Long non-coding RNA in cancer Hauptman, Nina; Glavač, Damjan
International Journal of Molecular Sciences,
02/2013, Letnik:
14, Številka:
3
Journal Article, Book Review
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Long non-coding RNAs (lncRNAs) are pervasively transcribed in the genome and are emerging as new players in tumorigenesis due to their various functions in transcriptional, posttranscriptional and ...epigenetic mechanisms of gene regulation. LncRNAs are deregulated in a number of cancers, demonstrating both oncogenic and tumor suppressive roles, thus suggesting their aberrant expression may be a substantial contributor in cancer development. In this review, we will summarize their emerging role in human cancer and discuss their perspectives in diagnostics as potential biomarkers.
Differentiation between adenocarcinomas is sometimes challenging. The promising avenue for discovering new biomarkers lies in bioinformatics using DNA methylation analysis. Utilizing a 2853-sample ...identification dataset and a 782-sample independent verification dataset, we have identified diagnostic DNA methylation biomarkers that are hypermethylated in cancer and differentiate between breast invasive carcinoma, cholangiocarcinoma, colorectal cancer, hepatocellular carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma and stomach adenocarcinoma. The best panels for cancer type exhibit sensitivity of 77.8-95.9%, a specificity of 92.7-97.5% for tumors, a specificity of 91.5-97.7% for tumors and normal tissues and a diagnostic accuracy of 85.3-96.4%. We have shown that the results can be extended from the primary cancers to their liver metastases, as the best panels diagnose and differentiate between pancreatic adenocarcinoma liver metastases and breast invasive carcinoma liver metastases with a sensitivity and specificity of 83.3-100% and a diagnostic accuracy of 86.8-91.9%. Moreover, the panels could detect hypermethylation of selected regions in the cell-free DNA of patients with liver metastases. At the same time, these were unmethylated in the cell-free DNA of healthy donors, confirming their applicability for liquid biopsies.
Malignant liver tumors, including primary malignant liver tumors and liver metastases, are among the most frequent malignancies worldwide. The disease carries a poor prognosis and poor overall ...survival, particularly in cases involving liver metastases. Consequently, the early detection and precise differentiation of malignant liver tumors are of paramount importance for making informed decisions regarding patient treatment. Significant research efforts are currently directed towards the development of diagnostic tools for different types of cancer using minimally invasive techniques. A prominent area of focus within this research is the evaluation of circulating microRNA, for which dysregulated expression is well documented in different cancers. Combining microRNAs in panels using serum or plasma samples derived from blood holds great promise for better sensitivity and specificity for detection of certain types of cancer.
The cytosine–phosphate–guanine (CpG) island methylator phenotype (CIMP) represents one of the pathways involved in the development of colorectal cancer, characterized by genome-wide hypermethylation. ...To identify samples exhibiting hypermethylation, we used unsupervised hierarchical clustering on genome-wide methylation data. This clustering analysis revealed the presence of four distinct subtypes within the tumor samples, namely, CIMP-H, CIMP-L, cluster 3, and cluster 4. These subtypes demonstrated varying levels of methylation, categorized as high, intermediate, and very low. To gain further insights, we mapped significant probes from all clusters to Ensembl Regulatory build 89, with a specific focus on those located within promoter regions or bound regions. By intersecting the methylated promoter and bound regions across all methylation subtypes, we identified a total of 253 genes exhibiting aberrant methylation patterns in the promoter regions across all four subtypes of colorectal cancer. Among these genes, our comprehensive genome-wide analysis highlights bone morphogenic protein 4 (BMP4) as the most prominent candidate. This significant finding was derived through the utilization of various bioinformatics tools, emphasizing the potential role of BMP4 in colorectal cancer development and progression.
Malignant liver tumors include primary malignant liver tumors and liver metastases. They are among the most common malignancies worldwide. The disease has a poor prognosis and poor overall survival, ...especially with liver metastases. Therefore, early detection and differentiation between malignant liver tumors are critical for patient treatment selection. The detection of cancer and the prediction of its origin is possible with a DNA methylation profile of the tumor DNA compared to that of normal cells, which reflects tissue differentiation and malignant transformation. New technologies enable the characterization of the tumor methylome in circulating tumor DNA (ctDNA), providing a variety of new ctDNA methylation biomarkers, which can provide additional information to clinical decision-making. Our review of the literature provides insight into methylation changes in ctDNA from patients with common malignant liver tumors and can serve as a starting point for further research.
Mortality and morbidity associated with colorectal cancer (CRC) are increasing globally, partly due to lack of early detection of the disease. The screening is usually performed with colonoscopy, ...which is invasive and unpleasant, discouraging participation in the screening. As a source of noninvasive and easily accessible biomarkers, liquid biopsies are emerging. Blood-based biomarkers have the potential as diagnostic and prognostic tool in CRC. Early stage detection of CRC with high sensitivity and specificity would likely lead to higher participation in the screening test. It would also improve the prognosis of the disease and improve the recurrence risk. In this review, we summarize the potential biomarkers for early detection and monitoring of CRC.
Epithelial-mesenchymal transition (EMT) plays a pivotal role in carcinogenesis, influencing cancer progression, metastases, stemness, immune evasion, metabolic reprogramming and therapeutic ...resistance. EMT in most carcinomas, including colorectal carcinoma (CRC), is only partial, and can be evidenced by identification of the underlying molecular drivers and their regulatory molecules. During EMT, cellular reprogramming is orchestrated by core EMT transcription factors (EMT-TFs), namely
,
,
(
) and
(
). While microRNAs have been clearly defined as regulators of EMT, the role of long non-coding RNAs (lncRNAs) in EMT is poorly defined and controversial. Determining the role of lncRNAs in EMT remains a challenge, because they are involved in a number of cellular pathways and are operating through various mechanisms. Adding to the complexity, some lncRNAs have controversial functions across different tumor types, acting as EMT promotors in some tumors and as EMT suppressors in others. The aim of this review is to summarize the role of lncRNAs involved in the regulation of EMT-TFs in human CRC. Additional candidate lncRNAs were identified through a bioinformatics analysis.
Abstract Fibrosis is an important complication in inflammatory bowel diseases. Previous studies suggest an important role of matrix Gla protein (MGP) and thrombospondin 2 (THBS2) in fibrosis in ...various organs. Our aim was to analyse their expression together with regulatory miRNAs in submucosal and subserosal fibroblasts in ulcerative colitis (UC) and Crohn’s disease (CD) using immunohistochemistry and qPCR. Digital pathology was used to compare collagen fibre characteristics of submucosal and subserosal fibrosis. Immunohistochemistry showed expression of MGP, but not THBS2 in submucosa in UC and CD. In the subserosa, there was strong staining for both proteins in CD but not in UC. qPCR showed significant upregulation of THBS2 and MGP genes in CD subserosa compared to the submucosa. Digital pathology analysis revealed higher proportion of larger and thicker fibres that were more tortuous and reticulated in subserosal fibrosis compared to submucosal fibrosis. These results suggest distinct fibroblast populations in fibrostenosing CD, and are further supported by image analysis showing significant differences in the morphology and architecture of collagen fibres in submucosal fibrosis in comparison to subserosal fibrosis. Our study is the first to describe differences in submucosal and subserosal fibroblast populations, contributing to understanding of the pathogenesis of fibrostenosis in CD.
Epithelial-mesenchymal transition (EMT) is a fundamental physiologically relevant process that occurs during morphogenesis and organ development. In a pathological setting, the transition from ...epithelial toward mesenchymal cell phenotype is hijacked by cancer cells, allowing uncontrolled metastatic dissemination. The competing endogenous RNA (ceRNA) hypothesis proposes a competitive environment resembling a large-scale regulatory network of gene expression circuits where alterations in the expression of both protein-coding and non-coding genes can make relevant contributions to EMT progression in cancer. The complex regulatory diversity is exerted through an array of diverse epigenetic factors, reaching beyond the transcriptional control that was previously thought to single-handedly govern metastatic dissemination. The present review aims to unravel the competitive relationships between naturally occurring ceRNA transcripts for the shared pool of the miRNA-200 family, which play a pivotal role in EMT related to cancer dissemination. Upon acquiring more knowledge and clinical evidence on non-genetic factors affecting neoplasia, modulation of the expression levels of diverse ceRNAs may allow for the development of novel prognostic/diagnostic markers and reveal potential targets for the disruption of cancer-related EMT.
Cell-free DNA (cfDNA) from patient blood is emerging as a noninvasive diagnostic avenue for various cancers. We aimed to identify reliable biomarkers in cfDNA by investigating genes exhibiting ...significant differences between colorectal cancer and control samples. Our objective was to identify genes that showed a positive difference between cancer and control samples. To achieve this, we conducted an in silico analysis to identify genes that exhibit no significant variation in methylation between genomic DNA (gDNA) and cfDNA. We collected experimental data from publicly available repositories, which included 5-hydroxymethylcytosine (5hmC) profiles of gDNA and cfDNA samples from both cancer patients and healthy individuals. By comparing and overlapping these two groups, we identified 187 genes of interest, of which 53 genes had a positive difference among colon cancer patients and healthy individuals. Next, we performed an ANOVA test on these genes, resulting in the identification of 12 genes that showed statistically significant higher levels of 5hmC in cfDNA and gDNA from cancer patients compared to healthy individuals. Additionally, we compared the 5hmC status of these genes between cfDNA and gDNA from cancer patients. Interestingly, we found that the 5hmC of the toll like receptor 4 (TLR4) gene was not statistically different between cfDNA and gDNA from cancer patients, indicating consistency between cfDNA and gDNA. These findings have important implications, not only for experimental validation but also for the development of more sensitive and robust noninvasive methods to improve diagnostic, prognostic, and treatment options for colon cancer.
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