ABSTRACT
Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-ß (TGFß)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFß through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFß axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.
Subject(s)
Bacteroidaceae Infections/complications , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/pathology , Porphyromonas gingivalis/physiology , Transforming Growth Factor beta/physiology , Acyltransferases , Adaptor Proteins, Signal Transducing/metabolism , Adult , Aged , Animals , Bacteroidaceae Infections/metabolism , Bacteroidaceae Infections/mortality , Bacteroidaceae Infections/pathology , Cells, Cultured , Disease Progression , Drosophila , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/microbiology , Esophageal Neoplasms/mortality , Esophageal Squamous Cell Carcinoma/metabolism , Esophageal Squamous Cell Carcinoma/microbiology , Esophageal Squamous Cell Carcinoma/mortality , Female , Follow-Up Studies , HCT116 Cells , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Signal Transduction/physiology , Smad Proteins/metabolism , Survival Analysis , Transcription Factors/metabolism , Transforming Growth Factor beta/metabolism , YAP-Signaling ProteinsABSTRACT
Background: The aim of this study was to identify prognostic markers for esophageal squamous cell carcinoma (ESCC) and build an effective prognostic nomogram for ESCC. Methods: A total of 365 patients with ESCC from three medical centers were divided into four cohorts. In the discovery phase of the study, we analyzed transcriptional data from 179 cancer tissue samples and identified nine marker genes using edgeR and rbsurv packages. In the training phase, penalized Cox regression was used to select the best marker genes and clinical characteristics in the 179 samples. In the verification phase, these marker genes and clinical characteristics were verified by internal validation cohort (n = 58) and two external cohorts (n = 81, n = 105). Results: We constructed and verified a nomogram model based on multiple clinicopathologic characteristics and gene expression of a patient cohort undergoing esophagectomy and adjuvant radiochemotherapy. The predictive accuracy for 4-year overall survival (OS) indicated by the C-index was 0.75 (95% CI, 0.72-0.78), which was statistically significantly higher than that of the American Joint Committee on Cancer (AJCC) seventh edition (0.65). Furthermore, we found two marker genes (TM9SF1, PDZK1IP) directly related to the OS of esophageal cancer. Conclusion: The nomogram presented in this study can accurately and impersonally predict the prognosis of ESCC patients after partial resection of the esophagus. More research is required to determine whether it can be applied to other patient populations. Moreover, we found two marker genes directly related to the prognosis of ESCC, which will provide a basis for future research.