Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism

Abstract

BackgroundPancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32–34. In this study, our goal was to discover the identity of the familial pancreatic cancer gene on 4q32 and determine the function of that gene.Methods and FindingsA customized microarray of the candidate chromosomal region affecting pancreatic cancer susceptibility revealed the greatest expression change in palladin (PALLD), a gene that encodes a component of the cytoskeleton that controls cell shape and motility. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members. The mutational change is not a known single nucleotide polymorphism. Palladin RNA, measured by quantitative RT-PCR, was overexpressed in the tissues from precancerous dysplasia and pancreatic adenocarcinoma in both familial and sporadic disease. Transfection of wild-type and P239S mutant palladin gene constructs into HeLa cells revealed a clear phenotypic effect: cells expressing P239S palladin exhibited cytoskeletal changes, abnormal actin bundle assembly, and an increased ability to migrate.ConclusionsThese observations suggest that the presence of an abnormal palladin gene in familial pancreatic cancer and the overexpression of palladin protein in sporadic pancreatic cancer cause cytoskeletal changes in pancreatic cancer and may be responsible for or contribute to the tumor's strong invasive and migratory abilities.

Binding of pro-prion to filamin A disrupts cytoskeleton and correlates with poor prognosis in pancreatic cancer

“…Mutation in palladin has been linked to familial pancreatic cancer (63). However, this mutation was not found in other families with familial pancreatic cancer (64,65).…”

Palladin Is an Actin Cross-linking Protein That Uses Immunoglobulin-like Domains to Bind Filamentous Actin

“…A recent report has linked a point mutation in palladin to a form of familial pancreatic cancer, and has also shown that palladin RNA levels are increased in familial and sporadic precancerous and cancerous pancreatic tissues (67). The disease-causing mutation occurs in the ␣-actinin-binding region of palladin, and HeLa cells transfected with the mutated form of palladin showed cytoskeletal abnormalities, altered localization of palladin, and increased motility (67). In addition to pancreatic cancer, other human diseases and conditions in which palladin has been implicated include pre-eclampsia (68,69), invasive breast cancer (70), and increased risk of heart attack (71).…”

Differential Quantitative Proteomics of Human Microvascular Endothelial Cells 1 by iTRAQ Reveals Palladin to be a New Biomarker During TGF-?1 Induced Endothelial Mesenchymal Transition

“…Palladin levels are up-regulated in metastatic cancer cells and play an important role in organizing actin arrays within migrating cells and in invasive motility [32]. The palladin gene was found within a cluster of invasion-specific genes in pancreatic and colorectal cancers [40][41][42]. The palladin protein levels increase significantly in human dermal fibroblasts in response to TGF-β 1 treatment, and during myofibroblast differentiation in the presence of TGF-β1 [39].…”