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Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis.

ABSTRACT: Esophageal squamous cell cancer (ESCC) is a high incidence and mortality disease worldwide. However, specificity and sensitivity of its diagnostic and prognostic biomarkers are still unsatisfactory. Recently, circular RNAs (circRNAs) as biomarkers have been studied extensively while the expression profile and clinical significance of circRNAs in ESCC have rarely been studied. We performed circular RNA microarray in 3 pairs of ESCC frozen tumor and non-tumor tissues to identify ESCC-related circRNAs and found 1045 up-regulated and 1032 down-regulated circRNAs among which 6 circRNAs (hsa_circ_0062459, hsa_circ_0076535, hsa_circ_0072215, hsa_circ_0042261, hsa_circ_0001946, and hsa_circ_0043603) displayed consistency with microarray results by qRT-PCR. 3 circRNAs (hsa_circ_0062459, hsa_circ_0001946, and hsa_circ_0043603) were also detected in plasma and 2 of them except hsa_circ_0062459 could be used as diagnostic biomarkers and found in exosome of cell-conditioned culture conditioned media. The AUC, sensitivity and specificity of hsa_circ_0001946 were 0.894, 92, 80%, of hsa_circ_0043603 were 0.836, 64, 92% while a signature combining them were 0.928, 84 and 98%. Hsa_circ_0001946 was confirmed to predict the recurrence, overall survival (OS) and disease-free survival (DFS) in frozen and FFPE tissues, while its overexpression decreased cell proliferation, migration, and invasion.

SUBMITTER: Fan L

PROVIDER: S-EPMC6343327 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis.

Fan Liyuan L Cao Qiang Q Liu Jia J Zhang Junpeng J Li Baosheng B

Molecular cancer 20190123 1

Esophageal squamous cell cancer (ESCC) is a high incidence and mortality disease worldwide. However, specificity and sensitivity of its diagnostic and prognostic biomarkers are still unsatisfactory. Recently, circular RNAs (circRNAs) as biomarkers have been studied extensively while the expression profile and clinical significance of circRNAs in ESCC have rarely been studied. We performed circular RNA microarray in 3 pairs of ESCC frozen tumor and non-tumor tissues to identify ESCC-related circR ...[more]

PMID: 30674324

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Project description:The abnormality of RNA-binding proteins (RBPs) is closely related to the tumorigenesis and development of esophageal squamous cell carcinoma (ESCC), and has been an area of interest for research recently. In this study, 162 tumors and 11 normal samples are obtained from The Cancer Genome Atlas database, among which 218 differentially expressed RBPs are screened. Finally, a prognostic model including seven RBPs (CLK1, DDX39A, EEF2, ELAC1, NKRF, POP7, and SMN1) is established. Further analysis reveals that the overall survival (OS) rate of the high-risk group is lower than that of the low-risk group. The area under the receiver operating characteristic (ROC) curve (AUC) of the training group and testing group is significant (AUCs of 3 years are 0.815 and 0.694, respectively, AUCs of 5 years are 0.737 and 0.725, respectively). In addition, a comprehensive analysis of seven identified RBPs shows that most RBPs are related to OS in patients with ESCC, among which EEF2 and ELCA1 are differentially expressed at the protein level of ESCC and control tissues. CLK1 and POP7 expressions in esophageal cancer tumor samples are undertaken using the tissue microarray, and show that CLK1 mRNA levels are relatively lower, and POP7 mRNA levels are higher compared with non-cancerous esophageal tissues. Survival analysis reveals that a higher expression of CLK1 predicts a significant worse prognosis, and a lower expression of POP7 predicts a worse prognosis in esophageal cancer. These results suggest that CLK1 may promote tumor progression, and POP7 may hinder the development of esophageal cancer. In addition, gene set enrichment analysis reveals that abnormal biological processes related to ribosomes and abnormalities in classic tumor signaling pathways such as TGF-β are important driving forces for the occurrence and development of ESCC. Our results provide new insights into the pathogenesis of ESCC, and seven RBPs have potential application value in the clinical prognosis prediction of ESCC.

Project description:Abnormal expression of non-coding circular RNAs (circRNAs) have been reported in many types of tumors. circRNA have been suggested to be an ideal candidate biomarker for diagnostic and therapeutic implications in cancers. The aim of this study was to assess the circRNA expression profile of laryngeal squamous cell carcinomas (LSCC). The biopsy samples from patients with LSCC were obtained intra-operatively. The circRNA expression was performed using secondary sequencing. Among 10 patients with LSCC, 2 were well differentiated, 3 were moderately differentiated and 5 were adjunctive samples with normal and LSCC tissues. A total of 21,444 distinct circRNA candidates were detected. Among them, we defined the statistical criteria for selecting aberrant-expressed circRNA using a q-value of < 0.001 with a fold change of > 2.0 or < 0.5. A total of 29 circRNA were upregulated and 19 circRNA were downregulated significantly in the LSCC tissues. The intersection of these dysregulated circRNAs of normal-well differentiated set and normal-moderately differentiated set was then assessed to narrow the upregulated and downregulated circRNAs down to 18 and 5 respectively. Furthermore, an association of the circRNA-miRNA-mRNA was investigated, showing that 20 dysregulated circRNA successfully predicted an interaction with several cancer-related miRNAs. Finally, a further KEGG analysis showed that PPAR, Axon guidance, Wnt and Cell cycle signaling pathway were key putative pathways in the process of LSCC. hsa_circ:chr20:31876585-31,897,648 was found to be able to differentiate most of LSCC from the matching normal tissues. This observational study demonstrated dysregulation of circRNA in LSCC, which may have an impact on development of potential biomarkers in this disease. Validation of down-regulation of hsa_circ:chr20:31876585-31,897,648 in LSCC compared to each adjunctive tissue by Q-RT-PCR, indicating that hsa_circ:chr20:31876585-31,897,648 may be a novel promising tumor suppresser in LSCC.

Project description:BackgroundThe identification of effective tumor markers is of paramount importance for the early diagnosis, treatment, and prognosis of esophageal squamous cell carcinoma (ESCC). The present study endeavors to identify efficacious serological markers that can differentiate patients with early-stage ESCC from those with benign esophageal lesions and healthy controls (HC). Cystatin-SN (CST1), an active cysteine protease inhibitor belonging to the Cystatin (CST) superfamily, is implicated in the pathogenesis of inflammation and tumorigenesis. The objective of this investigation is to assess the diagnostic, therapeutic, and prognostic potential of serum CST1 in ESCC.MethodsIn our prior RNA sequencing and screening endeavors, we have identified ten genes that are up-regulated in relation to esophageal cancer. Subsequently, we have verified the gene CST1 from the transcriptome data of the The Cancer Genome Atlas Program (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) database. Following this, we conducted an enzyme-linked immunosorbent assay (ELISA) to ascertain the expression levels of CST1 in serum samples from clinical cohorts.ResultsThe study revealed a significant elevation in serum CST1 levels among patients with early-stage esophageal squamous cell carcinoma (ESCC) (7.41 ± 4.32 ng/ml) compared to those with esophageal benign lesions (4.67 ± 2.43 ng/ml) (p < 0.0001) and healthy controls (4.87 ± 2.77 ng/ml) (p < 0.0001). The diagnostic sensitivity of CST1 for ESCC was 75.68% (specificity 70.83%, AUC 0.775). Combination of CST1 and SCC-Ag exhibited the AUC up to 0.819. Additionally, serum CST1 levels exhibited a significant decrease at 1-2 weeks post-surgery (4.49 ± 3.31 ng/ml) compared to pre-surgery levels (7.68 ± 3.71 ng/ml) (p<0.0001). Survival analysis demonstrated a strong association between high (844/415-1543 d) or low (1490/645-1710 d) serum CST1 levels at diagnosis and overall survival time (p < 0.001). Furthermore, multivariate regression analysis confirmed CST1 (p=0.024, HR=2.023, 95%CI 1.099-3.725) as an independent prognostic factor.ConclusionSerum CST1 has the potential to function as a diagnostic indicator for distinguishing early-stage esophageal squamous cell carcinoma (ESCC) from individuals with benign esophageal lesions and healthy individuals. Additionally, it could serve as a prognostic predictor and therapeutic efficacy indicator for patients with ESCC.

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Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis.

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Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis.

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