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Identification of the long non-coding RNA H19 in plasma as a novel biomarker for diagnosis of gastric cancer.

ABSTRACT: Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are regarded as useful tools for cancer detection, particularly for the early stage; however, little is known about their diagnostic impact on gastric cancer (GC). We hypothesized that GC-related lncRNAs might release into the circulation during tumor initiation and could be utilized to detect and monitor GC. 8 lncRNAs which previously found to be differently expressed in GC were selected as candidate targets for subsequent circulating lncRNA assay. After validating in 20 pairs of tissues and plasma in training set, H19 was selected for further analysis in another 70 patients and 70 controls. Plasma level of H19 was significantly higher in GC patients compared with normal controls (p < 0.0001). By receiver operating characteristic curve (ROC) analysis, the area under the ROC curve (AUC) was 0.838; p < 0.001; sensitivity, 82.9%; specificity, 72.9%). Furthermore, H19 expression enabled the differentiation of early stage GC from controls with AUC of 0.877; sensitivity, 85.5%; specificity, 80.1%. Besides, plasma levels of H19 were significantly lower in postoperative samples than preoperative samples (p = 0.001). In conclusion, plasma H19 could serve as a potential biomarker for diagnosis of GC, in particular for early tumor screening.

SUBMITTER: Zhou X

PROVIDER: S-EPMC4476094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRecent studies have demonstrated that long non-coding RNAs (lncRNAs) were present in the blood of cancer patients and have shown great potential as powerful and non-invasive tumor markers. However, little is known about the value of lncRNAs in the diagnosis of esophageal squamous cell carcinoma (ESCC). We hypothesized that ESCC-related lncRNAs might be released into the circulation during tumor initiation and could be utilized to detect and monitor ESCC.MethodsTen lncRNAs (HOTAIR, AFAP1-AS1, POU3F3, HNF1A-AS1, 91H, PlncRNA1, SPRY4-IT1, ENST00000435885.1, XLOC_013104 and ENST00000547963.1) which previously found to be differently expressed in esophageal cancer were selected as candidate targets for subsequent circulating lncRNA assay. A four-stage exploratory study was conducted to test the hypothesis: (1) optimization of detected method to accurately and reproducibly measure ESCC-related lncRNAs in plasma and serum; (2) evaluation of the stability of circulating lncRNAs in human plasma or serum; (3) exploration the origin of ESCC-related lncRNAs in vitro and in vivo; (4) evaluation the diagnostic power of circulating lncRNAs for ESCC.ResultsESCC-related lncRNAs were detectable and stable in plasma of cancer patients, and derived largely from ESCC tumor cells. Furthermore, plasma levels of POU3F3, HNF1A-AS1 and SPRY4-IT1 were significantly higher in ESCC patients compared with normal controls. By receiver operating characteristic curve (ROC) analysis, among the three lncRNAs investigated, plasma POU3F3 provided the highest diagnostic performance for detection of ESCC (the area under the ROC curve (AUC), 0.842; p < 0.001; sensitivity, 72.8%; specificity, 89.4%). Moreover, use of POU3F3 and SCCA in combination could provide a more effective diagnosis performance (AUC, 0.926, p < 0.001, sensitivity, 85.7%; specificity, 81.4%). Most importantly, this combination was effective to detect ESCC at an early stage (80.8%).ConclusionsPlasma POU3F3 could serve as a potential biomarker for diagnosis of ESCC, and the combination of POU3F3 and SCCA was more efficient for ESCC detection, in particular for early tumor screening.

Project description:Aim:Traditional non-invasive diagnostic markers for gastric cancer (GC) exhibit insufficient sensitivity and specificity. Circulating exosomes are clinically useful non-invasive biomarkers for tumor diagnosis. In addition to their potential role in cancer biology, circulating long non-coding RNAs (lncRNAs) are a new class of promising cancer biomarkers. In the present study, we aimed to identify lncRNAs in circulating exosomes with potential as biomarkers for GC detection. Methods:We compared the expression of CEBPA-AS1 between GC cells and gastric epithelial cells. The biological function of exosomal CEBPA-AS1 was determined by cell phenotype experiments and rescue assays. We also compared the expression of CEBPA-AS1 in cancerous tissue from GC patients and corresponding adjacent normal tissues, as well as the expression of CEBPA-AS1 in plasma exosomes of GC patients and healthy controls. Diagnostic accuracy was assessed by the receiver operating characteristic (ROC) curve and area under the curve (AUC). Results:CEBPA-AS1 was highly expressed in both GC cells and in exosomes secreted by GC cells. In addition, CEBPA-AS1-containing exosomes secreted by GC cells could promote cell proliferation and inhibit apoptosis, thereby inducing the malignant behavior of GC cells. The level of CEBPA-AS1 was also significantly increased in tissues and plasma exosomes of GC patients. Stability tests showed that most plasma CEBPA-AS1 was encased in exosomes, thus avoiding degradation by RNases. We evaluated the diagnostic accuracy of exosome-derived CEBPA-AS1. The AUC value of CEBPA-AS1 in discriminating GC patients from healthy controls was 0.824, which was higher than the diagnostic accuracy of other traditional tumor biomarkers. Conclusion:CEBPA-AS1-containing exosomes secreted from GC cells could promote cell proliferation, inhibit apoptosis, and induce GC progression, indicating that exosomal CEBPA-AS1 is involved in cell-to-cell communication in GC carcinogenesis. Exosomal CEBPA-AS1 is a promising new biomarker for clinical diagnosis of GC.

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Identification of the long non-coding RNA H19 in plasma as a novel biomarker for diagnosis of gastric cancer.

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