A novel class of tsRNA signatures as biomarkers for diagnosis and prognosis of pancreatic cancer.
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ABSTRACT:
SUBMITTER: Jin F
PROVIDER: S-EPMC8285832 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Small, noncoding RNAs are short untranslated RNA molecules, some of which have been associated with cancer development. Recently we showed that a class of small RNAs generated during the maturation process of tRNAs (tRNA-derived small RNAs, hereafter "tsRNAs") is dysregulated in cancer. Specifically, we uncovered tsRNA signatures in chronic lymphocytic leukemia and lung cancer and demonstrated that the ts-4521/3676 cluster (now called "ts-101" and "ts-53," respectively), ts-46, and ts-47 are down-regulated in these malignancies. Furthermore, we showed that tsRNAs are similar to Piwi-interacting RNAs (piRNAs) and demonstrated that ts-101 and ts-53 can associate with PiwiL2, a protein involved in the silencing of transposons. In this study, we extended our investigation on tsRNA signatures to samples collected from patients with colon, breast, or ovarian cancer and cell lines harboring specific oncogenic mutations and representing different stages of cancer progression. We detected tsRNA signatures in all patient samples and determined that tsRNA expression is altered upon oncogene activation and during cancer staging. In addition, we generated a knocked-out cell model for ts-101 and ts-46 in HEK-293 cells and found significant differences in gene-expression patterns, with activation of genes involved in cell survival and down-regulation of genes involved in apoptosis and chromatin structure. Finally, we overexpressed ts-46 and ts-47 in two lung cancer cell lines and performed a clonogenic assay to examine their role in cell proliferation. We observed a strong inhibition of colony formation in cells overexpressing these tsRNAs compared with untreated cells, confirming that tsRNAs affect cell growth and survival.
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Project description:Pancreatic cancer (PC) is one of the most malignant tumors. Despite considerable progress in the treatment of PC, the prognosis of patients with PC is poor. The aim of this study was to identify potential biomarkers for the diagnosis and prognosis of PC. First, the original data of three independent mRNA expression datasets were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases and screened for differentially expressed genes (DEGs) using the R software. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the DEGs were performed, and a protein-protein interaction (PPI) network was constructed to screen for hub genes. The hub genes were analyzed for genetic variations, as well as for survival, prognostic, and diagnostic value, using the cBioPortal and Gene Expression Profiling Interactive Analysis (GEPIA) databases and the pROC package. After screening for potential biomarkers, the mRNA and protein levels of the biomarkers were verified at the tissue and cellular levels using the Cancer Cell Line Encyclopedia, GEPIA, and the Human Protein Atlas. As a result, a total of 248 DEGs were identified. The GO terms enriched in DEGs were related to the separation of mitotic sister chromatids and the binding of the spindle to the extracellular matrix. The enriched pathways were associated with focal adhesion, ECM-receptor interaction, and phosphatidylinositol 3-kinase (PI3K)/AKT signaling. The top 20 genes were selected from the PPI network as hub genes, and based on the analysis of multiple databases, MCM2 and NUSAP1 were identified as potential biomarkers for the diagnosis and prognosis of PC. In conclusion, our results show that MCM2 and NUSAP1 can be used as potential biomarkers for the diagnosis and prognosis of PC. The study also provides new insights into the underlying molecular mechanisms of PC.
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Project description:The relatively high incidence and mortality rates for colorectal carcinoma (CRC) make it a formidable malignant tumor. Comprehensive strategies have been applied to predict patient survival and diagnosis. Various clinical regimens have also been developed to improve the therapeutic outcome. Extracellular vesicles (EVs) are recently proposed cellular structures that can be produced by natural or artificial methods and have been extensively studied. In addition to their innate functions, EVs can be manipulated to be drug carriers and exert many biological functions. The composition of EVs, their intravesicular components, and the surrounding tumor microenvironment are closely related to the development of colorectal cancer. Determining the expression profiles of exocytosis samples and using them as indicators for selecting effective combination therapy is an indispensable direction for EV study and should be regarded as a novel prediction platform in addition to cancer stage, prognosis, and other clinical assessments. In this review, we summarize the function, regulation, and application of EVs in the colon cancer research field. We provide an update on and discuss potential values for clinical applications of EVs. Moreover, we illustrate the specific markers, mediators, and genetic alterations of EVs in colorectal carcinogenesis. Furthermore, we outline the vital markers present in the EVs and discuss their plausible uses in colon cancer patient therapy in combination with the currently used clinical strategies. The development and application of these EVs will significantly improve the accuracy of diagnosis, lead to more precise prognoses, and may lead to the improved treatment of colorectal cancer.
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Project description:Background: Ferroptosis is a novel regulated cell death that is characterized by iron-dependent oxidative damage. Renal cancer is the second most common cancer of the urinary system, which is highly correlated with iron metabolism. The aim of our present study was to identify suitable ferroptosis-related prognosis signatures for renal cancer. Methods: We downloaded the RNA-seq count data of renal cancer from The Cancer Genome Atlas database and used the DESeq2, Survival, and Cox regression analyses to screen the prognosis signatures. Results: We identified 5 ferroptosis-related differentially expressed lncRNAs (FR-DELs) (DOCK8-AS1, SNHG17, RUSC1-AS1, LINC02609, and LUCAT1) to be independently correlated with the overall survival (OS) of patients with renal cancer. The risk assessment model and diagnosis model constructed by those 5 FR-DELs could well predict the outcome and the diagnosis of renal cancer. Conclusion: Our present study not only suggested those 5 FR-DELs could be used as prognosis and diagnosis signatures for renal cancer but also provided strategies for other cancers in the screening of ferroptosis-related biomarkers.
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Project description:ObjectiveDysregulation of transfer RNA (tRNA)-derived small noncoding RNA (tsRNA) signatures in human serum has been found in various diseases. Here, we determine whether the signatures of tsRNAs in serum can serve as biomarkers for diagnosis or prognosis of systemic lupus erythematosus (SLE).MethodsInitially, small RNA sequencing was employed for the screening serum tsRNAs obtained from SLE patients, followed by validation with TaqMan probe-based quantitative reverse transcription-PCR (RT-PCR) assay. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic efficacy. The biological functions of tsRNAs were identified by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) assay.ResultsWe first analyzed tsRNA signatures in SLE serum and identified that tRF-His-GTG-1 was significantly upregulated in SLE serum. The combination of tRF-His-GTG-1 and anti-dsDNA could serve as biomarkers for diagnosing SLE with a high area under the curve (AUC) of 0.95 (95% CI = 0.92-0.99), sensitivity (83.72%), and specificity (94.19%). Importantly, the noninvasive serum tRF-His-GTG-1 could also be used to distinguish SLE with LN or SLE without LN with AUC of 0.81 (95% CI, 0.73-0.88) and performance (sensitivity 66.27%, specificity 96.15%). Moreover, the serum tsRNA is mainly secreted via exosome and can directly target signaling molecules that play crucial roles in regulating the immune system.ConclusionIn this study, it has been demonstrated for the first time that serum tsRNAs can be employed as noninvasive biomarkers for the efficient diagnosis and prediction of nephritis in SLE.
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Project description:MicroRNAs (miRNAs) are one abundant class of small, endogenous non-coding RNAs, which regulate various biological processes by inhibiting expression of target genes. miRNAs have important functional roles in carcinogenesis and development of colorectal cancer (CRC), and emerging evidence has indicated the feasibility of miRNAs as robust cancer biomarkers. This review summarizes the progress in miRNA-related research, including study of its oncogene or tumour-suppressor roles and the advantages of miRNA biomarkers for CRC diagnosis, treatment and recurrence prediction. Along with analytical technique improvements in miRNA research, use of the emerging extracellular miRNAs is feasible for CRC diagnosis and prognosis.
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Project description:Noninvasive biomarkers for predicting the risk of muscle-invasive bladder cancer (MIBC) may expedite appropriate therapy and reduce morbidity and cost. Genome-wide miRNA analysis by Miseq sequencing followed by two phases of reverse transcription quantitative real-time PCR (RT-qPCR) assays were performed on serum from 207 MIBC patients, 285 nonmuscle-invasive bladder cancer (NMIBC) patients and 193 controls. A four-miRNA panel (miR-422a-3p, miR-486-3p, miR-103a-3p and miR-27a-3p) was developed for MIBC prediction with an area under the receiver operating characteristic curve (AUC) of 0.894 (95% CI, 0.846-0.931) for training set. Prospective evaluation of the miRNA panel revealed an AUC of 0.880 (95% CI, 0.834 to 0.917) in validation set, which was significantly higher than those of grade and urine cytology (both p < 0.05). Moreover, Kaplan-Meier analysis showed that MIBC patients with low miR-486-3p and miR-103a-3p levels had worse overall survival (p = 0.002 and p = 0.034, respectively). Cox analysis indicated miR-486-3p and miR-103a-3p were independently associated with overall survival of MIBC (p = 0.042 and p = 0.021, respectively). In conclusion, serum miRNA signatures might have considerable clinical values in predicting and providing prognostic information for MIBC.
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Project description:Transforming growth factor (TGF)-? signaling pathway, may act both as a tumor suppressor and as a tumor promoter in pancreatic cancer, depending on tumor stage and cellular context. TGF-? pathway has been under intensive investigation as a potential therapeutic target in the treatment of cancer. We hypothesized a correlation between TGF-?R2/SMAD4 expression in the tumor, plasma TGF-?1 ligand level, genetic variation in TGF-B pathway and prognosis of pancreatic cancer.We examined TGF-?R2 and SMAD4 protein expression in biopsy or surgical samples from 91 patients with pancreatic ductal adenocarcinoma (PDAC) using immunohistochemistry. Plasma level of TGF-?1 was measured in 644 patients with PDAC using ELISA. Twenty-eight single nucleotide polymorphisms (SNP) of the TGF-?1, TGF-?2, TGF-?3, TGF-?R1, TGF-?R2, and SMAD4 genes were determined in 1636 patients with PDAC using the Sequenom method. Correlation between protein expression in the tumor, plasma TGF-?1 level, and genotypes with overall survival (OS) was evaluated with Cox proportional regression models.The expression level of TGF-?R2 and SMAD4 as an independent marker was not associated with OS. However, patients with both low nuclear staining of TGF-?R2 and high nuclear staining of SMAD4 may have better survival (P = 0.06). The mean and median level of TGF-?1 was 15.44 (SD: 10.99) and 12.61 (interquartile range: 8.31 to 19.04) ng/ml respectively. Patients with advanced disease and in the upper quartile range of TGF-?1 level had significantly reduced survival than those with low levels (P = 0.02). A significant association of SMAD4 SNP rs113545983 with overall survival was observed (P<0.0001).Our data provides valuable baseline information regarding the TGF-? pathway in pancreatic cancer, which can be utilized in targeted therapy clinical trials. High TGF-?1 plasma level, SMAD4 SNP or TGF-?R2/SMAD4 tumor protein expression may suggest a dependence on this pathway in patients with advanced pancreatic cancer.
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Project description:The development of cancer is driven by the accumulation of scores of alterations affecting the structure and function of the genome. Equally important in this process are genetic alterations and epigenetic changes. Whereas the former disrupt normal patterns of gene expression, sometimes leading to the expression of abnormal, constitutively active proteins, the latter deregulate the mechanisms such as transcriptional control leading to the inappropriate silencing or activation of cancer-associated genes. Both types of changes are inheritable at the cellular level, thus contributing to the clonal expansion of cancer cells. In this review, we summarize current knowledge on how genetic alterations in oncogenes or tumour suppressor genes, as well as epigenetic changes, can be exploited in the clinics as biomarkers for cancer detection, diagnosis and prognosis. We propose a rationale for identifying alterations that may have a functional impact within a background of "passenger" alterations that may occur solely as the consequence of deregulated genetic and epigenetic stability. Such functional alterations may represent candidates for targeted therapeutic approaches.
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