Abstract
Gastric cancer (GC) is characterized by poor efficacy and the modest clinical impact of current therapies. Apoptosis evasion represents a causative factor for treatment failure in GC as in other cancers. Since intracellular calcium homeostasis regulation has been found to be associated with apoptosis resistance, the aberrant expression of intracellular calcium regulator genes (CaRGs) could have a prognostic value in GC patients. We analyzed the association of the expression levels of 98 CaRGs with prognosis by the log-rank test in a collection of 1524 GC samples from four gene expression profiling datasets. We also evaluated differential gene expression in comparison with normal stomach tissue, and then we crossed results with tissue microarrays from the Human Protein Atlas. Among the investigated CaRGs, patients with high levels of TRPV2 expression were characterized by a shorter overall survival. TRPV2 expression was found to increase according to tumor stage. Both mRNA and protein levels were significantly higher in tumor than normal stomach samples. TRPV2 was also associated with poor prognosis in the Lauren’s intestinal type GC and in patients treated with adjuvant therapy. Overall, we highlighted the relevance of TRPV2 not only as a prognostic biomarker but also as a potential therapeutic target to improve GC treatment efficacy.
Highlights
Gastric cancer (GC) is the fifth and third most common type of cancer worldwide for incidence and mortality, respectively
We found a small number of Ca2+ regulator genes (CaRGs) whose gene expression was significantly associated with differences in overall survival (OS), progression-free survival (PFS), or both in a large cohort of GC patients
As regards to PFS (Figure 1b), we found 27 genes in the KMplot dataset (359 samples), 24 genes in the GSE62254 dataset (300 samples), and 15 genes in the TCGA–STAD dataset (320 samples) whose transcription levels were associated with survival differences
Summary
Gastric cancer (GC) is the fifth and third most common type of cancer worldwide for incidence and mortality, respectively. The treatment efficacy is low for the first-line setting and is based on platinum compounds (cisplatin/oxaliplatin), which activate apoptosis by DNA crosslinking, plus a fluoropyrimidine (5-FU, capecitabine, and S-1) that causes cell death by thymidine synthesis inhibition These are combined with docetaxel, a microtubules depolymerization inhibitor, or trastuzumab, an anti-epidermal growth factor 2 (HER2) monoclonal antibody [3]. By means of high-throughput-omics techniques (genomic, proteomic, and metabolomic approaches), significant advances have been made to unveil the molecular features of GC and, among a multitude of perspectives, define new possible molecular targets [12,13] In this view, one of the most relevant cellular processes in cancer cells is represented by intracellular calcium (Ca2+) concentration homeostasis. Our results suggest that Ca2+ regulation-related signatures could have a prognostic significance and could potentially represent innovative and effective therapeutic targets in GC [18]
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