Oncotarget

Research Papers:

Downregulation of Friend Leukemia Integration 1 (FLI1) follows the stepwise progression to gastric adenocarcinoma

Armando Del Portillo, Elena V. Komissarova, Aqiba Bokhari, Caitlin Hills, Anne Koehne de Gonzalez, Sarawut Kongkarnka, Helen E. Remotti, Jorge L. Sepulveda and Antonia R. Sepulveda

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Oncotarget. 2019; 10:3852-3864. https://doi.org/10.18632/oncotarget.26974

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Abstract

Armando Del Portillo1, Elena V. Komissarova1, Aqiba Bokhari1, Caitlin Hills1, Anne Koehne de Gonzalez1, Sarawut Kongkarnka1, Helen E. Remotti1, Jorge L. Sepulveda1 and Antonia R. Sepulveda1

1 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA

Correspondence to:

Antonia R. Sepulveda,email: as4400@cumc.columbia.edu

Keywords: gastric cancer; FLI1; dysplasia; tumor suppressor; methylation

Received: November 29, 2018     Accepted: April 04, 2019     Published: June 11, 2019

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.


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