategies for pancreatic cancer are ineffective, and the prognosis is very poor. This study aimed to characterize the molecular aberrations in pancreatic cancer and to highlight putative target genes that may serve as novel diagnostic markers or targets for therapy. More specifically, it concentrated on the characterization of the amplified region at chromosome 19q13 and functional studies of putative target genes within this locus.
The first study explored DNA copy number changes at the 19q13 locus in pancreatic cancer cell lines using fluorescence in situ hybridization. A 1.1 Mb amplicon with a 660-kb core region of high-level amplification was delineated. The prevalence of the 19q13 amplification and its possible correlation with clinicopathological features was investigated in over 500 primary pancreatic tumors. 19q13 copy number changes were found in more than 10% of ductal adenocarcinomas. Importantly, these changes correlated with advanced tumor stage and grade.
Genes located within the amplified region were identified and their expression levels were defined by quantitative real-time PCR. A number of genes within the amplicon were overexpressed through amplification. To select functionally important targets, an RNA inhibition (RNAi)-based viability screen was applied to identify genes for which downregulation attenuated cell viability. The expression screen and RNAi profiling results identified MED29 as the most promising candidate target in the 19q13 amplicon.
RNAi-mediated downregulation of MED29 in cells with high endogenous MED29 expression led to inhibition of several cancer cell-associated characteristics, such as cell growth, migration, invasion, and colony formation on soft agar. Unexpectedly, the lentiviral-based induction of MED29 expression in pancreatic cancer cells with low endogenous MED29 levels also led to growth inhibition. When MED29-overexpressing pancreatic cancer cells were inoculated into nude mice, a dramatic reduction in tumor incidence and tumor growth was observed compared to mice inoculated with control cells. A genome-wide microarray-based gene expression analysis was utilized to uncover the mechanisms involved in the growth differences between the MED29 and the control cells. This analysis identified a large group of differentially expressed genes that are involved in cell cycle- and cell division-related processes.
MED29 is part of a large, multisubunit complex that is involved in the regulation of transcription and has recently been linked to the pathogenesis of several cancers. This study shows for the first time that MED29 possesses an important but complex role in pancreatic cancer pathogenesis.
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