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ONECUT2 Accelerates Tumor Proliferation Through Activating ROCK1 Expression in Gastric Cancer

Authors Chen J, Chen J, Sun B, Wu J, Du C

Received 31 March 2020

Accepted for publication 30 June 2020

Published 21 July 2020 Volume 2020:12 Pages 6113—6121

DOI https://doi.org/10.2147/CMAR.S256316

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Beicheng Sun


Jie Chen,* Jinggui Chen,* Bo Sun, Jianghong Wu, Chunyan Du

Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Chunyan Du; Jianghong Wu
Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University, 1205 Rm., 3# Bldg., 270 Dong an Road, Shanghai 200032, People’s Republic of China
Email chunyanfudan@126.com elite53@163.com

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

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