ABSTRACT
INTRODUCTION: Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. Aryl hydrocarbon receptor interacting protein (AIP) in one of AHR ligands. The aim of this study is to analyze the prognostic influence of AIP in pancreatic carcinoma. MATERIAL AND METHODS: Retrospective case series with immunohistochemical analysis of AIP. We have estimated a multivariate Cox's model for the outcome (progression free and overall survival). RESULTS: 204 patients were included in the study. As expected prognosis was poor and 67.8% died of disease. As for AIP 9.8% of the cases showed nuclear staining of the epithelial tumor cells and 59.4% a cytoplasmic one. Stroma was stained in 53.1% of the cases. Univariate survival analysis revealed a significantly worse prognosis of patients with cytoplasmic AIP expression (stroma and epithelium), but nuclear expression was associated to a better prognosis. In the multivariate analysis stromal AIP expression was an independent prognosticator of progression free survival, together with pT stage, histological grade and history of diabetes. DISCUSSION: AIP Is a conserved cochaperone protein binding to many proteins. AIP has been proposed as a potential tumor suppressor gene. To date, no study has analyzed the immunohistochemical expression of AIP in pancreatic carcinoma. Our results indicate that both epithelial and stromal cytoplasmic expression of AIP is associated to bad prognosis, while nuclear translocation seems to improve prognosis. CONCLUSION: Although we must deepen into the complex signaling pathways underlying this potential association, our results open a way to inhibiting AHR as a potential target against pancreatic carcinoma.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Receptors, Aryl Hydrocarbon/metabolism , Aged , Female , Humans , Immunohistochemistry/methods , MAP Kinase Signaling System/genetics , Male , Margins of Excision , Middle Aged , Molecular Targeted Therapy , Neoplasm Staging/methods , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/surgery , Prognosis , Progression-Free Survival , Receptors, Aryl Hydrocarbon/drug effects , Retrospective Studies , Survival Analysis , Pancreatic NeoplasmsABSTRACT
The transcription factor Twist1 is involved in the epithelial-mesenchymal transition and contributes to cancer metastasis through mostly unknown mechanisms. In colorectal cancer, Twist1 expression is mainly restricted to the tumor stroma. We found that human fibroblast cell lines stably transfected with Twist1 acquired characteristics of activated cancer-associated fibroblasts (CAFs), such as hyperproliferation, an increased ability to migrate and an alignment of the actin cytoskeleton. Further, Twist1-activated fibroblasts promoted increased matrix stiffness. Using quantitative proteomics, we identified palladin and collagen α1(VI) as two major mediators of the Twist1 effects in fibroblast cell lines. Co-immunoprecipitation studies indicated that palladin and Twist1 interact within the nucleus, suggesting that palladin could act as a transcription regulator. Palladin was found to be more relevant for the cellular biomechanical properties, orientation and polarity, and collagen α1(VI) for the migration and invasion capacity, of Twist1-activated fibroblasts. Both palladin and collagen α1(VI) were observed to be overexpressed in colorectal CAFs and to be associated with poor colorectal cancer patient survival and relapse prediction. Our results demonstrate that Twist1-expressing fibroblasts mimic the properties of CAFs present at the tumor invasive front, which likely explains the prometastatic activities of Twist1. Twist1 appears to require both palladin and collagen α1(VI) as downstream effectors for its prometastatic effects, which could be future therapeutic targets in cancer metastasis.
Subject(s)
Collagen Type VI/genetics , Colorectal Neoplasms/genetics , Cytoskeletal Proteins/genetics , Nuclear Proteins/genetics , Phosphoproteins/genetics , Twist-Related Protein 1/genetics , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , Cell Line, Tumor , Cell Movement/genetics , Colorectal Neoplasms/pathology , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Male , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Neoplasm Metastasis , Nuclear Proteins/metabolism , Transcriptional Activation/genetics , Twist-Related Protein 1/metabolismABSTRACT
The transcription factor (TF) Snail1 is a major inducer of the epithelial-mesenchymal transition (EMT) during embryonic development and cancer progression. Ectopic expression of Snail in murine mesenchymal stem cells (mMSC) abrogated their differentiation to osteoblasts or adipocytes. We used either stable isotopic metabolic labeling (SILAC) for 3T3-L1 cells or isobaric labeling with tandem mass tags (TMT) for mMSC stably transfected cells with Snail1 or control. We carried out a proteomic analysis on the nuclear fraction since Snail is a nuclear TF that mediates its effects mainly through the regulation of other TFs. Proteomics data have been deposited in ProteomeXchange via the PRIDE partner repository with the dataset identifiers PXD001529 and PXD002157 (Vizcaino et al., 2014) [1]. Data are associated with a research article published in Molecular and Cellular Proteomics (Pelaez-Garcia et al., 2015) [2].
