In addition to mutations or aberrant expression in the protein-coding genes, mutations and misregulation of noncoding RNAs, in particular long noncoding RNAs (lncRNA), appear to play major roles in cancer. Genome-wide association studies of tumor samples have identified a large number of lncRNAs associated with various types of cancer. Alterations in lncRNA expression and their mutations promote tumorigenesis and metastasis. LncRNAs may exhibit tumor-suppressive and -promoting (oncogenic) functions. Because of their genome-wide expression patterns in a variety of tissues and their tissue-specific expression characteristics, lncRNAs hold strong promise as novel biomarkers and therapeutic targets for cancer. In this article, we have reviewed the emerging functions and association of lncRNAs in different types of cancer and discussed their potential implications in cancer diagnosis and therapy. Cancer Res; 77(15); 3965-81. ©2017 AACR.

/pdf/long-noncoding-rna-and-cancer-a-new-paradigm-29nsfrlmw7.pdf

Long Noncoding RNA and Cancer: A New Paradigm.

Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes.

A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response

The sustained growth, invasion, and metastasis of cancer cells depend upon bidirectional cell-cell communication within complex tissue environments. Such communication predominantly involves the secretion of soluble factors by cancer cells and/or stromal cells within the tumour microenvironment (TME), although these cell types have also been shown to export membrane-encapsulated particles containing regulatory molecules that contribute to cell-cell communication. These particles are known as extracellular vesicles (EVs) and include species of exosomes and shed microvesicles. EVs carry molecules such as oncoproteins and oncopeptides, RNA species (for example, microRNAs, mRNAs, and long non-coding RNAs), lipids, and DNA fragments from donor to recipient cells, initiating profound phenotypic changes in the TME. Emerging evidence suggests that EVs have crucial roles in cancer development, including pre-metastatic niche formation and metastasis. Cancer cells are now recognized to secrete more EVs than their nonmalignant counterparts, and these particles can be isolated from bodily fluids. Thus, EVs have strong potential as blood-based or urine-based biomarkers for the diagnosis, prognostication, and surveillance of cancer. In this Review, we discuss the biophysical properties and physiological functions of EVs, particularly their pro-metastatic effects, and highlight the utility of EVs for the development of cancer diagnostics and therapeutics.

Extracellular vesicles in cancer - implications for future improvements in cancer care.

Extracellular vesicles (EVs) are diverse, nanoscale membrane vesicles actively released by cells Similar-sized vesicles can be further classified (eg, exosomes, microvesicles) based on their biogenesis, size, and biophysical properties Although initially thought to be cellular debris, and thus under-appreciated, EVs are now increasingly recognized as important vehicles of intercellular communication and circulating biomarkers for disease diagnoses and prognosis Despite their clinical potential, the lack of sensitive preparatory and analytical technologies for EVs poses a barrier to clinical translation New analytical platforms including molecular ones are thus actively being developed to address these challenges Recent advances in the field are expected to have far-reaching impact in both basic and translational studies This article aims to present a comprehensive and critical overview of emerging analytical technologies for EV detection and their clinical applications

/pdf/new-technologies-for-analysis-of-extracellular-vesicles-5g2ou3q31v.pdf

New Technologies for Analysis of Extracellular Vesicles

https://www.gastrojournal.org/article/S0016-5085(15)01005-7/pdf

Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

Background:Long non-coding RNA and mRNAs are long RNAs ({greater than or equal to} 200 nucleotides) compared to microRNAs. In blood, long RNAs may be protected by serum extracellular vesicles, such as apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXOs). They are potential biomarker for identifying cancer. Methods:Sera from 76 pre-operative CRC patients, 76 age- and sex-matched healthy subjects and 20 colorectal adenoma (CA) patients without CRC were collected. We investigate the distribution of long RNAs the three vesicles. Seventy-nine cancer-related long RNA were chosen and detected using quantitative PCR (qPCR). Results: OThe quantity of long RNA have varying distribution among three subtypes of extracellular vesicles in serum. Most mRNAs and lncRNAs genes had higher quantity in EXOs than that in ABs and MVs, while MVs contain lowest quantity. We investigated 79 long RNAs chosen from the The Cancer Genome Atlas (TCGA) and the LncRNADisease database in the sera of healthy patients, and those with colorectal cancer (CRC). In the training and test sets, the areas under the curves (AUC) were 0.936 and 0.877 respectively. The AUC of total serum RNA was lower (0.857) than that of exosomal RNA in the same samples (0.936). Conclusions:The present study shows that exosomal mRNAs and lncRNAs in serum could be used as biomarkers to detect CRC. Impact:Among three types of vesicles in sera, EXOs were the richest reservoir for almost all measured long RNAs. the combination of 2 mRNAs, KRTAP5-4, MAGEA3, and 1 lncRNA, BCAR4 could be potential candidates to detect colorectal cancer.

https://cebp.aacrjournals.org/content/cebp/25/7/1158.full.pdf

Circulating Long RNAs in Serum Extracellular Vesicles: Their Characterization and Potential Application as Biomarkers for Diagnosis of Colorectal Cancer

The examination of circulating nucleic acids (CNAs) is an emerging noninvasive diagnostic technique. However, it is unclear if serum long noncoding RNAs (lncRNAs) represent a novel marker to detect gastric cancer (GC). In this study, we measured 39 candidate cancer-associated lncRNAs by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in sera from 110 patients with GC, 106 age- and sex-matched healthy subjects and 15 patients with gastric peptic ulcer, markers were validated and assessed by RT-qPCR. The correlation of the expression levels of the candidate serum lncRNAs with clinical parameters of GC patients was performed. A three-lncRNA signature, including CUDR, LSINCT-5 and PTENP1, was identified that may be potential diagnostic marker for GC. The areas under the receiver operating characteristic (ROC) curve for this serum three-lncRNA signature were 0.920 and 0.829 for the two sets of serum samples. Moreover, a risk model for the serum three-lncRNA signature demonstrated that healthy samples can be distinguished from early GC samples. Three-lncRNA signature in serum was identified as diagnostic marker for GC. This work may facilitate the detection of GC and serve as the basis for further studies of the clinical value of serum lncRNAs in maintaining surveillance and forecasting prognosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.29484

Circulating CUDR, LSINCT-5 and PTENP1 long noncoding RNAs in sera distinguish patients with gastric cancer from healthy controls

Recently, long noncoding RNAs (lncRNAs) were demonstrated to play important regulatory roles in biological processes and cancer biology. However, the overall pathophysiological contribution of lncRNAs to gastric cancer (GC) remains largely unknown. In this study, differentially expressed lncRNAs in GC and paired adjacent normal tissue samples were identified by microarray and were validated using quantitative real-time polymerase chain reaction (qRT-PCR). One particular lncRNA, tumour suppressor candidate 7 (TUSC7), was analyzed in sequential large cohorts, and the Kaplan-Meier method with the log-rank test for comparisons was used to analyse the survival data. The results indicated that TUSC7 was downregulated in GC samples and was an independent prognostic indicator of disease-free survival (DFS) and disease-specific survival (DSS) in GC patients. Applying loss-of-function and gain-of-function approaches, we determined that TUSC7 suppressed tumour cell growth in vitro and in vivo. Furthermore, we showed that TUSC7 was a direct transcriptional target of p53 via interaction of p53 with the putative p53-response element in the upstream region of TUSC7. Finally, we demonstrated reciprocal repression between TUSC7 and miR-23b; in contrast to TUSC7, miR-23b promoted cell growth. The results indicated that TUSC7 is a p53-regulated tumour suppressor that acts in part by repressing miR-23b and that TUSC7 may be a key regulatory hub in GC.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.29516

Reciprocal repression between TUSC7 and miR-23b in gastric cancer.

Accumulating evidence demonstrates that lncRNAs play important roles in regulating gene expression and are involved in various pathological processes. In the present study, we screened the lncRNAs profile in clear cell renal cell carcinoma (ccRCC) from The Cancer Genome Atlas (TCGA) database, and got linc00152, a differentially expressed lncRNA that haven't been reported in ccRCC. To further explore its role in ccRCC, the level of Linc00152 was detected in 77 paired ccRCC tissues and renal cancer cell lines by qRT-PCR, and its association with overall survival was assessed by statistical analysis. Linc00152 expression was significantly up-regulated in cancerous tissues and cell lines compared with normal counterparts, and high Linc00152 expression was closely associated with advanced TNM stage. Moreover, Linc00152 was found to be able to serve as an independent predictor of overall survival. Further experiments demonstrated that overexpression of Linc00152 can significantly promote cell proliferation and invasion, inhibit cell cycle arrest in G1 phase and dramatically decrease apoptosis in both 786O and Caki-2 cell lines, whereas the opposite results were observed with attenuated Linc00152 expression. Our data suggest that Linc00152 is a novel molecule involved in ccRCC progression as well as a potential prognostic biomarker and therapeutic target.

Wei Wei Weng

Papers

Circulating Long RNAs in Serum Extracellular Vesicles: Their Characterization and Potential Application as Biomarkers for Diagnosis of Colorectal Cancer

Circulating CUDR, LSINCT-5 and PTENP1 long noncoding RNAs in sera distinguish patients with gastric cancer from healthy controls

Reciprocal repression between TUSC7 and miR-23b in gastric cancer.

Long non-coding RNA Linc00152 is a positive prognostic factor for and demonstrates malignant biological behavior in clear cell renal cell carcinoma.

Long Non-Coding RNA LSINCT5 Predicts Negative Prognosis and Exhibits Oncogenic Activity in Gastric Cancer