Transcribed Ultraconserved Regions Research Articles

CSIG-05. A FIRST COMPREHENSIVE ANALYSIS OF TRANSCRIBED ULTRA CONSERVED REGIONS UNCOVERS IMPORTANT REGULATORY FUNCTIONS OF NOVEL NON-CODING TRANSCRIPTS IN GLIOMAS

Abstract Most glioma research has focused on protein-coding genes and much less on non-coding RNAs (ncRNAs). Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of ncRNAs that are highly conserved across multiple species, including 100% conservation in mouse and rat genomes. These 481 transcripts are highly resistant to variation and are commonly deregulated in cancer, which suggests regulatory and functional importance when considered along with their high degree of conservation. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We first annotated all TUCRs in gliomas and described their genomic locations. We then showed that numerous TUCRs are highly expressed and deregulated in gliomas, and that this deregulation is associated with clinical outcomes. We then used a WGCNA pipeline to predict the functions for all TUCRs in gliomas by compiling gene ontology (GO) terms for coregulated genes. These data were used to identify several TUCRs that are potentially relevant to glioma initiation and progression. Of these, we investigated the most highly upregulated intergenic TUCR, uc.110, in vitro and in vivo in GBM. Knockdown of uc.110 in vitro reduced GBM cell accumulation and invasion and knockdown in vivo inhibited GBM xenograft growth and increased animal survival. We then performed mechanistic analyses of uc.110 and found that it regulates the expression of a Wnt pathway member, membrane frizzled-related protein (MFRP). We discovered that uc.110 sponges the tumor suppressor microRNA miR-544, which targets and inhibits MFRP, thus increasing the bioavailability of MFRP in GBM. This study is the first of its kind in gliomas. It shows important regulatory roles for TUCRs in gliomas and outlines novel methods for studying TUCRs in any disease context.

Abstract 3747: Transcribed ultra-conserved regions (TUCRs): A first computational and molecular characterization of an understudied class of molecules in gliomas

Abstract Gliomas are the most common malignant primary brain tumors. Particularly, glioblastoma (GBM) is the most common and deadliest malignant brain tumor. Most glioma research has focused on protein-coding genes and much less on the non-coding transcripts that make up 98% of cellular RNA. Transcribed Ultra-Conserved Regions (TUCRs) represent an understudied class of molecules that are found highly conserved across multiple species, including 100% conservation in mouse and rat genomes. These 481 transcripts are highly resistant to variation and are commonly deregulated in cancer, which suggests regulatory and functional importance when considered along with their high degree of conservation. We performed the first-ever characterization of TUCRs in gliomas in silico. Using an elaborate workflow, we annotated and identified TUCRs that are deregulated in GBM and low-grade glioma (LGG), associated with patient outcomes, and predicted their function in glioma initiation and progression. Most TUCRs were long non-coding RNAs. Of these, we investigated the most highly upregulated intergenic TUCR, uc.110, in vitro and in vivo in glioma cell lines. Knockdown of uc.110 expression via siRNA resulted in reduced glioma cell accumulation, viability, and invasion in vitro while reducing tumor volume and increasing overall survival in vivo. Concurrent lentiviral overexpression of uc.110 partially rescued wild-type expression, accumulation, viability, and invasion in vitro. Therefore, it is likely that this TUCR is functioning as an oncogene within the context of GBM. Our study represents the first comprehensive characterization of TUCRs in gliomas and can serve as a foundation and framework for similar studies in gliomas and other cancers. Citation Format: Myron K. Gibert, Bilhan Chagari, Christian Roig-Laboy, Aditya Sarkar, Roger Abounader. Transcribed ultra-conserved regions (TUCRs): A first computational and molecular characterization of an understudied class of molecules in gliomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3747.

Construction of a three-component regulatory network of transcribed ultraconserved regions for the identification of prognostic biomarkers in gastric cancer.

Altered expression and functional roles of the transcribed ultraconserved regions (T-UCRs), as genomic sequences with 100% conservation between the genomes of human, mouse, and rat, in the pathophysiology of neoplasms has already been investigated. Nevertheless, the relevance of the functions for T-UCRs in gastric cancer (GC) is still the subject of inquiry. In the current study, we first used a genome-wide profiling approach to analyze the expression of T-UCRs in GC patients. Then, we constructed a three-component regulatory network and investigated potential diagnostic and prognostic values of the T-UCRs. The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) dataset was used as a resource for the RNA-sequencing data. FeatureCounts was utilized to quantify the number of reads mapped to each T-UCR. Differential expression analysis was then conducted using DESeq2. In the following, interactions between T-UCRs, microRNAs (miRNAs), and messenger RNAs (mRNAs) were combined into a three-component network. Enrichment analyses were performed and a protein-protein interaction (PPI) network was constructed. The R Survival package was utilized to identify survival-related significantly differentially expressed T-UCRs (DET-UCRs). Using an in-house cohort of GC tissues, expression of two DET-UCRs was furthermore experimentally verified. Our results showed that several T-UCRs were dysregulated in TCGA-STAD tumoral samples compared to nontumoral counterparts. The three-component network was constructed which composed of DET-UCRs, miRNAs, and mRNAs nodes. Functional enrichment and PPI network analyses revealed important enriched signaling pathways and gene ontologies such as "pathway in cancer" and regulation of cell proliferation and apoptosis. Five T-UCRs were significantly correlated with the overall survival of GC patients. While no expression of uc.232 was observed in our in-house cohort of GC tissues, uc.343 showed an increased expression, although not statistically significant, in gastric tumoral tissues. The constructed three-component regulatory network of T-UCRs in GC presents a comprehensive understanding of the underlying gene expression regulation processes involved in tumor development and can serve as a basis to investigate potential prognostic biomarkers and therapeutic targets.

Transcribed Ultraconserved Regions: New regulators in cancer signaling and potential biomarkers.

The ultraconserved regions (UCRs) are 481 genomic elements, longer than 200 bp, 100% conserved in human, mouse, and rat genomes. Usually, coding regions are more conserved, but more than 80% of UCRs are either intergenic or intronic, and many of them produce long non-coding RNAs (lncRNAs). Recently, the deregulated expression of transcribed UCRs (T-UCRs) has been associated with pathological conditions. But, differently from many lncRNAs with recognized crucial effects on malignant cell processes, the role of T-UCRs in the control of cancer cell networks is understudied. Furthermore, the potential utility of these molecules as molecular markers is not clear. Based on this information, the present review aims to organize information about T-UCRs with either oncogenic or tumor suppressor role associated with cancer cell signaling, and better describe T-UCRs with potential utility as prognosis markers. Out of 481 T-UCRs, 297 present differential expression in cancer samples, 23 molecules are associated with tumorigenesis processes, and 12 have more clear potential utility as prognosis markers. In conclusion, T-UCRs are deregulated in several tumor types, highlighted as important molecules in cancer networks, and with potential utility as prognosis markers, although further investigation for translational medicine is still needed.

A comprehensive review on miR-153: Mechanistic and controversial roles of miR-153 in tumorigenicity of cancer cells

miRNAs play a crucial role in regulating genes involved in cancer progression. Recently, miR-153 has been mainly well-known as a tumor suppressive miRNA modulating genes in proliferation, metastasis, EMT, angiogenesis and drug resistance ability of a variety types of cancer. Mechanistic activity of miR-153 in tumorigenicity has not been fully reviewed. This manuscript presents a comprehensive review on the tumor suppressive activity of miR-153 as well as introducing the controversial role of miR-153 as an oncogenic miRNA in cancer. Furthermore, it summarizes all potential non-coding RNAs such as long non-coding RNAs (LncRNAs), transcribed ultra-conserved regions (T-UCRs) and circular RNAs (CircRNAs) targeting and sponging miR-153. Understanding the critical role of miR-153 in cell growth, metastasis, angiogenesis and drug resistance ability of cancer cells, suggests miR-153 as a potential prognostic biomarker for detecting cancer as well as providing a novel treatment strategy to combat with several types of cancer.

Role of transcribed ultraconserved regions in gastric cancer and therapeutic perspectives.

Gastric cancer (GC) is the fourth leading cause of cancer-related death. The occurrence and development of GC is a complex process involving multiple biological mechanisms. Although traditional regulation modulates molecular functions related to the occurrence and development of GC, the comprehensive mechanisms remain unclear. Ultraconserved region (UCR) refers to a genome sequence that is completely conserved in the homologous regions of the human, rat and mouse genomes, with 100% identity, without any insertions or deletions, and often located in fragile sites and tumour-related genes. The transcribed UCR (T-UCR) is transcribed from the UCR and is a new type of long noncoding RNA. Recent studies have found that the expression level of T-UCRs changes during the occurrence and development of GC, revealing a new mechanism underlying GC. Therefore, this article aims to review the relevant research on T-UCRs in GC, as well as the function of T-UCRs and their regulatory role in the occurrence and development of GC, to provide new strategies for GC diagnosis and treatment.

Analysis of Long Non-Coding RNA (lncRNA) uc.38 and uc.63 Expression in Breast Carcinoma Patients.

Background. The role of the transcribed ultra-conserved regions (T-UCRs) has not yet been fully discovered, but the studies showed some indications that impaired expression of T-UCRS were present in malignant tumors, including breast cancer. Aim. The presented work assessed the expression of two transcribed-ultra conserved regions–uc.63 and uc.38–in breast cancer tissue samples. Material and methods. The research was carried out on a group of 100 patients with invasive ductal carcinoma and 100 patients (test group) with benign tumors in breast tissue (control group). Results. As a result of the statistical analysis, it was shown that the expression of uc.63 and uc.38 is statistically significant, and, accordingly, higher (p < 0.0001) and lower (p < 0.0001) in the test group than in the control group. Statistical dependency analysis of the expression of uc.63 and uc.38 and the selected clinical and pathological factors showed that the expression of uc.63 statistically drops with the patient’s age (p = 0.04), and is higher in the breast cancer tissue type M1 according to the TNM classification (p = 0.036) and in tissues with overexpressed HER2 (p = 0.035). Conclusion. The obtained results of the statistical analysis indicate a relationship between the expression of uc.63 and uc.38 and the occurrence of breast cancer.

The dark matter of the human genome and its role in human cancers.

The transcribed ultra-conserved regions (T-UCRs) are a novel family of non-coding RNAs which are absolutely conserved (100%) across orthologous regions of the human, mouse, and rat genomes. T-UCRs represent a small portion of the human genome that is likely to be functional but does not code for proteins and is referred to as the "dark matter" of the human genome. Although T-UCRs are ubiquitously expressed, tissue- and disease-specific expression of T-UCRs have also been observed. Accumulating evidence suggests that T-UCRs are differentially expressed and involved in the malignant transformation of human tumors through various genetic and epigenetic regulatory mechanisms. Therefore, T-UCRs are novel candidate predisposing biomarkers for cancer development. T-UCRs have shown to drive malignant transformation of human cancers through regulating non-coding RNAs and/or protein coding genes. However, the functions and fate of most T-UCRs remain mysterious. Here, we review and highlight the current knowledge on these ultra-conserved elements in the formation and progression of human cancers.

Overexpression of ultraconserved region 83- induces lung cancer tumorigenesis.

The expression of non–coding RNAs (ncRNAs) is dysregulated in human cancers. The transcribed ultraconserved regions (T-UCRs) express long ncRNAs involved in human carcinogenesis. T-UCRs are non-coding genomic sequence that are 100% conserved across humans, rats and mice. Conservation of genomic sequences across species intrinsically implies an essential functional role and so we considered the expression of T-UCRs in lung cancer. Using a custom microarray we analyzed the global expression of T-UCRs. Among these T-UCRs, the greatest variation was observed for antisense ultraconserved element 83 (uc.83-), which was upregulated in human lung cancer tissues compared with adjacent non cancerous tissues. Even though uc.83- is located within the long intergenic non-protein coding RNA 1876 (LINC01876) gene, we found that the transcribed uc.83- is expressed independently of LINC01876 and was cloned as a 1143-bp RNA gene. In this study, functional analysis confirmed important effects of uc.83- on genes involved in cell growth of human cells. siRNA against uc.83- decreased the growth of lung cancer cells while the upregulation through a vector overexpressing the uc.83- RNA increased cell proliferation. We also show the oncogenic function of uc.83- is mediated by the phosphorylation of AKT and ERK 1/2, two important biomarkers of lung cancer cell proliferation. Based on our findings, inhibition against uc.83- could be a future therapeutic treatment for NSCLC to achieve simultaneous blockade of pathways involved in lung carcinogenesis.

UC.183, UC.110, and UC.84 Ultra-Conserved RNAs Are Mutually Exclusive with miR-221 and Are Engaged in the Cell Cycle Circuitry in Breast Cancer Cell Lines

In the human genome, there are about 600 ultra-conserved regions (UCRs), long DNA sequences extremely conserved in vertebrates. We performed a large-scale study to quantify transcribed UCR (T-UCR) and miRNA levels in over 6000 cancer and normal tissue samples to find possible correlation between these kinds of regulatory molecules. Our analysis evidenced several non-coding RNAs showing negative co-regulation with miRNAs; among them, we focused on miR-221 to investigate any relationship with its pivotal role in the cell cycle. We have chosen breast cancer as model, using two cell lines with different phenotypes to carry out in vitro treatments with siRNAs against T-UCRs. Our results demonstrate that the expression of uc.183, uc.110, and uc.84 T-UCRs is mutually exclusive with miR-221 and is engaged in the regulation of CDKN1B expression. In addition, tests with a set of anticancer drugs, including BYL719, AZD5363, AZD8055, AZD7762, and XL765, revealed the modulation of specific T-UCRs without alteration of miR-221 levels.

The transcribed ultraconserved region uc.160+ enhances processing and A-to-I editing of the miR-376 cluster: hypermethylation improves glioma prognosis.

Transcribed ultraconserved regions (T‐UCRs) are noncoding RNAs derived from DNA sequences that are entirely conserved across species. Their expression is altered in many tumor types, and, although a role for T‐UCRs as regulators of gene expression has been proposed, their functions remain largely unknown. Herein, we describe the epigenetic silencing of the uc.160+ T‐UCR in gliomas and mechanistically define a novel RNA–RNA regulatory network in which uc.160+ modulates the biogenesis of several members of the miR‐376 cluster. This includes the positive regulation of primary microRNA (pri‐miRNA) cleavage and an enhanced A‐to‐I editing on its mature sequence. As a consequence, the expression of uc.160+ affects the downstream, miR‐376‐regulated genes, including the transcriptional coregulators RING1 and YY1‐binding protein (RYBP) and forkhead box P2 (FOXP2). Finally, we elucidate the clinical impact of our findings, showing that hypermethylation of the uc.160+ CpG island is an independent prognostic factor associated with better overall survival in lower‐grade gliomas, highlighting the importance of T‐UCRs in cancer pathophysiology.

The transcribed ultraconserved element uc.51 promotes the proliferation and metastasis of breast cancer by stabilizing NONO.

Long noncoding RNAs have recently emerged as significant contributors to cancers, including breast cancer (BC). One class of long noncoding RNAs called transcribed ultraconserved regions (T-UCRs) is highly conserved in many species and closely related to diverse physiological and pathological processes. However, the function of T-UCRs in BC remains largely unclear. In this study, we identified uc.51, a T-UCR that is overexpressed in both BC tissues and cell lines and is correlated with larger tumor size. Loss- and gain-of-function assays were performed in vitro and demonstrated that uc.51 promotes the proliferation, migration, and invasion of BC cells. Mechanistically, non-POU domain-containing octamer-binding protein (NONO) was found to physically interact with uc.51 by RNA pulldown followed by mass spectrometry. This interaction was further verified by RNA immunoprecipitation. Moreover, uc.51 positively regulated the expression of NONO, maintained its stability through the ubiquitin-proteasome system, and activated the phosphorylation of CREB. Rescue experiments demonstrated that NONO overexpression compensated for the attenuated influence on BC progression resulting from downregulation of uc.51, indicating that NONO functions downstream of uc.51. In vivo functional experiments also revealed a positive correlation between uc.51 expression and tumor size. Ki-67 and NONO levels in the lv-uc.51-shRNA group were decreased compared with those in the lv-con-shRNA group, according to the immunohistochemical staining results, and a decreased incidence of distant metastasis was observed in the lv-uc.51-shRNA group in the xenograft model. Collectively, our results reveal a substantial role for the uc.51-NONO axis in BC progression and indicate that the uc.51-NONO axis has potential to be a therapeutic target for BC.

In Silico Analysis of miRNA-mediated ceRNAs as Potential Molecular Biomarkers in Glioblastoma

Objectives: Glioblastoma multiforme (GBM) is defined as the most frequent and lethal form of the primary brain tumors in the central nervous system (CNS) in adults. Recent studies have focused on the identification of the new targets for the diagnosis and treatment of GBM and resulted in great interest for miRNAs due to their regulatory effects in cancer pathogenesis. Thus, we aimed to characterize novel molecular biomarkers for GBM by computational analysis. Methods: 118 miRNAs that are clinically related with glioblastoma and proven by experimentally were exported through miRTarBase database. 1016 genes projected by these 118 miRNAs were determined via ComiR database. Subsequently, the genes with transcribed ultraconserved regions (T-UCRs) in their exonic regions were designated and the genes which have potential competing endogenous RNA (ceRNA) activities were extracted. Genes with remarkable expression profile differences between glioblastoma and normal brain tissues among ceRNAs that are associated with glioblastoma involving T-UCR were identified. Results: The statistical analysis of the correlation between PBX3 and NRXN3 genes and glioblastoma was carried out by Spearman correlation test. PBX3 and NRXN3 expression was significantly higher and lower in glioblastoma than in normal brain tissues, respectively. On the other hand, the other genes did not have any remarkable differential expression pattern. Conclusion: Based on the findings of the current study, it is determined that NRXN3 acts as a tumor suppressor gene and NRXN3 gene is downregulated in GBM. PBX3 gene functions as an oncogene and is upregulated in GBM.

Long Non-coding RNA T-uc.189 Modulates Neural Progenitor Cell Fate by Regulating Srsf3 During Mouse Cerebral Cortex Development.

Neurogenesis is a complex process that depends on the delicate regulation of spatial and temporal gene expression. In our previous study, we found that transcribed ultra-conserved regions (T-UCRs), a class of long non-coding RNAs that contain UCRs, are expressed in the developing nervous systems of mice, rhesus monkeys, and humans. In this study, we first detected the full-length sequence of T-uc.189, revealing that it was mainly concentrated in the ventricular zone (VZ) and that its expression decreased as the brain matured. Moreover, we demonstrated that knockdown of T-uc.189 inhibited neurogenesis. In addition, we found that T-uc.189 positively regulated the expression of serine-arginine-rich splicing factor 3 (Srsf3). Taken together, our results are the first to demonstrate that T-uc.189 regulates the expression of Srsf3 to maintain normal neurogenesis during cortical development.

Uc.77- Downregulation Promotes Colorectal Cancer Cell Proliferation by Inhibiting FBXW8-Mediated CDK4 Protein Degradation.

Transcribed ultraconserved regions (T-UCRs) are a new type of long non-coding RNA, and the UCR has 481 segments longer than 200 base pairs that are 100% conserved between humans, rats, and mice. T-UCRs involved in colorectal cancer (CRC) have not been studied in detail. We performed T-UCR microarray analysis and found that uc.77- was significantly downregulated in CRC tissues and cell lines. Ectopic expression of uc.77- significantly inhibited the proliferation of CRC cells in vitro and the growth of xenograft tumors in nude mice in vivo. Mechanistic studies showed that uc.77- competed with FBXW8 mRNA for binding to microRNA (miR)-4676-5p through a competing endogenous RNA mechanism and inhibited the proliferation of CRC cells by negatively regulating CDK4. The present findings highlight the role of the uc.77-/miR-4676-5p/FBXW8 axis in CRC and identify uc.77- as a potential novel target for the treatment of CRC.

Involvement of transcribed lncRNA uc.291 and SWI/SNF complex in cutaneous squamous cell carcinoma

While non-melanoma skin cancers (NMSCs) are the most common tumours in humans, only the sub-type cutaneous squamous cell carcinoma (cSCC), might become metastatic with high lethality. We have recently identified a regulatory pathway involving the lncRNA transcript uc.291 in controlling the expression of epidermal differentiation complex genes via the interaction with ACTL6A, a component of the chromatin remodelling complex SWI/SNF. Since transcribed ultra-conserved regions (T-UCRs) are expressed in normal tissues and are deregulated in tumorigenesis, here we hypothesize a potential role for dysregulation of this axis in cSCC, accounting for the de-differentiation process observed in aggressive poorly differentiated cutaneous carcinomas. We therefore analysed their expression patterns in human tumour biopsies at mRNA and protein levels. The results suggest that by altering chromatin accessibility of the epidermal differentiation complex genes, down-regulation of uc.291 and BRG1 expression contribute to the de-differentiation process seen in keratinocyte malignancy. This provides future direction for the identification of clinical biomarkers in cutaneous SCC. Analysis of publicly available data sets indicates that the above may also be a general feature for SCCs of different origins.

SNPs in lncRNA Regions and Breast Cancer Risk.

Long non-coding RNAs (lncRNAs) play crucial roles in human physiology, and have been found to be associated with various cancers. Transcribed ultraconserved regions (T-UCRs) are a subgroup of lncRNAs conserved in several species, and are often located in cancer-related regions. Breast cancer is the most common cancer in women worldwide and the leading cause of female cancer deaths. We investigated the association of genetic variants in lncRNA and T-UCR regions with breast cancer risk to uncover candidate loci for further analysis. Our focus was on low-penetrance variants that can be discovered in a large dataset. We selected 565 regions of lncRNAs and T-UCRs that are expressed in breast or breast cancer tissue, or show expression correlation to major breast cancer associated genes. We studied the association of single nucleotide polymorphisms (SNPs) in these regions with breast cancer risk in the 122970 case samples and 105974 controls of the Breast Cancer Association Consortium’s genome-wide data, and also by in silico functional analyses using Integrated Expression Quantitative trait and in silico prediction of GWAS targets (INQUISIT) and expression quantitative trait loci (eQTL) analysis. The eQTL analysis was carried out using the METABRIC dataset and analyses from GTEx and ncRNA eQTL databases. We found putative breast cancer risk variants (p < 1 × 10–5) targeting the lncRNA GABPB1-AS1 in INQUISIT and eQTL analysis. In addition, putative breast cancer risk associated SNPs (p < 1 × 10–5) in the region of two T-UCRs, uc.184 and uc.313, located in protein coding genes CPEB4 and TIAL1, respectively, targeted these genes in INQUISIT and in eQTL analysis. Other non-coding regions containing SNPs with the defined p-value and highly significant false discovery rate (FDR) for breast cancer risk association were discovered that may warrant further studies. These results suggest candidate lncRNA loci for further research on breast cancer risk and the molecular mechanisms.

SAT-LB105 A Transcribed Ultraconserved Noncoding RNA, Uc.336-As, Promotes White to Brown Conversion in 3T3-L1 Cells

Brown adipose tissue (BAT) has gained its popularity since it shows great potential in counteracting obesity and metabolic diseases development. Transcribed ultraconserved regions (T-UCRs), a novel class of long non-coding RNA (lncRNAs), have been implicated in regulating diverse biological processes, including the process of white fat browning. However, the functional and mechanistic details of T-UCRs in the browning process are poorly understood. Here, we identified that a T-UCR, uc.336-as, played an important role during the browning process. Uc.336-as was significantly elevated during browning process induced by glucagon-like peptide-1 receptor agonist (exendin-4) or β3-adrenergic agonist (CL316,243). Overexpression of uc.336-as reduces the differentiation of 3T3-L1 preadipocytes into white adipocytes (inhibited lipid accumulation and decreased the expression of several adipogenesis markers) and induces brown characteristics during differentiation of 3T3-L1 preadipocytes (spurred browning adipocytes phenotypes and increased the expression of the browning associated genes). Moreover, we found that uc.336-as inhibited adipogenesis and promoted browning process via influencing the serine/threonine kinase (AKT)-mammalian target of rapamycin (mTOR) axis, an essential signal pathway in adipocyte metabolism. Taken together, our data show that uc.336-as acts as a negative regulator in white adipocyte differentiation and promotes the browning process, suggesting a potential therapeutic role for uc.336-as in controlling obesity.

SAT-584 Uc.336-As Inhibits White Adipocyte Differentiation and Promotes White to Brown Conversion

Brown adipose tissue (BAT) has gained its popularity since it shows great potential in counteracting obesity and metabolic diseases development. Transcribed ultraconserved regions (T-UCRs), a novel class of long non-coding RNA (lncRNAs), have been implicated in regulating diverse biological processes, including the process of white fat browning. However, the functional and mechanistic details of T-UCRs in the browning process are poorly understood. Here, we identified that a T-UCR, uc.336-as, played an important role during the browning process. uc.336-as was significantly elevated during browning process induced by exendin-4 or β3-adrenergic agonist (CL316,243). Moreover, we found that uc.336-as promoted browning process and inhibited adipogenesis. Finally, we identified that uc.336-as promoted the expression of browning-related genes via influencing the p38 mitogen-activated protein kinase (p38 MAPK) signaling, an essential signal pathway in metabolism. Taken together, our data show that uc.336-as acts as a negative regulator in white adipocyte differentiation and promotes the browning process, suggesting a potential therapeutic role for uc.336-as in controlling obesity.

Uc.63+ contributes to gastric cancer progression through regulation of NF-kB signaling.

The transcribed ultraconserved regions (T-UCRs) are a novel class of long non-coding RNAs and are involved in the development of several types of cancer. Although several different papers have described the oncogenic role of Uc.63+, there are no reports mentioning its importance in gastric cancer (GC) biology. In this study, we evaluated Uc.63+ expression using clinical samples of GC by qRT-PCR, and also assessed the correlation between Uc.63+ expression and clinico-pathological factors. The upregulation of Uc.63+ was significantly correlated with advanced clinico-pathological features. Knockdown of Uc.63+ significantly repressed GC cell growth and migration, whereas overexpression of Uc.63+ conversely promoted those of GC cells. In situ hybridization of Uc.63+ revealed its preferential expression in poorly differentiated adenocarcinoma. We further conducted a microarray analysis using MKN-1 cells overexpressing Uc.63- and found that NF-κB signaling was significantly upregulated in accordance with Uc.63+ expression. Our results suggest that Uc.63+ could be involved in GC progression by regulating GC cell growth and migration via NF-κB signaling.