Clinical significance of Fusobacterium nucleatum, epithelial–mesenchymal transition, and cancer stem cell markers in stage III/IV colorectal cancer patients

Xuebing Yan,1,* Liguo Liu,2,* Hao Li,1,* Huanlong Qin,1 Zhenliang Sun1,3 1Department of General Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 2Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 3Central Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, South Campus, Shanghai, China *These authors contributed equally tothis work Abstract: Colorectal cancer (CRC) is a common digestive malignancy and emerging studies have closely linked its initiation and development with gut microbiota changes. Fusobacterium nucleatum (Fn) has been recently identified as a pathogenic bacteria for CRC; however, its prognostic significance for patients is poorly investigated and is less for patients within late stage. Therefore, in this study, we made efforts to analyze its level and prognostic significance in a retrospective cohort of 280 stage III/IV CRC patients. We found that the Fn level was abnormally high in tumor tissues and correlated with tumor invasion, lymph node metastasis status, and distant metastasis. We also identified it as an independent adverse prognostic factor for cancer-specific survival (CSS) and disease-free survival (DFS). The following subgroup analysis indicated that Fn level could stratify CSS and DFS in stage IIIB/C and IV patients but failed in stage IIIA patients. In addition, stage III/IV patients with low Fn level were found to benefit more from adjuvant chemotherapy than those with high Fn level, in terms of DFS. Finally, we analyzed the expression and clinical significance of epithelial-to-mesenchymal transition (EMT) markers (E-cadherin and N-cadherin) and cancer stem cell (CSC) markers (Nanog, Oct-4, and Sox-2) in CRC tissues. The results indicated that N-cadherin, Nanog, Oct-4, and Sox-2 were adverse prognostic factors in these patients, while the opposite was true for E-cadherin. More importantly, expression of E-cadherin, N-cadherin, and Nanog was significantly correlated with Fn level in tumor tissues, suggesting the potential involvement of Fn in EMT-CSC cross talk during CRC progression. Taken together, these findings indicate that Fn is a novel predictive biomarker for clinical management in stage III/IV patients, and targeting Fn may be an effective adjuvant approach for preventing CRC metastasis and chemotherapy resistance. Keywords: colorectal cancer, Fn, EMT, cancer stem cell, prognosis