Abstract
BackgroundThe 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).MethodsCancer-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.ResultsThe 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.ConclusionsThe 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 registrationA prospective study of diagnosis biomarkers of esophageal squamous cell carcinoma, ChiCTR2000031507. Registered 3 April 2016 - Retrospectively registered.
Highlights
The tRNA-derived small RNAs are produced in a nuclease-dependent manner in responses to variety of stresses that are common in cancers
By comparing the small RNAs in salivary exosomes of esophageal squamous cell carcinoma (ESCC) patients with that of healthy controls, we discovered two cancer-enriched small RNAs, tRNAGlyGCC-5 and a previously uncharacterized small RNA for which we coined the name “small RNA identified in Exosome from Saliva of ESCC patients”
Compared to the immortalized esophageal epithelial cells, both tRNA-GlyGCC-5 and sRESE were highly expressed in exosomes secreted into the conditioned media and ESCC cell lines
Summary
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). Esophageal squamous cell carcinoma (ESCC) is ranked seventh for cancer morbidity and sixth for cancer mortality worldwide [1]. Li et al Molecular Cancer (2022) 21:21 eligibility for curative surgical resection, early detection and diagnosis of ESCC is expected to be important. Biomarkers suitable for detection of early stage ESCC are lacking. Adjuvant radiotherapy and chemotherapy was important for ESCC, but their clinical benefit is controversial [5,6,7]. There are no biomarkers for predicting benefits of adjuvant therapies for ESCC either. Early detection of patients and more precise stratification to guide adjuvant treatments are urgently needed for this malignancy
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