Abstract
Gastric adenocarcinoma (GC) is a leading cause of cancer-related deaths worldwide. The transcription factor gene Friend Leukemia Integration 1 (FLI1) is methylated and downregulated in human GC tissues. Using human GC samples, we determined which cells downregulate FLI1, when FLI1 downregulation occurs, if FLI1 downregulation correlates with clinical-pathologic characteristics, and whether FLI1 plays a role in invasion and/or proliferation of cultured cells. We analyzed stomach tissues from 98 patients [8 normal mucosa, 8 intestinal metaplasia (IM), 7 dysplasia, 91 GC] by immunohistochemistry for FLI1. Epithelial cells from normal, IM, and low-grade dysplasia (LGD) showed strong nuclear FLI1 staining. GC epithelial cells showed significantly less nuclear FLI1 staining as compared to normal epithelium, IM and LGD (P=1.2×10-5, P=1.4×10-6 and P=0.006, respectively). FLI1 expression did not correlate with tumor stage or differentiation, but was associated with patient survival, depending on tumor differentiation. We tested the functional role of FLI1 by assaying proliferation and invasion in cultured GC cells. Lentiviral-transduced FLI1 overexpression in GC AGS cells inhibited invasion by 73.5% (P = 0.001) and proliferation by 31.5% (P = 0.002), as compared to controls. Our results support a combined role for FLI1 as a suppressor of invasiveness and proliferation in gastric adenocarcinoma, specifically in the transition from pre-cancer lesions and dysplasia to invasive adenocarcinoma, and suggest that FLI1 may be a prognostic biomarker of survival in gastric cancers.
Highlights
Gastric cancer (GC) is the 5th most common cancer and the 4th leading cause of cancer-related deaths worldwide [1, 2]
Since we previously found decreased transcription of Friend Leukemia Integration 1 (FLI1) in gastric adenocarcinoma tissues [21], we hypothesized that FLI1 may act as a tumor suppressor and that its expression would decrease in the progression of gastric carcinogenesis from normal epithelium to dysplasia and adenocarcinoma
Since IHC for FLI1 showed variable staining in normal epithelium and gastric adenocarcinoma cells, we employed a composite scoring system taking into account both intensity and frequency of positive nuclei in the tissue of interest to generate an H-score [29], where the proportion and intensity scores only included epithelial cells
Summary
Gastric cancer (GC) is the 5th most common cancer and the 4th leading cause of cancer-related deaths worldwide [1, 2]. Helicobacter pylori infection of the stomach leads to interaction of the bacteria and inflammatory mediators with gastric epithelial cells, including progenitor and stem cells, resulting in accumulation of mutations, epigenetic modifications and deregulation of cellular function that may lead to dysplasia and adenocarcinoma [7, 8]. Along this cancer progression pathway, gastric epithelial cells undergo alterations in their transcriptional program, either due to genetic events (e.g. mutations, translocations, genetic losses and gains) or by epigenetic events, including DNA methylation
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