Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 13, Pages -Publisher
MDPI
DOI: 10.3390/ijms22136784
Keywords
gastric cancer; EMT; cell motility; FNBP1; Sp1
Funding
- National Research Foundation of Korea (NRF) - Korean Government (MSIT) [NRF-2018R1A5A2025079]
- Seok-San Biomedical Science Scholarship, Yonsei University College of Medicine
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This study identifies FNBP1 as a key molecule in high-level cell motility, specifically present in aggressive gastric cancer cells. The transcription factor Sp1 is found to drive FNBP1 expression in EMT-type GC cells, leading to increased invasion ability. Inhibition of Sp1 results in down-regulation of FNBP1 and loss of invasive potential, suggesting a potential therapeutic target for aggressive gastric cancer.
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.
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