Background: Transcription factors (TFs) are key regulators which control gene expression during cancer initiation and progression. In the current study, we aimed to explore the proliferative function and clinical significance of TFs in gastric cancer (GC).
Methods: Differential analysis was used to investigate the overall expression difference between normal and tumor tissues of each TF in TCGA-STAD cohort. The quantitative real-time polymerase chain reaction (qRT-PCR) was performed to confirm the mRNA expression of one cut homeobox 2 (ONECUT2 ) in GC tissues. Western blot analysis was conducted to confirm the protein knockdown efficiency. Cell counting, colony formation, and GC xenograft model assays were performed to confirm the proliferative function of ONECUT2 in GC cells. Gene set enrichment analysis (GESA) and qRT-PCR were conducted to confirm the affected signaling pathways and downstream targets of ONECUT2.
Results: Our data indicated that a TF named ONECUT2  was highly expressed in GC and correlated with patients’ poor prognosis. Importantly, knockdown of ONECUT2  dramatically decreased GC cells proliferation, whereas overexpression of ONECUT2  promoted carcinogenesis in GC. Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed that the upregulating ONECUT2  induced the activation of Wnt signaling pathway and cell cycle regulation pathway. We further identified that ONECUT2  boosted gastric cancer cell proliferation through enhancing ROCK1  (Rho associated coiled-coil containing protein kinase 1) mRNA expression. High level of ROCK1  expression rescued proliferative behavior of ONECUT2 -deficient GC cells.
Conclusion: Our findings demonstrated that ONECUT2  promoted GC cells proliferation through activating ROCK1  expression at the DNA level, suggesting that ONECUT2-ROCK1  axis might be a potential therapeutic target in GC.
Keywords: transcriptional factor, ONECUT2 , ROCK1 , gastric cancer, carcinogenesis