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
Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC.
