In silico analysis of the transportome in human pancreatic ductal adenocarcinoma

Abstract

The altered expression and/or activity of ion channels and transporters (transportome) have been associated with malignant behavior of cancer cells and were proposed to be a hallmark of cancer. However, the impact of altered transportome in epithelial cancers, such as pancreatic ductal adenocarcinoma (PDAC), as well as its pathophysiological consequences, still remains unclear. Here, we report the in silico analysis of 840 transportome genes in PDAC patients' tissues. Our study was focused on the transportome changes and their correlation with functional and behavioral responses in PDAC tumor and stromal compartments. The dysregulated gene expression datasets were filtered using a cut-off of fold-change values ≤-2 or ≥2 (adjusted p value ≤0.05). The dysregulated transportome genes were clearly associated with impaired physiological secretory mechanisms and/or pH regulation, control of cell volume, and cell polarity. Additionally, some down-regulated transportome genes were found to be closely linked to epithelial cell differentiation. Furthermore, the observed decrease in genes coding for calcium and chloride transport might be a mechanism for evasion of apoptosis. In conclusion, the current work provides a comprehensive overview of the altered transportome expression and its association with predicted PDAC malignancy with special focus on the epithelial compartment.

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

“…Dual localization of the channel, i.e. expression of Kv1.3 in mitochondrial and plasma membranes, had already been found in breast cancer MCF-7, prostate cancer PC3, osteosarcoma SAOS-2, melanoma B16F10, Jurkat T cell lymphoma [22,26,27] and pancreas carcinoma [28]. In addition, recent data indicate the presence of Kv1.3 also in cis-Golgi [29] and in the nuclear membrane [30], which is also consistent with the present studies.…”

The A818–6 system as an in-vitro model for studying the role of the transportome in pancreatic cancer

“…To further authenticate our hypothesis that the HS/ ML system is a valid system to study the role of transportome in the de-differentiation process in PDAC, we compared the above described results with our recently reported transportome analysis in PDAC patients' tissues [31,32]. Previously, we compared the gene expression profile of 19 PDAC patients' malignant pancreatic microdissected tissue specimens (tumour epithelium) with 13 different normal pancreatic epithelial specimens (normal epithelium) that were performed using a 133 A/B Affymetrix microarray technology (tissue microarray).…”

“…The experiment was performed using the Agilent technology Sureprint G3 Human GE 8 × 60 K (Agilent, Santa Clara, CA, USA) and it was analysed by imaGenes (Agilent Expression Profiling service, Berlin). Regarding the tissue microarray, the mRNA expression levels were investigated using U133 A/B Affymetrix GeneChip, the detailed methodology was previously reported [31,32]. The patients gave consents and the ethical committee approved the original study [31], which performed a whole genome expression analysis from which we have only taken a subset for further interpretation.…”

“…The ethical committee of medical faculty of Christian Albrechts university of Kiel approved the study under the number A110/99. The gene expression database used in this study including the patients' consents to participate was previously published [31,32]. nCounter® ion channel assay, (Nanostring technologies®, Seattle, USA)…”

“…This list was defined according to IUPHAR-DB [33], "Guide to Receptor and Channels" [34], and HUGO Gene Nomenclature Committee [35]. The description of the transportome gene list was previously described [32]. The differential expression values extracted for the 838 transportome genes were further validated by setting an adjusted p-value of ≤0.05 (Benjamini, and Hochberg correction) and a fold change (FC) ≤ − 2 or ≥ 2 for the both the cell and tissue microarrays.…”