Abstract
Cancer is heterogeneous among patients, requiring a thorough understanding of molecular subtypes and the establishment of therapeutic strategies based on its behavior. Gastric cancer (GC) is adenocarcinoma with marked heterogeneity leading to different prognoses. As an effort, we previously identified a stem-like subtype, which is prone to metastasis, with the worst prognosis. Here, we propose FNBP1 as a key to high-level cell motility, present only in aggressive GC cells. FNBP1 is also up-regulated in both the GS subtype from the TCGA project and the EMT subtype from the ACRG study, which include high portions of diffuse histologic type. Ablation of FNBP1 in the EMT-type GC cell line brought changes in the cell periphery in transcriptomic analysis. Indeed, loss of FNBP1 resulted in the loss of invasive ability, especially in a three-dimensional culture system. Live imaging indicated active movement of actin in FNBP1-overexpressed cells cultured in an extracellular matrix dome. To find the transcription factor which drives FNBP1 expression in an EMT-type GC cell line, the FNBP1 promoter region and DNA binding motifs were analyzed. Interestingly, the Sp1 motif was abundant in the promoter, and pharmacological inhibition and knockdown of Sp1 down-regulated FNBP1 promoter activity and the transcription level, respectively. Taken together, our results propose Sp1-driven FNBP1 as a key molecule explaining aggressiveness in EMT-type GC cells.
Highlights
Advances in genomic technology have brought new ideas in understanding cancers by uncovering genetic heterogeneity and resulting phenotypical differences among patients [1].Gastric cancer (GC) is mostly adenocarcinoma; it is known for its great differences between subtypes [2,3]
In an effort to identify the critical factors contributing to the aggressive behavior of gastric cancer, we found that Formin-binding protein 1 (FNBP1) expression is correlated with the worst prognosis
FNBP1 Is Highly Expressed in Aggressive Subtype of GC Patients
Summary
Advances in genomic technology have brought new ideas in understanding cancers by uncovering genetic heterogeneity and resulting phenotypical differences among patients [1].Gastric cancer (GC) is mostly adenocarcinoma; it is known for its great differences between subtypes [2,3]. The Cancer Genome Atlas (TCGA) project defined four molecular subtypes of GC; Epstein–Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN) [4]. Cancer Research Group (ACRG) analyzed clinically relevant molecular subtypes of GC; MSI, epithelial-to-mesenchymal transition (EMT), microsatellite-stable/TP53- (MSS/TP53), and MSS/TP53+ GC [5]. The GS subtype from the TCGA project and the EMT subtype from the ACRG study are not identical but have similarities in having high portions of diffuse histologic type with worse prognosis [6]. We have defined a stem-like subtype of GC patients with mesenchymal features which bring chemo-resistance and low survival rate [7]. There is no targeted therapeutics available for this subtype with a high degree of EMT, requiring thorough investigation of the molecular factors contributing to the aggressiveness of this specific subtype compared to others
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