Cytidine Deaminase Enhances Liver Cancer Invasion by Modulating Epithelial-Mesenchymal Transition via NFκB Signaling

Chia-Jung Liao; Yang-Hsiang Lin; Huei-Tzu Chien; Yi-Wen Wang; Tzu-Kang Lin; Chau-Ting Yeh; Kwang-Huei Lin

doi:10.1016/j.bj.2024.100789

Cytidine Deaminase Enhances Liver Cancer Invasion by Modulating Epithelial-Mesenchymal Transition via NFκB Signaling

Biomed J. 2024 Sep 19:100789. doi: 10.1016/j.bj.2024.100789. Online ahead of print.

Authors

Chia-Jung Liao¹, Yang-Hsiang Lin², Huei-Tzu Chien³, Yi-Wen Wang⁴, Tzu-Kang Lin⁵, Chau-Ting Yeh⁶, Kwang-Huei Lin⁷

Affiliations

¹ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan (R.O.C).
² Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan (R.O.C); Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (R.O.C).
³ Department of Nutrition and Health Sciences, Chang Gung University of Science and Technology, Taoyuan City, 33303, Taiwan (R.O.C); Geriatric and Long-Term Care Research Center, Chang Gung University of Science and Technology, Taoyuan City, 33303, Taiwan (R.O.C).
⁴ School of Nursing, College of Medicine, Chang Gung University, Taoyuan, Taiwan (R.O.C).
⁵ Neurosurgery, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan (R.O.C); Neurosurgery, Department of Surgery, Fu Jen Catholic University Hospital, New Taipei City 24352, Taiwan (R.O.C).
⁶ Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (R.O.C).
⁷ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan (R.O.C); Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (R.O.C); Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan (R.O.C). Electronic address: khlin@mail.cgu.edu.tw.

PMID: 39305991
DOI: 10.1016/j.bj.2024.100789

Abstract

Background: Cancer metastasis is the leading cause of cancer-related deaths, underscoring the importance of understanding its underlying mechanisms. Hepatocellular carcinoma (HCC), a highly malignant type of cancer, was selected as our research model.

Material and methods: We aimed to develop high-metastatic cell lines using in vitro and in vivo selection strategies and identify critical metastasis-related genes through microarray analyses by comparing them with parental cells.

Results: Our results showed that the high-metastatic cell lines exhibited significantly stronger invasion abilities than parental cells. Microarray analyses identified cytidine deaminase (CDA), a gene associated with systemic chemotherapy resistance, as one of the overexpressed genes in the high-metastatic cells. Data analysis from The Cancer Genome Atlas Program revealed that while CDA is downregulated in HCC, patients with high CDA expression tend to have poorer prognoses. Cell models confirmed that CDA overexpression enhances cell migration and invasion, whereas CDA knockdown inhibits these abilities. Investigating the key molecules involved in the epithelial-mesenchymal transition (EMT), we found that CDA overexpression increases the expression of fascin, N-cadherin, β-catenin, and snail while decreasing E-cadherin expression. Conversely, CDA knockdown produced opposite results. Additionally, we discovered that CDA regulates NF-κB signaling, which controls the expression of N-cadherin, thereby promoting the invasion capability of HCC cells.

Conclusions: We isolated highly metastatic cells and identified potential HCC metastasis-related genes. CDA promotes cell invasion by regulating EMT through the NF-κB pathway. Future studies are warranted to explore the potential of CDA as a biomarker for prognosis and therapeutic decision-making.

Keywords: NF-κB; cytidine deaminase; epithelial-mesenchymal transition; hepatocellular carcinoma; metastasis.