Abstract
Advanced gastric cancer (GC) is one of the most lethal cancer types, thus a better understanding of its biology in patients is urgently needed. MicroRNA (miR)-29a is a known tumor suppressive miR that is related to metastasis, but its clinical relevance in GC remains ambiguous. Here, using a large GC patient cohort we hypothesized that low expression of miR-29a in GC is associated with aggressive cancer biology and worse survival. We demonstrated that low miR-29a GC enriched cell proliferation, apoptosis, metastasis, and angiogenesis related gene sets, as well as the higher expression of related genes. Low miR-29a GC was associated with less anti-cancer immune cell infiltration as well as immune related scoring. Low miR-29a GC demonstrated a worse overall survival (OS) as well as disease specific survival (DSS) compared with high expressing miR-29a GC. Notably, low miR-29a expression was the only factor, other than residual tumor status, to be an independent prognostic biomarker of worse OS and DSS. In conclusion, low miR-29a GC was associated with aggressive cancer biology and worse OS as well as DSS. Additionally, low expression of miR-29a was an independent prognostic biomarker of OS and DSS in gastric cancer patients.
Highlights
We performed gene set enrichment analysis (GSEA), which revealed that low expressing miR-29a gastric cancer (GC) enriched all of cell proliferation-related Hallmark gene sets including E2F Targets, G2M Checkpoint, MYC Targets V1, MYC Targets V2, and Mitotic Spindle (Fig. 1A; normalized enrichment score (NES) = − 1.49 false discovery rate (FDR) = 0.090, NES = − 1.63 FDR = 0.063, NES = − 1.48 FDR = 0.093, NES = − 1.15 FDR = 0.23, and NES = − 1.79 FDR = 0.048 respectively)
In order to validate miR-29a expression with apoptosis, we investigated the expression of genes that are wellknown to be related with apoptosis
We demonstrated that low expressing miR-29a GC enriched cell proliferation and apoptosis related gene sets and was associated with high expression of apoptosis related genes, but not with pathological grade nor MKI67 expression
Summary
According to Zhao et al, cyclin dependent kinase 2 (CDK 2), CDK4, and CDK6 are the target of miR-29a and miR-29a, which inhibited the cell proliferation by those genes in vitro[17]. Zhang et al reported that miR-29a suppressed angiogenesis in GC by targeting VEGF expression in vitro and in vivo[18]. Whether the results of preclinical studies can directly translate into the clinical setting is unknown until it is investigated in large patient cohorts. We aimed to elucidate the clinical relevance of miR-29a expression levels in GC patients utilizing a large publicly available cohort, The Cancer Genome Atlas (TCGA). We hypothesized that low expressing miR-29a GC is associated with aggressive GC biology including cell proliferation, angiogenesis, and metastasis, as well as worse prognosis
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