Yang Liu1,2, Yoshifumi Baba2,3, Takatsugu Ishimoto2,4, Hiroyasu Tsutsuki5, Tianli Zhang5, Daichi Nomoto2, Kazuo Okadome2, Kensuke Yamamura2, Kazuto Harada2, Kojiro Eto2, Yukiharu Hiyoshi2, Masaaki Iwatsuki2, Yohei Nagai2, Shiro Iwagami2, Yuji Miyamoto2, Naoya Yoshida2, Yoshihiro Komohara6, Masaki Ohmuraya7, Xiaoming Wang8, Jaffer A Ajani9, Tomohiro Sawa5, Hideo Baba10,11. 1. Second Oncology Department, Shengjing Hospital affiliated of China Medical University, Shenyang, Liaoning, China. 2. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 3. Department of Next-Generation Surgical Therapy Development, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 4. International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan. 5. Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 6. Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 7. Department of Genetics, Hyogo College of Medicine, Hyogo, Japan. 8. Radiology Department, Shengjing Hospital affiliated of China Medical University, Shenyang, Liaoning, China. 9. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 10. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. hdobaba@kumamoto-u.ac.jp. 11. Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan. hdobaba@kumamoto-u.ac.jp.
Abstract
BACKGROUND: Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC). METHODS: We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance. RESULTS: ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens. CONCLUSIONS: F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.
BACKGROUND:Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancerpatients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC). METHODS: We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance. RESULTS: ESCC patients with F. nucleatuminfection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatuminfection and ATG7 expression in 284 ESCC specimens. CONCLUSIONS:F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.
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