Deregulation Of lncRNAs Research Articles

Assessment of Expression of lncRNAs in Autistic Patients.

Autism is a severe neurodevelopmental condition with unknown pathobiology. Nevertheless, multiple pieces of evidence suggest long non-coding RNA (lncRNA) dysregulation may be a contributing factor to this disorder. We investigated the association between the expression of five specific lncRNAs and autism. Peripheral blood was collected from 30 children with autism and 41 healthy children. The expression levels ofPCAT-29, lincRNA-ROR, LINC-PINT, lincRNA-p21, and PCAT-1 were calculated. Then, their significance as biomarkers was also evaluated.The expression of LincRNA-ROR (27 times), LINC-PINT (5.26 times), LincRNA-p21 (4.54 times), PCAT-29 (16.66 times), and PCAT-1 (25 times) genes was significantly decreased in patients compared to the control group (p values < 0.05). According to the ROC curve analysis for each lncRNA, LincRNA-ROR, LINC-PINT, LincRNA-p21, PCAT-29, and PCAT-1 lncRNAs with diagnostic power of 0.85, 0.67, 0.64, 0.74, and 0.84, respectively, could be used as diagnostic biomarkers for autism. Additionally, significant positive correlations were reported between expression levels of PCAT-1 and PCAT-29 genes. Moreover, a positive correlation was detected between expression levels of lincRNA-ROR and patients' age. The current study shows further pieces of evidence for deregulation of lncRNAs in autistic patients that show these lncRNAs may play an important part in the pathogenesis of ASD. However, the role of lncRNA in the neurobiology of autism needs to be investigated further.

The roles of long non-coding RNAs in ovarian cancer: from functions to therapeutic implications.

Long non-coding RNAs (lncRNAs) are multifunctional and participate in a variety of biological processes and gene regulatory networks. The deregulation of lncRNAs has been extensively implicated in diverse human diseases, especially in cancers. Overwhelming evidence demonstrates that lncRNAs are essential to the pathophysiological processes of ovarian cancer (OC), acting as regulators involved in metastasis, cell death, chemoresistance, and tumor immunity. In this review, we illustrate the expanded functions of lncRNAs in the initiation and progression of OC and elaborate on the signaling pathways in which they pitch. Additionally, the potential clinical applications of lncRNAs as biomarkers in the diagnosis and treatment of OC were emphasized, cementing the bridge of communication between clinical practice and basic research.

LncRNA Biomarkers of Glioblastoma Multiforme.

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood.

Alteration in the expression of long non-coding RNAs in the circulation of migraineurs.

Current studies have shown emerging roles of lncRNAs in the pathobiology of neuropathic pain and migraine. We have chosen five lncRNAs, namely, PVT1, DSCAM-AS, MEG3, LINC-ROR, and SPRY4-IT1 for assessment of their expression in the circulation of migraineurs. Expressions of PVT1 and MEG3 were higher in total migraineurs and both subgroups compared with controls (P < 0.0001). Meanwhile, expression of both lncRNA was higher in migraineurs with aura versus migraineurs without aura (P value < 0.0001 and = 0.01, respectively). Expression of DSCAM-AS1 was not different between any groups of patients compared with controls. Expression of LINC-ROR was elevated in total patients and patients with aura compared with controls (P value = 0.0002 and < 0.0001, respectively). It was also over-expressed in migraineurs with aura vs. migraineurs without aura (P = 0.01). Finally, expression of SPRY4-IT1 was higher in total patients and patients without aura compared with migraine-free persons (P values < 0.0001). Expressions of five mentioned lncRNAs were correlated in almost all study groups. In patients without aura, correlations were significant only for two pairs (SPRY4-IT1/PVT1 and SPRY4-IT1/DSCAM-AS1). PVT1 and MEG3 had the appropriate AUC, sensitivity and specificity values for separation of total migraineurs and both groups of patients from controls. The highest AUC value was reported for PVT1 in separation of migraineurs with aura from healthy controls (AUC = 0.98). Cumulatively, our study shows evidence for deregulation of lncRNAs in migraineurs.

LncRNA VLDLR-AS1 Gene Expression in Colorectal Cancer in Patients from East Azerbaijan Province, Iran

Background: Colorectal cancer (CRC) is the third most common cancer that frequently spreads to other parts of the body, with a low chance of recovery and a high mortality rate. Long non-coding RNAs are considered significant prognostic and diagnostic indicators because they are dysregulated in various cancers and have distinctive expression patterns and high tissue- and cell-specificity. VLDLR-AS1 lncRNA deregulation has been associated with several malignancies. Objectives: This study aimed to evaluate the expression levels of VLDLR-AS1 in CRC. It was the first time this assessment was conducted. Methods: We studied 188 samples, including 94 tumor samples and 94 paired adjacent non-tumor tissues. Total RNA was extracted, and its quantity and purity were assessed. TaKaRa PrimeScript 1st Strand cDNA Synthesis Kit (Kusatsu, Japan) was used for the reaction. The StepOnePlus Real-Time PCR System (Applied Biosystems) was set up to assess the relative expression of VLDLR-AS1. Results: According to the qRT-PCR data, the VLDLR-AS1 expression levels in CRC tissues were significantly lower than in tumor margins (P &lt; 0.0001). In addition, receiver operating characteristic curve analysis demonstrated that VLDLR-AS1 expression can discriminate between tumor and non-tumor samples with the sensitivity and specificity of 72.34% and 51.06%, respectively (P = 0.03, AUC = 0.6274). However, no significant association was found between the expression levels of VLDLR-AS1 and clinicopathological features in CRC patients. Conclusions: The results of this study indicated that VLDLR-AS1 lncRNA is significantly downregulated in the tumor tissues of CRC patients compared to healthy tumor margin tissues. This evidence shows the potential of this gene as a promising biomarker for the early detection of CRC development.

Long non‑coding RNAs, lipid metabolism and cancer (Review).

Cancer has emerged as the most common cause of death in China. The change in lipid metabolism has been confirmed to have a role in several tumor types, such as esophageal, gastric, colorectal and liver cancer. Cancer cells use lipid metabolism for energy and then rapidly proliferate, invade and migrate. The main pathway by which cancer cell lipid metabolism influences cancer progression is increased fatty acid synthesis. Long non-coding (lnc)RNAs are important ncRNAs that were indicated to have significant roles in the development of human tumors. They are considered potential tumor biomarkers. Increased lipid synthesis or uptake due to deregulation of lncRNAs contributes to rapid tumor growth. In the present review, current studies on the relationship between lncRNAs, lipid metabolism and the occurrence and development of tumors were collated and summarized, and their mechanism of action was discussed. The review is expected to provide a theoretical basis for tumor treatment and prognosis evaluation based on the effective regulation of lncRNAs and lipid metabolism.

HNRNPA2B1-mediated m6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis

BackgroundAccumulating data indicate that N6-methyladenosine (m6A) RNA methylation and lncRNA deregulation act crucial roles in cancer progression. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as an m6A “reader” has been reported to be an oncogene in multiple malignancies. We herein aimed to elucidate the role and underlying mechanism by which HNRNPA2B1-mediated m6A modification of lncRNAs contributes to non-small cell lung cancer (NSCLC).MethodsThe expression levels of HNRNPA2B1 and their association with the clinicopathological characteristics and prognosis in NSCLC were determined by RT-qPCR, Western blot, immunohistochemistry and TCGA dataset. Then, the role of HNRNPA2B1 in NSCLC cells was assessed by in vitro functional experiments and in vivo tumorigenesis and lung metastasis models. HNRNPA2B1-mediated m6A modification of lncRNAs was screened by m6A-lncRNA epi-transcriptomic microarray and verified by methylated RNA immunoprecipitation (Me-RIP). The lncRNA MEG3-specific binding with miR-21-5p was evaluated by luciferase gene report and RIP assays. The effects of HNRNPA2B1 and (or) lncRNA MEG3 on miR-21-5p/PTEN/PI3K/AKT signaling were examined by RT-qPCR and Western blot analyses.ResultsWe found that upregulation of HNRNPA2B1 was associated with distant metastasis and poor survival, representing an independent prognostic factor in patients with NSCLC. Knockdown of HNRNPA2B1 impaired cell proliferation and metastasis in vitro and in vivo, whereas ectopic expression of HNRNPA2B1 possessed the opposite effects. Mechanical investigations revealed that lncRNA MEG3 was an m6A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased MEG3 m6A levels but increased its mRNA levels. Furthermore, lncRNA MEG3 could act as a sponge of miR-21-5p to upregulate PTEN and inactivate PI3K/AKT signaling, leading to the suppression of cell proliferation and invasion. Low expression of lncRNA MEG3 or elevated expression of miR-21-5p indicated poor survival in patients with NSCLC.ConclusionsOur findings uncover that HNRNPA2B1-mediated m6A modification of lncRNA MEG3 promotes tumorigenesis and metastasis of NSCLC cells by regulating miR-21-5p/PTEN axis and may provide a therapeutic target for NSCLC.

Long non-coding RNAs as critical regulators and novel targets in cervical cancer: current status and future perspectives.

Cervical cancer is among the leading causes of cancer-associated mortality in women. In spite of vaccine availability, improved screening procedures, and chemoradiation therapy, cervical cancer remains the most commonly diagnosed cancer in 23 countries and the leading cause of cancer deaths in 36 countries. There is, therefore, a need to come up with novel diagnostic and therapeutic targets. Long non-coding RNAs (lncRNAs) play a remarkable role in genome regulation and contribute significantly to several developmental and disease pathways. The deregulation of lncRNAs is often observed in cancer patients, where they are shown to affect multiple cellular processes, including cell cycle, apoptosis, angiogenesis, and invasion. Many lncRNAs are found to be involved in the pathogenesis as well as progression of cervical cancer and have shown potency to track metastatic events. This review provides an overview of lncRNA mediated regulation of cervical carcinogenesis and highlights their potential as diagnostic and prognostic biomarkers as well as therapeutic targets for cervical cancer. In addition, it also discusses the challenges associated with the clinical implication of lncRNAs in cervical cancer.

LncTarD 2.0: an updated comprehensive database for experimentally-supported functional lncRNA-target regulations in human diseases.

An updated LncTarD 2.0 database provides a comprehensive resource on key lncRNA-target regulations, their influenced functions and lncRNA-mediated regulatory mechanisms in human diseases. LncTarD 2.0 is freely available at (http://bio-bigdata.hrbmu.edu.cn/LncTarD or https://lnctard.bio-database.com/). LncTarD 2.0 was updated with several new features, including (i) an increased number of disease-associated lncRNA entries, where the current release provides 8360 key lncRNA-target regulations, with 419 disease subtypes and 1355 lncRNAs; (ii) predicted 3312 out of 8360 lncRNA-target regulations as potential diagnostic or therapeutic biomarkers in circulating tumor cells (CTCs); (iii) addition of 536 new, experimentally supported lncRNA-target regulations that modulate properties of cancer stem cells; (iv) addition of an experimentally supported clinical application section of 2894 lncRNA-target regulations for potential clinical application. Importantly, LncTarD 2.0 provides RNA-seq/microarray and single-cell web tools for customizable analysis and visualization of lncRNA-target regulations in diseases. RNA-seq/microarray web tool was used to mining lncRNA-target regulations in both disease tissue samples and CTCs blood samples. The single-cell web tools provide single-cell lncRNA-target annotation from the perspectives of pan-cancer analysis and cancer-specific analysis at the single-cell level. LncTarD 2.0 will be a useful resource and mining tool for the investigation of the functions and mechanisms of lncRNA deregulation in human disease.

LncRNA deregulation in childhood acute lymphoblastic leukemia: A systematic review.

Childhood acute lymphoblastic leukemia (ALL), the most common pediatric cancer, is a heterogeneous disease comprised of multiple molecular subtypes with distinct somatic genetic alterations, which results in different outcomes for the patients. Accurate patient risk stratification through genetic markers could increase survival rates, but the identification of reliable biomarkers is needed, as 20‑30% of B‑ALL patients cannot be classified in the clinic with routine techniques and some patients classified as low‑risk and good‑responders to treatment will eventually relapse. Long non‑coding RNAs(lncRNAs) can represent novel candidates with diagnostic, classification, prognosis, and treatment response potential. However, regarding childhood ALL, there is inconsistency in the data reported due to the lack of a consensus nomenclature for lncRNA naming and the methodology and designing applied for their study. Therefore, the aim of the article is to clarify the potential of lncRNAs as biomarkers in childhood ALL through a systematic review. From a revision of 23 manuscripts, it was found that AWPPH overexpression could represent a novel marker for ALL diagnosis, including both B and Timmunophenotypes, and 18 lncRNAs were specifically associated with B‑cell ALL(B‑ALL) patients. We identified subtype‑specific signatures for ETV6‑RUNX1, hyperdiploidy and KMT2A subtypes. These signatures hold promise as novel diagnostic markers and could refine the classification of patients.

Down-regulation of long non-coding RNAs in reproductive aging and analysis of the lncRNA-miRNA-mRNA networks in human cumulus cells.

Long non-coding RNAs (lncRNAs) control gene expression at multiple levels. By interacting with microRNAs (miRNAs), they regulate their mRNA targets creating dynamic regulatory networks involved in different cellular processes. Their role in follicle development and oocyte maturation has recently emerged. lncRNA deregulation has been found associated with different pathological conditions. In this study, we identified differentially expressed lncRNAs in cumulus cells (CCs) isolated from MII oocytes of advanced maternal age women and proposed ceRNA-networks involved in signaling pathways crucial in ovarian folliculogenesis and female germ cell maturation. We performed a high-throughput analysis of the expression profile of 68 lncRNAs from CCs of aged and young women by using NanoString technology. By miRNet, TarPmiR, miRTarBase, OKdb, and KEGG we predicted some ceRNA-networks involving the differentially expressed (DE) lncRNAs, miRNA interactors, and their mRNA target genes. We identified 28 lncRNAs down-regulated in CC samples from aged women. The analysis revealed that the miRNAs binding 11 of the DE lncRNAs and their mRNA targets are included in ceRNA-networks involved in the regulation of the PI3K-Akt, FOXO, and p53 signaling pathways. We proposed that the lncRNA down-regulation in CCs from aged women could influence the expression of genes encoding proteins deregulated in reproductive aging. A better understanding of the interplay of lncRNA-miRNA-mRNA networks in human CCs could increase our knowledge about the mechanisms of regulation of gene expression involved in aging, lead to the development of novel therapeutics, and improve reproductive outcomes in aged women.

Aberrant expression of lncRNAs SNHG6, TRPM2-AS1, MIR4435-2HG, and hypomethylation of TRPM2-AS1 promoter in colorectal cancer.

Accumulating evidence has indicated that deregulation of lncRNAs plays essential roles in colorectal cancer (CRC) carcinogenesis. The goal of this study was to analyze the expression of lncRNAs in colorectal cancer and their association with clinicopathological variables. Bioinformatics analysis of published CRC microarray data was performed to identify the important lncRNAs. The expression levels of candidate genes were assessed in the human colon cancer/normal cell lines, CRC, adenomatous colorectal polyps, and their marginal tissues by qRT-PCR. Moreover, the methylation status of the TRPM2-AS1 promoter was studied using qMSP assay. Furthermore, we investigated the molecular mechanisms of these lncRNAs in CRC progression using in silico analysis. Microarray analysis revealed that lncRNAs SNHG6, MIR4435-2HG, and TRPM2-AS1 were upregulated in CRC. These results were validated in colon cell lines. Moreover, qRT-PCR showed that the expression levels of SNHG6 and TRPM2-AS1 were upregulated in the colorectal tumor tissues compared with their paired tissues. Nonetheless, there was no significant increase in MIR4435-2HG expression in CRC samples. Furthermore, we observed a significant hypomethylation of TRPM2-AS1 promoter and its activation in CRC tissues. By in silico analysis, we found that the lncRNAs upregulation could promote proliferation and drug resistance of colorectal cancer cells via miRNAs sponging and modulation of their targets expression. In conclusion, based on our results upregulation of SNHG6 and TRPM2-AS1, and hypomethylation of TRPM2-AS1 promoter might be considered as potential diagnostic biomarkers for CRC initiation and development.

The lncRNA TEX41 is upregulated in pediatric B-Cells Acute Lymphoblastic Leukemia and it is necessary for leukemic cell growth

BackgroundLong non-coding RNAs (lncRNAs) represent a diverse class of RNAs involved in the regulation of various physiological and pathological cellular processes, including transcription, intracellular trafficking, and chromosome remodeling. LncRNAs deregulation was linked to the development and progression of various cancer types, such as acute leukemias. In this context, lncRNAs were also evaluated as a novel class of biomarkers for cancer diagnosis and prognosis. Here, we analyzed TEX41 in childhood B cell acute lymphoid leukemia (B-ALL).MethodsTotal RNA was extracted from pediatric B-ALL patients (at diagnosis and after induction of therapy) and from healthy subjects. Total RNA was also extracted from different leukemia cell line models. The expression level of TEX41 was evaluated by q-RT-PCR. Also, the dataset deposited by St. Jude Children’s Research Hospital was consulted. Furthermore, the silencing of TEX41 in RS4;11 cell line was obtained by 2′-Deoxy, 2′Fluroarabino Nucleic Acids (2′F-ANAs) Oligonucleotides, and the effect on cell proliferation was evaluated. Cell cycle progression and its regulators were analyzed by flow cytometry and immunoblotting.ResultsWe exploited the St Jude Cloud database and found that TEX41 is a lncRNA primarily expressed in the case of B-ALL (n = 79) while its expression levels are low/absent for T-cell ALL (n = 25) and acute myeloid leukemia (n = 38). The association of TEX41 with B-ALL was confirmed by real-time PCR assays. TEX41 disclosed increased expression levels in bone marrow from patients with B-ALL at diagnosis, while its expression levels became low or absent when retested in Bone Marrow cells of the same patient after 1 month of induction therapy. Also, silencing experiments performed on RS4;11 cells showed that TEX41 downregulation impaired in vitro leukemic cell growth determining their arrest in the G2-M phase and the deregulation of cell cycle proteins.ConclusionsOur findings highlight that TEX41 is an upregulated lncRNA in the case of B-ALL and this feature makes it a novel potential biomarker for the diagnosis of this leukemia subtype in pediatric patients. Finally, TEX41 expression seems to be critical for leukemic proliferation, indeed, silencing experiments targeting TEX41 mRNA in the RS4;11 cell line hampered in vitro cell growth and cell cycle progression, by inducing G2-M arrest as confirmed propidium iodide staining and by the upregulation of p53 and p21 proteins.

Abnormal Expression Of WT1-As, MEG3 and ANRIL Long Non-Coding RNAs In Primary Myelofibrosis and Their Clinical Correlates

A growing body of evidence suggests that long non-coding RNAs (lncRNAs) are involved in the regulation of gene expression in normal and cancer cells by recruiting chromatin remodeling complexes to specific genomic loci [Rinn JL, et al. Cell. 2007; Mattick JS, et al. Bioessays 2009]. For this reason, lncRNAs deregulation can play key roles in malignant transformation and cancer cell behavior. [Kogo R, et al. Cancer Res 2011; Yang F, et al. Hepatology 2011].Despite the increasing number of studies on lncRNAs expression and their involvement in some solid tumors, lncRNAs are far from being extensively characterized in malignant hematopoiesis [Heuston EF, Front Genet 2011]. In particular, lncRNAs expression has never been investigated in cells from primary myelofibrosis (PMF) patients.PMF is a Philadelphia negative chronic Myeloproliferative Neoplasm (MPN) that originates from deregulated clonal proliferation of hematopoietic stem cell associated with overproduction of mature blood cells. Molecular mechanisms underlying MPN pathogenesis were partially unraveled in 2005-2006 with the identification of somatic gain-of-function mutations of JAK2 [James C, et al. Nature 2005; Kralovics R, et al. N Engl J Med 2005; Levine RL, et al. Cancer Cell 2005] and MPL [Pardanani AD, et al. Blood 2006] after which many other mutations were identified. Recently, several new molecular pathogenetic mechanisms were proposed, such as the aberrant expression of coding and non-coding RNAs.After extensive screening of the long non-coding RNA database (lncRNAdb), which is a database providing comprehensive annotations of eukaryotic lncRNAs (http://www.lncrnadb.org) [Amaral PP, Nucleic Acids Res 2011], we identified some previously described lncRNAs as potentially involved in hematological malignancies, such as CDKN2B-antisense (ANRIL), MEG3 and WT1-antisense lncRNAs.With the aim to describe possible abnormalities of lncRNAs in MPN, we investigated the expression of those lncRNAs in CD34+ cells from PMF patients. Since the perturbation of the antisense RNA could alter the expression of the sense gene, we also analyzed the expression of the ANRIL and WT1-as coding genes, called CDKN2B and WT1, to evaluate the correlation of each sense/antisense couple.This study included a total of 26 PMF patients and 16 healthy donors. The diagnosis of PMF was made according to World Health Organization (WHO) criteria.The results evidenced that the majority of PMF samples (74%) displayed a co-upregulation of WT1 and its antisense RNA compared to healthy controls. We found that the large part (61%) of patients harboring concordant upregulation of WT1 sense and antisense belongs to the intermediate-2 and high risk categories of DIPSS-plus scoring system (57.4% and 43.1% in the intermediate-1 and -2, respectively versus 0% in the high-risk category; P = .006) and presents low Hb level, higher percentage of circulating CD34+ cells and a blast count > 1% .Noteworthy, almost 90% of patients with increased expression of WT1 and its antisense showed concurrent upregulation of MEG3 and shared the same clinical variables associated with poor outcome. In fact, also patients harboring higher levels of MEG3 cluster in higher DIPSS-plus scoring system categories, suffer from anemia, have high levels of circulating CD34+ cells and a blast count >1%. These data suggest that not only high levels of WT1-as we previously described [Guglielmelli P, Stem Cells 2007], but also its antisense and MEG3 could identify PMF patients with more severe disease.Finally, we could observe a correlation between CDKN2B upregulation and the grade of BM fibrosis. In fact, the majority of samples having CDKN2B upregulation clustered in categories 2 and 3 (87.3%) as compared to only 4.5% in case of samples showing CDKN2B downregulation (P = .043). Noteworthy, 82% of patients overexpressing CDKN2B were JAK2V617F positive as compared to 22.1% among those with CDKN2B downregulation (P = .004)To our knowledge, this is the first study describing the expression profiles of human lncRNAs in CD34+ cells of PMF patients. Our data demonstrate that WT1-as, MEG3 and ANRIL lncRNAs are aberrantly expressed in PMF CD34+ cells compared to healthy controls. Moreover, different patterns of expression are correlated with some patient' clinical features. Therefore, our results suggest that a deregulated expression of these lncRNAs could play a role in PMF pathogenesis and progression. Disclosures:No relevant conflicts of interest to declare.

The Role of lncRNAs in the Pathobiology and Clinical Behavior of Multiple Myeloma.

Simple SummaryMultiple myeloma (MM), the second most common hematological neoplasm, is still considered an incurable disease. Long non-coding RNAs (lncRNAs), genes that do not encode proteins, participate in numerous biological processes, but their deregulation, like that of coding genes, can contribute to carcinogenesis. Increasing evidence points to the relevant role of lncRNAs in the development of human tumors, such that they emerge as attractive biomarkers and therapeutic targets for cancer treatment, including MM. Here we review the oncogenic or tumor-suppressor functions of lncRNAs in MM and provide an overview of novel therapeutic approaches based on lncRNAs that will help to improve the management of these patients.MM is a hematological neoplasm that is still considered an incurable disease. Besides established genetic alterations, recent studies have shown that MM pathogenesis is also characterized by epigenetic aberrations, such as the gain of de novo active chromatin marks in promoter and enhancer regions and extensive DNA hypomethylation of intergenic regions, highlighting the relevance of these non-coding genomic regions. A recent study described how long non-coding RNAs (lncRNAs) correspond to 82% of the MM transcriptome and an increasing number of studies have demonstrated the importance of deregulation of lncRNAs in MM. In this review we focus on the deregulated lncRNAs in MM, including their biological or functional mechanisms, their role as biomarkers to improve the prognosis and monitoring of MM patients, and their participation in drug resistance. Furthermore, we also discuss the evidence supporting the role of lncRNAs as therapeutic targets through different novel RNA-based strategies.

Long non-coding RNAs in castration-resistant and neuroendocrine prostate cancer: Potential role and therapeutic impact

Prostate cancer is the most commonly diagnosed malignancy and leading cause of cancer-related deaths in men worldwide. The disease is heterogeneous in nature exhibiting various clinical subtypes and genetic/transcriptomic features. Long non-coding RNAs (lncRNAs) are transcripts of more than 200 nucleotides that does not encode any protein and play important role in several biological processes as well as pathologic states. Deregulation of lncRNAs has been associated with human diseases. In prostate cancer, numerous key lncRNAs have been identified as novel players that contribute to the pathophysiology of the disease primarily regulated by androgen and its cognate receptor. The present review attempts to summarize the potential role of lncRNA and their mechanisms of action in prostate cancer with particular focus on lncRNAs regulated by androgen receptor expressed in castration-resistant and neuroendocrine differentiated subtypes. We also emphasize the potential of these lncRNAs for their development as therapeutic targets in prostate cancer.

The oncogenic role of LncRNA FAM83C-AS1 in colorectal cancer development by epigenetically inhibits SEMA3F via stabilizing EZH2.

Inactivation of Semaphorin 3F (SEMA3F) is involved in colorectal cancer development. However, the mechanism by which SEMA3F is regulated remains elusive. Deregulation of lncRNAs have been implicated in multiple human malignancies, including colorectal cancer (CRC). To date, it is still unclear whether and how lncRNA regulates SEMA3F expression and mediates CRC progression. Here we identify the oncogenic role of lncRNA FAM83C antisense RNA 1 (FAM83C-AS1) in CRC. FAM83C-AS1 is upregulated in tumor tissues and cells of CRC, which is negatively correlated with SEMA3F expression. Reciprocally, knockdown of FAM83C-AS1 exhibits inhibitory effects on the malignant transformation of CRC. Moreover, our data uncover that FAM83C-AS1 enhances methylation of SEMA3F promoter H3K27me3 via upregulating methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). Specifically, FAM83C-AS1 stabilizes EZH2 protein through recruiting the zinc finger RANBP2-type containing 1 (ZRANB1). Both in vitro and in vivo rescue assays exhibit that SEMA3F is dispensable for the tumor-promoting effects of FAM83C-AS1 on CRC progression. Our data thus demonstrate that the epigenetic role of FAM83C-AS1 in suppression of SEMA3F expression through stabilization of EZH2 to drive CRC progression, which may be conducive to discovering novel therapeutic targets for the treatment of CRC.

The expression patterns of NBAT1 and CASC15 are associated with colorectal cancer

LncRNAs are non-coding RNAs with more than 200 nucleotides which are critical regulators of gene expression in human diseases. LncRNAs deregulation is described in several diseases such as cancer and they can be used as a diagnostic or prognostic biomarkers. Previous research showed that lncRNAs CASC15 and NBAT1 is related to the biological behaviors of several cancers. Here, we aimed to explore in detail the expression profiles of CASC15 and NBAT1 in colorectal tumor tissues. In this study, NBAT1 and CASC15 LncRNAs were selected according to review literature and their expression levels were compared in 75 colorectal cancer (CRC) and adjacent normal tissues using RT-qPCR. Moreover, the expression of these genes assessed in TCGA-COA database. ROC curve analysis was performed to examine the diagnostic capacity of mentioned lncRNAs. Our results showed that the expression level of both CASC15 and NBAT1 increased significantly in tumor tissue compared to their normal tissue. The TCGA data verified high expression of these genes in CRC. The area under the curve (AUC) for CASC15 and NBAT1 were 0.879 and 0.6371 respectively. Additionally, CASC15 expression, but not NBAT1, was reduced significantly in patients under 65 years old in comparison to over 65 years old. In summary, although, CASC15 and NBAT1expression increased significantly in human CRC samples, only CASC15 suggested as a good biomarker for CRC diagnosis.

The Oncosuppressors MEN1 and CDC73 Are Involved in lncRNA Deregulation in Human Parathyroid Tumors.

A role for long non-coding RNAs (lncRNAs) in endocrine cancer pathogenesis is emerging. However, knowledge regarding their expression pattern, correlation with known genetic defects, and clinical implications in parathyroid tumors is still unclear. Here, we profiled 90 known lncRNAs in a first series of normal (PaN = 2), adenomatous (PAd = 12), and carcinomatous (PCa = 4) parathyroid glands and we confirmed deregulation of 11 lncRNAs using an independent cohort of patients (PaN = 4; PAd = 26; PCa = 9). Expression of lncRNAs was correlated with cytogenetic aberrations, status of genes multiple endocrine neoplasia 1 (MEN1) and cell division cycle 73 (CDC73), or clinical features. Globally, lncRNAs discriminate according to tissue histology. BC200 consistently identifies parathyroid cancers from adenomas and atypical adenomas. Loss-of-heterozygosity (LOH) at chromosomes 1, 11, 15, 21, and 22 significantly impacts expression of lncRNAs in PAds. Silencing of the key parathyroid gene MEN1 modulates the expression of six lncRNAs in primary PAds-derived cultures. Analogous levels of lncRNAs are measured in PAds with the mutation in the MEN1 gene compared with PAds with wild-type MEN1. Similarly, carcinomas with mutated CDC73 differ from PCas with wild-type protein in terms of expression of lncRNAs. PCas harboring CDC73 mutations overexpress BC200 compared to wild-type carcinomas. Overall, these findings shed light on deregulation of lncRNAs in human parathyroid tumors and propose that circuits between lncRNAs and the oncosuppressors MEN1 or CDC73 may have a role in parathyroid tumorigenesis as epigenetic modulators. © 2020 American Society for Bone and Mineral Research (ASBMR).

Comparative analyses of long non-coding RNA profiles in vivo in cystic fibrosis lung airway and parenchyma tissues

BackgroundRecent advances in the functional analyses of endogenous non-coding RNA (ncRNA) molecules, including long non-coding RNAs (LncRNAs), have provided a new perspective on the crucial roles of RNA in gene regulation. Consequently, LncRNA deregulation is a key factor in various diseases, including pulmonary disorders like Cystic Fibrosis (CF). CF is the most common life limiting recessive disease in the U.S., and is due to mutations in the CFTR gene. CF mutations, of which the most common is F508del-CFTR, prevents correct folding, trafficking and function of the mutant CFTR protein and is further manifested by the hyper-expression of pro-inflammatory cytokines and chemokines into the airway lumen leading to bronchiectasis and culminating in lung destruction.MethodsHere we report a distinct LncRNA signature and corresponding mRNAs that distinguishes CF lung (airway and parenchyma) tissues from matched non-CF controls (n = 4 each group), generated by microarray specific for LncRNAs which includes corresponding mRNA expressions. In silico analyses of the cellular processes that are impacted by these LncRNAs was performed using Gene Ontology (GO). A selected subset of LncRNAs were validated by quantitative real-time PCR.ResultsWe have identified 636 LncRNAs differentially expressed in CF airway epithelium and 1974 in CF lung parenchyma compared to matched non-CF controls (fold change ≥2, p < 0.05), majority of which (> 50%) are intergenic. Interestingly, 15 of these differentially expressed LncRNAs and 9 coding mRNAs are common to airway and parenchyma tissues. GO analyses indicates that signaling pathways and cell membrane functions are significantly affected by the alteration in LncRNA expressions in CF lung tissues. Seven of the differentially expressed LncRNAs, exhibit similar expression trends in CFBE41o- compared to control cells.ConclusionUnderstanding the mechanisms by which these LncRNAs regulate CF disease phenotype will help develop novel therapeutic targets for CF and related pulmonary diseases, such as COPD and Asthma.