Cell Cycle Regulation and DNA Damage Response Networks in Diffuse- and Intestinal-Type Gastric Cancer

Shihori Tanabe; Sabina Quader; Ryuichi Ono; Horacio Cabral; Kazuhiko Aoyagi; Akihiko Hirose; Hiroshi Yokozaki; Hiroki Sasaki

doi:10.3390/cancers13225786

Cell Cycle Regulation and DNA Damage Response Networks in Diffuse- and Intestinal-Type Gastric Cancer

Cancers (Basel). 2021 Nov 18;13(22):5786. doi: 10.3390/cancers13225786.

Authors

Shihori Tanabe¹, Sabina Quader², Ryuichi Ono³, Horacio Cabral⁴, Kazuhiko Aoyagi⁵, Akihiko Hirose¹, Hiroshi Yokozaki⁶, Hiroki Sasaki⁷

Affiliations

¹ Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki 210-9501, Japan.
² Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, Kawasaki 210-0821, Japan.
³ Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki 210-9501, Japan.
⁴ Department of Bioengineering, Graduate School of Engineering, University of Tokyo, Tokyo 113-0033, Japan.
⁵ Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
⁶ Department of Pathology, Kobe University of Graduate School of Medicine, Kobe 650-0017, Japan.
⁷ Department of Translational Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.

Abstract

Dynamic regulation in molecular networks including cell cycle regulation and DNA damage response play an important role in cancer. To reveal the feature of cancer malignancy, gene expression and network regulation were profiled in diffuse- and intestinal-type gastric cancer (GC). The results of the network analysis with Ingenuity Pathway Analysis (IPA) showed that the activation states of several canonical pathways related to cell cycle regulation were altered. The G₁/S checkpoint regulation pathway was activated in diffuse-type GC compared to intestinal-type GC, while canonical pathways of the cell cycle control of chromosomal replication, and the cyclin and cell cycle regulation, were activated in intestinal-type GC compared to diffuse-type GC. A canonical pathway on the role of BRCA1 in the DNA damage response was activated in intestinal-type GC compared to diffuse-type GC, where gene expression of BRCA1, which is related to G₁/S phase transition, was upregulated in intestinal-type GC compared to diffuse-type GC. Several microRNAs (miRNAs), such as mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451 and mir-605, were identified to have direct relationships in the G₁/S cell cycle checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in epithelial-mesenchymal transition (EMT) conditions. The alterations in the activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC highlighted the significance of cell cycle regulation in EMT.

Keywords: DNA damage response; cancer malignancy; cell cycle regulation; epithelial-mesenchymal transition (EMT); gastric cancer; molecular network; network analysis.

Abstract

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