Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of GAS5 tumour suppressor lncRNA: an independent molecular cancer biomarker for short-term relapse and progression in bladder cancer patients.

ABSTRACT:

Background

Bladder cancer (BlCa) heterogeneity and the lack of personalised prognosis lead to patients' highly variable treatment outcomes. Here, we have analysed the utility of the GAS5 tumour-suppressor lncRNA in improving BlCa prognosis.

Methods

GAS5 was quantified in a screening cohort of 176 patients. Hedegaard et al. (2016) (n = 476) and TCGA provisional (n = 413) were used as validation cohorts. Survival analysis was performed using recurrence and progression for NMIBC, or death for MIBC. Internal validation was performed by bootstrap analysis, and decision curve analysis was used to evaluate the clinical benefit on disease prognosis.

Results

GAS5 levels were significantly downregulated in BlCa and associated with invasive high-grade tumours, and high EORTC-risk NMIBC patients. GAS5 loss was strongly and independently correlated with higher risk for NMIBC early relapse (HR = 2.680, p = 0.011) and progression (HR = 6.362, p = 0.035). Hedegaard et al. and TCGA validation cohorts' analysis clearly confirmed the association of GAS5 loss with NMIBC worse prognosis. Finally, multivariate models incorporating GAS5 with disease established markers resulted in higher clinical benefit for NMIBC prognosis.

Conclusions

GAS5 loss is associated with adverse outcome of NMIBC and results in improved positive prediction of NMIBC patients at higher risk for short-term relapse and progression, supporting personalised prognosis and treatment decisions.

SUBMITTER: Avgeris M

PROVIDER: S-EPMC6288135 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Molecular and Cellular Mechanisms of Action of Tumour Suppressor GAS5 LncRNA.

Project description:It is increasingly recognised that lncRNAs play essential regulatory roles in fundamental biological processes and, consequently, that their dysregulation may contribute to major human diseases, including cancer. Better understanding of lncRNA biology may therefore offer new insights into pathogenetic mechanisms and thereby offer novel opportunities for diagnosis and therapy. Of particular interest in this regard is GAS5 lncRNA, which is down-regulated in multiple cancers, with expression levels related to both clinico-pathological characteristics and patient prognosis. Functional studies have further shown that GAS5 lncRNA both inhibits the proliferation and promotes the apoptosis of multiple cell types, and that together these cellular mechanisms of action are likely to form the basis of its tumour suppressor action. At the same time, advances have been made in our understanding of the molecular mechanisms of GAS5 lncRNA action in recent years, including riborepression of certain steroid hormone receptors and sequestration of miR-21, impacting key regulatory pathways of cell survival. Overall this accumulating knowledge has the potential to improve both the diagnosis and treatment of cancer, and ultimately patient outcome.

| S-EPMC4584312 | biostudies-literature

Novel Tumor Suppressor lncRNA Growth Arrest-Specific 5 (GAS5) In Human Cancer.

Project description:Long noncoding RNAs (lncRNAs) play crucial regulatory roles in fundamental biological processes, and deregulations of lncRNAs have been linked to numerous human diseases, especially cancers. Of particular interest in this regard is lncRNA GAS5, which is mainly identified as a tumor suppressor in several cancers. GAS5 was significantly low expressed in multiple cancers and was associated with clinic-pathological characteristics and patient survival, indicating a novel potential diagnostic and prognostic biomarker, and a therapeutic target for cancer. Functionally, GAS5 is involved in cell proliferation, metastasis, invasion, apoptosis, epithelial-mesenchymal transition (EMT), and drug resistance, among others, via multiple molecular mechanisms, such as binding to DNA sequences, forming RNA-DNA triplex complex, triggering or suppressing the expression of genes, binding proteins to form chromatin-modifying complex, which activates or represses gene expression, and acting as miRNA sponge to suppress miRNA expression, leading to regulation of miRNA target genes. This review provides an overview of the current state of knowledge and role of GAS5 in clinical relevance, biological functions and molecular mechanisms underlying the dysregulation of expression and function of GAS5 in cancer. Finally, the potential prospective role as diagnostic and prognostic biomarker and therapeutic target in cancer is discussed.

| S-EPMC6794681 | biostudies-literature

CBX7 is a tumour suppressor that inhibits bladder cancer

Project description:The Polycomb Group Proteins (PcG) are epigenetic regulatory complexes, dysregulation of which has been associated with multiple biological processes, including maintenance of cell identity, differentiation, proliferation, and cancer progression.PcGs form two multiprotein complexes, Polycomb repressive complex 1 (PRC1) and PRC2(1).The PRC2 protein complex mainly consists of Early embryonic deficient (EED), Suppressor of Zeste (SUZ12) and Enhancer of Zeste (EZH), which can catalyzes the trimethylation of histone H3 lysine 27 (H3K27me3), thereby leaving a transcriptionally repressive mark on the chromatin . Such alterations are recognized and read by canonical PRC1 which is composed of CBX (polycomb), PCGF (polycomb group factor), HPH (human polyhomeotic homolog), and the E3-ligase protein (RING) that catalyzes the monoubiquitination of histone H2A on lysine 119 (H2AK119ub1). The H3K27me3 mark is identified by and binds to the chromodomain within the CBX protein in PRC1, thereby ubiquitinating H2AK119 via the RING proteins. The interaction of PRC2 and PRC1 in chromatin contributes to chromatin compaction and transcriptional silencing of target genes.There are five chromobox proteins in humans, CBX2, 4, 6, 7 and 8. Increasing evidence supports essential roles of CBX proteins in tumorigenesis. Remarkably, CBX proteins have shown an opposite function in distinct cancer types in tumor development. For example, CBX7 is overexpressed in ovarian and prostate cancer , implying its oncogenic role in these tumor types. In contrast, CBX7 functions as a tumor suppressor and loss of CBX7 has been associated with increasing the malignancy grade in bladder, breast, pancreatic, glioma, and colon carcinomas (3 4 5 6 7), but its tumor suppression mechanism is unclear.

2021-06-15 | GSE158244 | GEO

Epigenetic therapy of novel tumour suppressor ZAR1 and its cancer biomarker function.

Project description:BACKGROUND:Cancer still is one of the leading causes of death and its death toll is predicted to rise further. We identified earlier the potential tumour suppressor zygote arrest 1 (ZAR1) to play a role in lung carcinogenesis through its epigenetic inactivation. RESULTS:We are the first to report that ZAR1 is epigenetically inactivated not only in lung cancer but also across cancer types, and ZAR1 methylation occurs across its complete CpG island. ZAR1 hypermethylation significantly correlates with its expression reduction in cancers. We are also the first to report that ZAR1 methylation and expression reduction are of clinical importance as a prognostic marker for lung cancer and kidney cancer. We further established that the carboxy (C)-terminally present zinc-finger of ZAR1 is relevant for its tumour suppression function and its protein partner binding associated with the mRNA/ribosomal network. Global gene expression profiling supported ZAR1's role in cell cycle arrest and p53 signalling pathway, and we could show that ZAR1 growth suppression was in part p53 dependent. Using the CRISPR-dCas9 tools, we were able to prove that epigenetic editing and reactivation of ZAR1 is possible in cancer cell lines. CONCLUSION:ZAR1 is a novel cancer biomarker for lung and kidney, which is epigenetically silenced in various cancers by DNA hypermethylation. ZAR1 exerts its tumour suppressive function in part through p53 and through its zinc-finger domain. Epigenetic therapy can reactivate the ZAR1 tumour suppressor in cancer.

| S-EPMC6894338 | biostudies-literature

TET1 is a tumour suppressor that inhibits bladder cancer progression

Project description:Ten-Eleven Translocation 1 (TET1) is a member of methylcytosine dioxygenase, which catalyse 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) that promote the demethylation process. The diminished expression of TET1 protein and 5-hmC in many tumors indicate a critical role for the maintenance of cell stability. However, role of TET1 in bladder cancer development remains unclear. Here we found that TET1 expression was downregulated in bladder cancer tissues compared with normal urothelium and was inversely related to patient overall survival. TET1 silencing in bladder cancer cells increase proliferation and inhibited cell migration and invasion while its re-expression inhibits their proliferation and the growth of tumor xenografts. Furthermore, we found that TET1 binds to the promoter of the TSG to maintain its hypomethylated which interacts with β-catenin and suppress its nuclear translocation, thus inhibiting β-catenin transcriptional activity and downstream genes. In conclusion, TET1 acts as a tumor suppressor gene in bladder cancer cells by suppressing β-catenin signaling. This study may facilitate efforts to therapeutic strategy for patients with bladder cancer.

2020-06-16 | GSE137646 | GEO

LncRNA GAS5 contributes to lymphatic metastasis in colorectal cancer.

Project description:Colorectal cancer (CRC) ranks the third most common type of cancer worldwide. However, the detailed molecular mechanisms underlying these processes are poorly understood. Recent studies have shown that lncRNAs play important roles in carcinogenesis and progression of CRC. The lncRNA growth arrest special 5 (GAS5), was previously identified to be down-regulated and functions as a tumor suppressor gene in many kinds of cancers. In current two-stage, case-control study, we systematically evaluated the potential role of lncRNA GAS5 and its genetic variation rs145204276 in the development and metastasis process of CRC in a Chinese population. We found the allele del of rs145204276 was significantly associated with 21% decreased risk of CRC (OR=0.79; 95% CI=0.70-0.89; P value = 5.21×10-5). Compared with the genotype ins/ins, both the genotype ins/del (OR=0.78; 95% CI=0.68-0.91) and del/del (OR=0.64; 95% CI=0.49-0.84) showed decreased susceptibility. For both in colon and rectum cancers, the associations kept statistically significant (OR=O.78 and 0.80, while P value = 4.56×10-4, and 3.80×10-3, respectively). The results also showed that the carriers of allele del are less likely to get lymph node metastasis (OR=0.80; 95% CI=0.68-0.95; P value = 0.010). Taken together, our findings provided strong evidence for the hypothesis that GAS5 rs145204276 were significantly associated with the susceptibility and progression of CRC.

| S-EPMC5347799 | biostudies-literature

Negative regulation of lncRNA GAS5 by miR-21.

Project description:In addition to protein-coding genes, the human genome makes a large amount of noncoding RNAs, including microRNAs and long noncoding RNAs (lncRNAs). Both microRNAs and lncRNAs have been shown to have a critical role in the regulation of cellular processes such as cell growth and apoptosis, as well as cancer progression and metastasis. Although it is well known that microRNAs can target a large number of protein-coding genes, little is known whether microRNAs can also target lncRNAs. In the present study, we determine whether miR-21 can regulate lncRNA expression. Using the lncRNA RT-PCR (reverse transcription-polymerase chain reaction) array carrying 83 human disease-related lncRNAs, we show that miR-21 is capable of suppressing the lncRNA growth arrest-specific 5 (GAS5). This negative correlation between miR-21 and GAS5 is also seen in breast tumor specimens. Of interest, GAS5 can also repress miR-21 expression. Whereas ectopic expression of GAS5 suppresses, GAS5-siRNA increases miR-21 expression. Importantly, there is a putative miR-21-binding site in exon 4 of GAS5; deletion of the miR-21-binding site abolishes this activity. Experiments with in vitro cell culture and xenograft mouse model suggest that GAS5 functions as a tumor suppressor. We further show that the biotin-labeled GAS5-RNA probe is able to pull down the key component (AGO2) of the RNA-induced silencing complex (RISC) and we subsequently identify miR-21 in this GAS5-RISC complex, implying that miR-21 and GAS5 may regulate each other in a way similar to the microRNA-mediated silencing of target mRNAs. Together, these results suggest that miR-21 targets not only tumor-suppressive protein-coding genes but also lncRNA GAS5.

| S-EPMC3792431 | biostudies-other

Extracellular Matrix-Related Six-lncRNA Signature as a Novel Prognostic Biomarker for Bladder Cancer.

Project description:IntroductionBladder cancer (BC) is the fourth-commones cancer and the sixth-leading cause of cancer-related death among men. However, a lack of reliable biomarkers remains a problem forprognosis and treatment of BC. lncRNAs have been shown to play important roles in various cancers, and have emerged as promising biomarkers for cancer prognosis and treatment.MethodsIn this study, using univariate and multivariate Cox regression analysis, we examined the differential expression profiles of 1,651 lncRNAs in the TCGA BLCA cohort and created a prognostic gene signature composed of six lncRNAs (for SNHG12, MAFG- DT, ASMTL-AS1, LINC02321, LINC01322, and LINC00922), designed the SMALLL signature.ResultsThe SMALLL signature displayed significant prognostic power for overall survival for BC patients in multiple cohorts. Gene Ontology analysis showed that genes coexpressed with the SMALLL signature were associated with the extracellular matrix network, and immune cell-infiltration analysis showed that activated naïve B cells, regulatory T cells, M0 macrophages, eosinophils, resting memory CD4 T cells and resting NK cells were significantly different in high- and low-risk groups. We also confirmed differential expression of the lncRNAs of the SMALLL signature in BC tissue and paracancer normal tissue by qRT-PCR analysis. Cell-invasion and -migration experiments showed that MAFG-AS1, ASMTL-AS1, LINC02321, and LINC00922 significantly affected cell invasion and migration.ConclusionOur study revealed that the lncRNA signature is an important predictive factor of prognosis and provides a promising biomarker for BC.

| S-EPMC7733340 | biostudies-literature

An androgen reduced transcript of LncRNA GAS5 promoted prostate cancer proliferation.

Project description:Prostate cancer (PCa) becomes a leading cause of death in males nowadays. Recent reports showed that androgen-responsive long non-coding RNAs played important roles in tumorigenesis and progression of PCa. In this study, we focused on a special transcript of GAS5 (ENST00000456293.5, GAS5-007), which was reported as a tumor suppressor. Here, we demonstrated GAS5-007 was reduced by androgen treatment and inhibited by AR. Next, we explored the expression level of GAS, finding the expression of it in PCa tissue was higher than normal tissue in both public databases and human tissue samples. Functional analysis of GAS5 showed it was related to regulating translational elongation, protein biosynthesis, and transcription. Moreover, we observed GAS5-007 knockdown inhibited the proliferation, cell cycle and promoted cell apoptosis of PCa. We also constructed a GAS5-miRNA network to explain the different roles of different GAS5 transcripts in PCa. This study provides novel insights to identify potential diagnostic biomarker and therapy target for prostate cancer in clinical treatment.

| S-EPMC5542543 | biostudies-literature