A signature of saliva-derived exosomal small RNAs as predicting biomarker for esophageal carcinoma: a multicenter prospective study.

BACKGROUND: The tRNA-derived small RNAs (tsRNAs) are produced in a nuclease-dependent manner in responses to variety of stresses that are common in cancers. We focus on a cancer-enriched tsRNA signature to develop a salivary exosome-based non-invasive biomarker for human esophageal squamous cell carcinoma (ESCC). METHODS: Cancer-enriched small RNAs were identified by RNA sequencing of salivary exosomes obtained from ESCC patients (n = 3) and healthy controls (n = 3) in a pilot study and further validated in discovery cohort (n = 66). A multicenter prospective observational study was conducted in two ESCC high-incidence regions (n = 320 and 200, respectively) using the newly developed biomarker signature. RESULTS: The tsRNA (tRNA-GlyGCC-5) and a previously undocumented small RNA were specifically enriched in salivary exosomes of ESCC patients, ESCC tissues and ESCC cells. The bi-signature composed of these small RNAs was able to discriminate ESCC patients from the controls with high sensitivity (90.50%) and specificity (94.20%). Based on the bi-signature Risk Score for Prognosis (RSP), patients with high-RSP have both shorter overall survival (OS) (HR 4.95, 95%CI 2.90-8.46) and progression-free survival (PFS) (HR 3.69, 95%CI 2.24-6.10) than those with low-RSP. In addition, adjuvant therapy improved OS (HR 0.47, 95%CI 0.29-0.77) and PFS (HR 0.36, 95%CI 0.21-0.62) only for patients with high but not low RSP. These findings are consistent in both training and validation cohort. CONCLUSIONS: The tsRNA-based signature not only has the potential for diagnosis and prognosis but also may serve as a pre-operative biomarker to select patients who would benefit from adjuvant therapy. TRIAL REGISTRATION: A prospective study of diagnosis biomarkers of esophageal squamous cell carcinoma, ChiCTR2000031507 . Registered 3 April 2016 - Retrospectively registered.

Clinical Significance of Porphyromonas gingivalis Enriching Cancer Stem Cells by Inhibiting Programmed Cell Death Factor 4 in Esophageal Squamous Cell Carcinoma.

Studies have confirmed that the colonization of Porphyromonas gingivalis (Pg) could promote the malignant evolution of esophageal squamous cell carcinoma (ESCC). Since pathogenic microorganisms can promote malignant tumor proliferation by inhibiting programmed cell death factor 4 (PDCD4) and the decrease of PDCD4 activity can enhance the stemness of cancer cells, we here investigated the functional mechanism by which Pg promoted ESCC chemoresistance and malignancy through inhibiting PDCD4 and enriching cancer stem cells (CSCs). The effects of Pg and PDCD4 on CSCs, chemoresistance and malignancy of ESCC cells were evaluated by in vitro studies. The expression of Pg, PDCD4, and ALDH1 in ESCC tissues were detected by IHC, and the correlations between each index and postoperative survival of ESCC patients were analyzed. The results showed that Pg could inhibit PDCD4 expression and lead to CSCs enrichment in ESCC cells. After eliminating Pg, the expression of PDCD4 was upregulated, the percentage of CSCs, chemoresistance and malignancy were decreased. ESCC patients with Pg-positive, PDCD4-negative, and ALDH1-positive have a significant shorter survival. This study proved that eliminating Pg and blocking CSCs enrichment caused by decreasing PDCD4 activity may provide a new strategy for ESCC treatment.

Porphyromonas gingivalis promotes malignancy and chemo-resistance via GSK3ß-mediated mitochondrial oxidative phosphorylation in human esophageal squamous cell carcinoma.

Our prior studies have confirmed that long-term colonization of Porphyromonas gingivalis (Pg) and overexpression of the inflammatory factor glycogen synthase kinase 3ß (GSK3ß) promote the malignant evolution of esophageal squamous cell carcinoma (ESCC). We aimed to investigate the functional mechanism by which Pg could promote ESCC malignancy and chemo-resistance through GSK3ß-mediated mitochondrial oxidative phosphorylation (mtOXPHOS), and the clinical implications. The effects of Pg and GSK3ß on mtOXPHOS, malignant behaviors and response to paclitaxel and cisplatin treatment of ESCC cells were evaluated by in vitro and in vivo studies. The results showed that Pg induced high expression of the GSK3ß protein in ESCC cells and promoted the progression and chemo-resistance via GSK3ß-mediated mtOXPHOS in human ESCC. Then, Pg infection and the expression of GSK3ß, SIRT1 and MRPS5 in ESCC tissues were detected, and the correlations between each index and postoperative survival of ESCC patients were analysed. The results showed that Pg-positive ESCC patients with high-expression of GSK3ß, SIRT1 and MRPS5 have significant short postoperative survival. In conclusion, we demonstrated that the effective removal of Pg and inhibition of its promotion of GSK3ß-mediated mtOXPHOS may provide a new strategy for ESCC treatment and new insights into the aetiology of ESCC.