Sp1-Induced FNBP1 Drives Rigorous 3D Cell Motility in EMT-Type Gastric Cancer Cells

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.

Membrane tension-mediated stiff and soft tumor subtypes closely associated with prognosis for prostate cancer patients

“…Several researches showed that FNBP1 could affect tumor migration and invasion through affecting the formation of filopodia in bladder cancer [ 64 ] and breast cancer cells [ 65 ]. In addition, a recent study found the loss of FNBP1 could result in the loss of invasive ability in gastric cancer [ 66 ]. Remarkably, a pan-cancer analysis based on bioinformatics found that except the metastatic cancer, low expression of FNBP1 was associated with worse prognosis in breast cancer and lung adenocarcinoma, while high expression of FNBP1 was related to the poor prognosis in stomach adenocarcinoma [ 67 ].…”

Membrane tension sensing molecule-FNBP1 is a prognostic biomarker related to immune infiltration in BRCA, LUAD and STAD

“…Sp1 motif-driven FNBP1 expression is a key molecule process in explaining the invasiveness of EMT-type GC cells. Pharmacological inhibition and knockdown of Sp1 down-regulate FNBP1 promoter activity and transcription level, respectively [ 16 ].…”

“…However, in tumor research, independent research on FNBP1 is extraordinarily limited. Only few studies have focused on migration and invasion, such as the three-dimensional movement of gastric cancer cells [ 16 ], suppression of FNBP1 affected the formation of filopodia in bladder cancer [ 19 ] and breast cancer cells [ 37 ]. Therefore, in this study, we used multiple databases for joint analysis to study the role of FNBP1 in a variety of tumors.…”

FNBP1 Facilitates Cervical Cancer Cell Survival by the Constitutive Activation of FAK/PI3K/AKT/mTOR Signaling

“…FNBP1 had been well documented to be extensively involved in cell motility and endocytosis [16][17][18]. However, emerging evidence indicates a novel role of FNBP1 in malignant tumor invasion and metastasis [19][20][21][22][23][24][25]. Here, FNBP1 was confirmed to play a crucial role in maintaining constitutive FAK/PI3K/AKT/mTOR survival signaling…”