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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Fusobacterium nucleatum colonization is associated with decreased survival of helicobacter pylori-positive gastric cancer patients
Yung-Yu Hsieh, Shui-Yi Tung, Hung-Yu Pan, Te-Sheng Chang, Kuo-Liang Wei, Wei-Ming Chen, Yi-Fang Deng, Chung-Kuang Lu, Yu-Hsuan Lai, Cheng-Shyong Wu, Chin Li
Yung-Yu Hsieh, Shui-Yi Tung, Te-Sheng Chang, Kuo-Liang Wei, Wei-Ming Chen, Yi-Fang Deng, Chung-Kuang Lu, Yu-Hsuan Lai, Cheng-Shyong Wu, Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
Yung-Yu Hsieh, Shui-Yi Tung, Te-Sheng Chang, Kuo-Liang Wei, Wei-Ming Chen, Cheng-Shyong Wu, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
Hung-Yu Pan, Department of Applied Mathematics, National Chiayi University, Chiayi 60035, Taiwan
Chin Li, Department of Biomedical Sciences, National Chung Cheng University, Chiayi 62130, Taiwan
Author contributions: Hsieh YY and Tung SY contributed equally to this work; Hsieh YY, Tung SY, Chang TS, Wei KL, Chen WM, and Wu CS recruited patients for the study and collected biopsies; Deng YF performed in vitro and sequencing experiments; Lai YH and Pan HY performed data and statistical analyses; Wu CS and Li C designed and supervised the study; Li C wrote the manuscript; All authors reviewed the manuscript.
Supported by Chiayi Chang Gung Memorial Hospital grants, including No. CORPG6G0021, No. CORPG6G0022 and No. CORPG6G0023 to Wu CS; No. CORPG6G0061, No. CORPG6G0062 and No. CORPG6G0063 to Tung SY; No. CORPG6G0071, No. CORPG6G0072 and No. CORPG6G0073 to Hsieh YY.
Institutional review board statement: All data acquisition and use of clinical specimens in this study were performed in accordance with the Declaration of Helsinki. Resected gastric cancer specimens were obtained from Tissue Bank, Department of Medical Research, Chang Gung Memorial Hospital at Chiayi. All the patients participating in this study were informed about the study and signed a written informed consent.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Chin Li, PhD, Associate Professor, Department of Biomedical Sciences, National Chung Cheng University, No. 168, Section 1, University Road, Minhsiung, Chiayi 62130, Taiwan.
biocl@ccu.edu.tw
Received: April 11, 2021
Peer-review started: April 11, 2021
First decision: May 24, 2021
Revised: May 31, 2021
Accepted: September 14, 2021
Article in press: September 14, 2021
Published online: November 14, 2021
Processing time: 213 Days and 5.1 Hours
BACKGROUND
An increased amount of Fusobacterium nucleatum (F. nucleatum) is frequently detected in the gastric cancer-associated microbiota of the Taiwanese population. F. nucleatum is known to exert cytotoxic effects and play a role in the progression of colorectal cancer, though the impact of F. nucleatum colonization on gastric cancer cells and patient prognosis has not yet been examined.
AIM
To identify F. nucleatum-dependent molecular pathways in gastric cancer cells and to determine the impact of F. nucleatum on survival in gastric cancer.
METHODS
Coculture of F. nucleatum with a gastric cancer cell line was performed, and changes in gene expression were investigated. Genes with significant changes in expression were identified by RNA sequencing. Pathway analysis was carried out to determine deregulated cellular functions. A cohort of gastric cancer patients undergoing gastrectomy was recruited, and nested polymerase chain reaction was performed to detect the presence of F. nucleatum in resected cancer tissues. Statistical analysis was performed to determine whether F. nucleatum colonization affects patient survival.
RESULTS
RNA sequencing and subsequent pathway analysis revealed a drastic interferon response induced by a high colonization load. This response peaked within 24 h and subsided after 72 h of incubation. In contrast, deregulation of actin and its regulators was observed during prolonged incubation under a low colonization load, likely altering the mobility of gastric cancer cells. According to the clinical specimen analysis, approximately one-third of the gastric cancer patients were positive for F. nucleatum, and statistical analysis indicated that the risk for colonization increases in late-stage cancer patients. Survival analysis demonstrated that F. nucleatum colonization was associated with poorer outcomes among patients also positive for Helicobacter pylori (H. pylori).
CONCLUSION
F. nucleatum colonization leads to deregulation of actin dynamics and likely changes cancer cell mobility. Cohort analysis demonstrated that F. nucleatum colonization leads to poorer prognosis in H. pylori-positive patients with late-stage gastric cancer. Hence, combined colonization of F. nucleatum and H. pylori is a predictive biomarker for poorer survival in late-stage gastric cancer patients treated with gastrectomy.
Core Tip: Fusobacterium nucleatum (F. nucleatum) is frequently enriched in the gastric cancer-associated microbiota. Here, we showed that F. nucleatum solicits a rapid but transient interferon response from gastric cancer cells. In addition, F. nucleatum leads to deregulation of the genes functioning in regulation of actin filament dynamics, likely changing cell mobility. In a patient cohort receiving gastrectomy, combined infection of F. nucleatum and Helicobacter pylori infection incurs poorer survival, indicating these two pathogens act synergistically to promote invasiveness of gastric cancer. Our finding suggests that F. nucleatum is a biomarker as treatment outcome predicator.
