Abstract
Aim:To investigate alterations in transcription of genes, encoding Ca2+ toolkit proteins, in oesophageal adenocarcinoma (OAC) and to assess associations between gene expression, tumor grade, nodal-metastatic stage, and patient survival.Methods:The expression of 275 transcripts, encoding components of the Ca2+ toolkit, was analyzed in two OAC datasets: the Cancer Genome Atlas [via the University of Alabama Cancer (UALCAN) portal] and the oesophageal-cancer, clinical, and molecular stratification [Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS)] dataset. Effects of differential expression of these genes on patient survival were determined using Kaplan-Meier log-rank tests. OAC grade- and metastatic-stage status was investigated for a subset of genes. Adjustment for the multiplicity of testing was made throughout.Results:Of the 275 Ca2+-toolkit genes analyzed, 75 displayed consistent changes in expression between OAC and normal tissue in both datasets. The channel-encoding genes, N-methyl-D-aspartate receptor 2D (GRIN2D), transient receptor potential (TRP) ion channel classical or canonical 4 (TRPC4), and TRP ion channel melastatin 2 (TRPM2) demonstrated the greatest increase in expression in OAC in both datasets. Nine genes were consistently upregulated in both datasets and were also associated with improved survival outcomes. The 6 top-ranking genes for the weighted significance of altered expression and survival outcomes were selected for further analysis: voltage-gated Ca2+ channel subunit α 1D (CACNA1D), voltage-gated Ca2+ channel auxiliary subunit α2 δ4 (CACNA2D4), junctophilin 1 (JPH1), acid-sensing ion channel 4 (ACCN4), TRPM5, and secretory pathway Ca2+ ATPase 2 (ATP2C2). CACNA1D, JPH1, and ATP2C2 were also upregulated in advanced OAC tumor grades and nodal-metastatic stages in both datasets.Conclusions:This study has unveiled alterations of the Ca2+ toolkit in OAC, compared to normal tissue. Such Ca2+ signalling findings are consistent with those from studies on other cancers. Genes that were consistently upregulated in both datasets might represent useful markers for patient diagnosis. Genes that were consistently upregulated, and which were associated with improved survival, might be useful markers for patient outcome. These survival-associated genes may also represent targets for the development of novel chemotherapeutic agents.
Highlights
Oesophageal malignancies are the sixth-leading cause of cancer-related mortality [1]
The 6 top-ranking genes for the weighted significance of altered expression and survival outcomes were selected for further analysis: voltage-gated Ca2+ channel subunit α 1D (CACNA1D), voltage-gated Ca2+ channel auxiliary subunit α2 δ4 (CACNA2D4), junctophilin 1 (JPH1), acid-sensing ion channel 4 (ACCN4), TRPM5, and secretory pathway Ca2+ ATPase 2 (ATP2C2)
CACNA1D, JPH1, and secretory pathway Ca2+ ATPase 2 BO (ATP2C2) were upregulated in advanced oesophageal adenocarcinoma (OAC) tumor grades and nodal-metastatic stages in both datasets
Summary
Oesophageal malignancies are the sixth-leading cause of cancer-related mortality [1]. There are two major distinct forms of OC: oesophageal squamous cell carcinoma (OSCC), derived from epithelial cells, and oesophageal adenocarcinoma (OAC), arising from glandular cells [5]. OAC is the most prevalent form in North America and Europe [5]. Risk factors for OAC include obesity, Barrett’s esophagus (BO, the replacement of normal, squamous epithelia with metaplastic columnar epithelia [6]), and gastroesophageal reflux disease (GORD) [1,2,3,4,5,6,7]. Two stomach-derived stimuli impacting oesophageal cells, because of GORD, are hydrochloric acid and bile acids (BAs) [8,9]. About how oesophageal cells detect and respond to these stimuli [10]
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