Intergenic Non-coding RNAs Research Articles

Linc-RAM is a metabolic regulator maintaining whole-body energy homeostasis in mice.

Long noncoding RNAs (lncRNAs) are known to have profound functions in regulating cell fate specification, cell differentiation, organogenesis, and disease, but their physiological roles in controlling cellular metabolism and whole-body metabolic homeostasis are less well understood. We previously identified a skeletal muscle-specific long intergenic noncoding RNA (linc-RNA) activator of myogenesis, Linc-RAM, which enhances muscle cell differentiation during development and regeneration. Here, we report that Linc-RAM exerts a physiological function in regulating skeletal muscle metabolism and the basal metabolic rate to maintain whole-body metabolic homeostasis. We first demonstrate that Linc-RAM is preferentially expressed in type-II enriched glycolytic myofibers, in which its level is more than 60-fold higher compared to that in differentiated myotubes. Consistently, genetic deletion of the Linc-RAM gene in mice increases the expression levels of genes encoding oxidative fiber versions of myosin heavy chains and decreases those of genes encoding rate-limiting enzymes for glycolytic metabolism. Physiologically, Linc-RAM-knockout mice exhibit a higher basal metabolic rate, elevated insulin sensitivity and reduced fat deposition compared to their wild-type littermates. Together, our findings indicate that Linc-RAM is a metabolic regulator of skeletal muscle metabolism and may represent a potential pharmaceutical target for preventing and/or treating metabolic diseases, including obesity.

M6A-modified lincRNA Dubr is required for neuronal development by stabilizing YTHDF1/3 and facilitating mRNA translation.

Long intergenic noncoding RNAs (lincRNAs) are crucial regulators in numerous biological processes. However, the functions and mechanisms of m6A-modified lincRNAs in neuronal development remain unclear. Here, we report an m6A-modified lincRNA, Dppa2 upstream binding RNA (Dubr), abundantly expressed at the early developmental stage of dorsal root ganglion (DRG) and cerebral cortex. Silencing Dubr impairs axon elongation of DRG neurons and axon projection and migration of cortical neurons, whereas lacking m6A modification of Dubr fully loses its functions. Mechanically, Dubr interacts with m6A-binding proteins, the YTHDF1/3 complex, through its m6A motifs to protect YTHDF1/3 from degradation via the proteasome pathway. Furthermore, Tau and Calmodulin are regulated by YTHDF1/3 and m6A-modified Dubr. Overexpression of YTHDF1/3 not only rescues the reduced Tau and Calmodulin but also restores axon elongation of DRG neurons by Dubr knockdown. This study uncovers a critical role of m6A-modified lincRNA in neuronal development by regulating the degradation of RNA-binding protein.

Role of Long Intergenic Noncoding RNAs in Cancers with an Overview of MicroRNA Binding.

Long intergenic noncoding RNAs are transcripts originating from the regions without annotated coding genes. They are located mainly in the nucleus and regulate gene expression. Long intergenic noncoding RNAs can be also found in the cytoplasm acting as molecular sponges of certain microRNAs. This is crucial in various biological and signaling pathways. Expression levels of many long intergenic noncoding RNAs are disease related. In this article, we focus on the long intergenic noncoding RNAs and their relation to different types of cancer. Studies showed that abnormal expression of long intergenic noncoding RNA deregulates signaling pathways due to the disrupted free microRNA pool. Hampered signaling pathways leads to abnormal cell proliferation and restricts cell death, thus resulting in oncogenesis. This review highlights promising therapeutic targets and enables the identification of potential biomarkers specific for a certain type of cancer. Moreover, we provide an outline of long intergenic noncoding RNAs/microRNA axes, which might be applied in further detailed experiments broadening our knowledge about the cellular role of those RNA species.

Silencing LINC01234 represses pancreatic cancer progression by inhibiting the malignant phenotypes of pancreatic cancer cells

ObjectivePrevious works have outlined the pivotal involvement of long intergenic non-coding RNA (lincRNA) in cancer progression, while the efficiency of LINC01234 in pancreatic cancer remained obscure. The purpose of this research is to unravel the regulatory mechanism of LINC01234 in pancreatic cancer via modulating microRNA (miR)-513a-3p and hexose 6-phosphate dehydrogenase (H6PD). MethodsPancreatic cancer cells were cultured and clinical tissue specimens were collected. LINC01234, miR-513a-3p and H6PD levels in pancreatic cancer cells and tissues were examined. Plasmids altering LINC01234, miR-513a-3p and H6PD expression were transfected into pancreatic cancer cells to assess the change in biological behaviors of pancreatic cancer cells. The targeting relations among LINC01234, miR-513a-3p and H6PD were validated. ResultsLINC01234 and H6PD levels were elevated while miR-513a-3p level was reduced in pancreatic cancer cells and tissues. LINC01234 deficiency hindered the malignant biological activities of pancreatic cancer cells. MiR-513a-3p depletion or H6PD elevation could abrogate the inhibitory effects of LINC01234 silencing on pancreatic cancer cells. LINC01234 sponged miR-513a-3p that targeted H6PD. ConclusionThe reduced LINC01234 exerts inhibitory impacts on pancreatic cancer cells via targeting miR-513a-3p to restrain H6PD level. The current study broadens the understanding of LINC01234 function and affords novel therapeutic targets for pancreatic cancer treatment.

A long noncoding RNA HILinc1 enhances pear thermotolerance by stabilizing PbHILT1 transcripts through complementary base pairing

As global warming intensifies, heat stress has become a major environmental constraint threatening crop production and quality worldwide. Here, we characterize Heat-induced long intergenic noncoding RNA 1 (HILinc1), a cytoplasm-enriched lincRNA that plays a key role in thermotolerance regulation of pear (Pyrus spp.). HILinc1 Target 1 (PbHILT1) which is the target transcript of HILinc1, was stabilized via complementary base pairing to upregulate its expression. PbHILT1 could bind to Heat shock transcription factor A1b (PbHSFA1b) to enhance its transcriptional activity, leading to the upregulation of a major downstream transcriptional regulator, Multiprotein bridging factor 1c (PbMBF1c), during heat response. Transient overexpressing of either HILinc1 or PbHILT1 increases thermotolerance in pear, while transient silencing of HILinc1 or PbHILT1 makes pear plants more heat sensitive. These findings provide evidences for a new regulatory mechanism by which HILinc1 facilitates PbHSFA1b activity and enhances pear thermotolerance through stabilizing PbHILT1 transcripts.

Genetic Polymorphisms of lncRNA LINC00673 as Predictors of Hepatocellular Carcinoma Progression in an Elderly Population.

Long noncoding (lnc)RNAs are reported to be key regulators of tumor progression, including hepatocellular carcinoma (HCC). The lncRNA long intergenic noncoding RNA 00673 (LINC00673) was indicated to play an important role in HCC progression, but the impacts of genetic variants (single-nucleotide polymorphisms, SNPs) of LINC00673 on HCC remain unclear. A TaqMan allelic discrimination assay was performed to analyze the genotypes of three tagging SNPs, viz., rs9914618 G > A, rs6501551 A > G, and rs11655237 C > T, of LINC00673 in 783 HCC patients and 1197 healthy subjects. Associations of functional SNPs of LINC00673 with HCC susceptibility and clinicopathologic variables were analyzed by logistic regression models. After stratification by confounding factor, we observed that elderly patients (≥60 years) with the LINC00673 rs9914618 A allele had an increased risk of developing HCC under a codominant model (p = 0.025) and dominant model (p = 0.047). Moreover, elderly patients carrying the GA + AA genotype of rs9914618 exhibited a higher risk of having lymph node metastasis compared to those who were homozygous for the major allele (p = 0.013). Genotype screening of rs9914618 in HCC cell lines showed that cells carrying the AA genotype expressed higher LINC00673 levels compared to the cells carrying the GG genotype. Further analyses of clinical datasets from the Cancer Genome Atlas (TCGA) showed that LINC00673 expressions were upregulated in HCC tissues compared to normal tissues, and were correlated with advanced clinical stages and poorer prognoses. In conclusions, our results suggested that the LINC00673 rs9914618 polymorphism may be a promising HCC biomarker, especially in elderly populations.

Cancer-Derived Extracellular Vesicles as Biomarkers for Cutaneous Squamous Cell Carcinoma: A Systematic Review.

Simple SummaryBiomarkers including DNA, RNA, and surface-associated proteins in tumor-derived extracellular vesicles promote accurate clinical diagnosis and indicate the prognosis of cancer. In this systematic review, pre-clinical and clinical studies on extracellular vesicles derived from cutaneous squamous cell carcinoma (cSCC-derived EVs) were summarized, for which studies on the genomics, transcriptomics, and proteomics of cSCC-derived EVs were highlighted. The contents in cSCC-derived EVs may reflect the mutational landscape of the original cancer cells or be selectively enriched in extracellular vesicles, as provided by the significant role of target molecules including desmoglein 2 protein (Dsg2), Ct-SLCO1B3 mRNA, CYP24A1 circular RNA (circRNA), long intergenic non-coding RNA (linc-PICSAR) and DNA Copy Number Alteration (CNA). Evidence of these studies implied the diagnostic and therapeutic potential of cSCC-derived EVs for cutaneous squamous cell carcinoma.Cutaneous squamous cell carcinoma (cSCC) as one of the most prevalent cancers worldwide is associated with significant morbidity and mortality. Full-body skin exam and biopsy is the gold standard for cSCC diagnosis, but it is not always feasible given constraints on time and costs. Furthermore, biopsy fails to reflect the dynamic changes in tumor genomes, which challenges long-term medical treatment in patients with advanced diseases. Extracellular vesicle (EV) is an emerging biological entity in oncology with versatile clinical applications from screening to treatment. In this systematic review, pre-clinical and clinical studies on cSCC-derived EVs were summarized. Seven studies on the genomics, transcriptomics, and proteomics of cSCC-derived EVs were identified. The contents in cSCC-derived EVs may reflect the mutational landscape of the original cancer cells or be selectively enriched in EVs. Desmoglein 2 protein (Dsg2) is an important molecule in the biogenesis of cSCC-derived EVs. Ct-SLCO1B3 mRNA, and CYP24A1 circular RNA (circRNA) are enriched in cSCC-derived EVs, suggesting potentials in cSCC screening and diagnosis. p38 inhibited cSCC-associated long intergenic non-coding RNA (linc-PICSAR) and Dsg2 involved in EV-mediated tumor invasion and drug resistance served as prognostic and therapeutic predictors. We also proposed future directions to devise EV-based cSCC treatment based on these molecules and preliminary studies in other cancers.

Epigenetic regulation of LINC01270 in breast cancer progression by mediating LAMA2 promoter methylation and MAPK signaling pathway.

Application of long non-coding RNAs (lncRNAs) for modulation of breast cancer (BC) has attracted much attention. Here, we probed into the role and underlying mechanism of long intergenic non-coding RNA 01270 (LINC01270) in BC. With the help of bioinformatics tools, we identified laminin subunit alpha 2 (LAMA2) as a BC-related differentially expressed gene to discern the effect of LAMA2 in BC cells. LAMA2 was initially poorly expressed while LINC01270 was highly expressed in BC. BC cells were subsequently treated with sh-LINC01270 or/and sh-LAMA2 for exploration of their regulatory mechanism in BC, which unfolded that LINC01270 inhibition up-regulated LAMA2 and inactivated the MAPK signaling pathway to suppress malignant characteristics of BC cells. Functional assays demonstrated that LINC01270 bound to DNMT1, DNMT3a, and DNMT3b promoted the methylation of CpG islands in LAMA2 promoter and inhibited the LAMA2 expression. Moreover, our data suggested that LAMA2 suppressed MAPK signaling pathway to inhibit BC cell malignant characteristics. The in vitro results were re-produced with the help of the in vivo experimentations. In conclusion, LINC01270 silencing inhibited the methylation of LAMA2 promoter to suppress the activation of MAPK signaling pathway, which subsequently restrained the BC progression. 1, Overexpression of LAMA2 inhibits malignant features of BC cells. 2, LINC01270 promotes LAMA2 promoter methylation by recruiting DNMTs to the LAMA2 promoter region. 3, 5-aza-dc reverses the promotion of LAMA2 promoter methylation by LINC01270. 4, LAMA2 inhibits malignant features of BC cells by suppressing the activation of MAPK signaling pathway.

Overexpression of LINC00551 promotes autophagy-dependent ferroptosis of lung adenocarcinoma via upregulating DDIT4 by sponging miR-4328.

According to mounting evidence, long noncoding RNAs (lncRNAs) play a vital role in regulated cell death (RCD). A potential strategy for cancer therapy involves triggering ferroptosis, a novel form of RCD. Although it is thought to be an autophagy-dependent process, it is still unclear how the two processes interact. This study characterized a long intergenic noncoding RNA, LINC00551, expressed at a low level in lung adenocarcinoma (LUAD) and some other cancers. Overexpression of LINC00551 suppresses cell viability while promoting autophagy and RSL-3-induced ferroptosis in LUAD cells. LINC00551 acts as a competing endogenous RNA (ceRNA) and binds with miR-4328 which up-regulates the target DNA damage-inducible transcript 4 (DDIT4). DDIT4 inhibits the activity of mTOR, promotes LUAD autophagy, and then promotes the ferroptosis of LUAD cells in an autophagy-dependent manner. This study provided an insight into the molecular mechanism regulating ferroptosis and highlighted LINC00551 as a potential therapeutic target for LUAD.

Tumor-derived exosomal lincRNA ROR promotes angiogenesis in nasopharyngeal carcinoma

Long intergenic noncoding RNAs (lincRNAs) are expressed aberrantly in several malignancies, including nasopharyngeal carcinoma (NPC), where linc-ROR expression was found to be elevated. Being a hallmark of malignant tumors, angiogenesis has prompted us to investigate the impact of linc-ROR on NPC angiogenesis. This study demonstrates that linc-ROR is substantially expressed in serum exosomes from NPC and can be taken up by HUVECs. Using qRT-PCR, the CCK8 test, the transwell migration assay, the wound healing assay, and the tube formation assay, we demonstrated that linc-ROR increases proliferation, migration, and angiogenesis in vitro. Similar to prior research, our results have shown that linc-ROR can stimulate tumor angiogenesis in the zebrafish model. Thus, the p-AKT/p-VEGFR2 pathway is the mechanism by which linc-ROR affects the aforementioned biological activities. By stimulating angiogenesis, linc-ROR appears to play a significant role in the course of NPC and could account for a therapeutic target.

A high-throughput approach to predict A-to-I effects on RNA structure indicates a change of double-stranded content in noncoding RNAs.

RNA molecules undergo a number of chemical modifications whose effects can alter their structure and molecular interactions. Previous studies have shown that RNA editing can impact the formation of ribonucleoprotein complexes and influence the assembly of membrane-less organelles such as stress granules. For instance, N6-methyladenosine (m6A) enhances SG formation and N1-methyladenosine (m1A) prevents their transition to solid-like aggregates. Yet, very little is known about adenosine to inosine (A-to-I) modification that is very abundant in human cells and not only impacts mRNAs but also noncoding RNAs. Here, we introduce the CROSSalive predictor of A-to-I effects on RNA structure based on high-throughput in-cell experiments. Our method shows an accuracy of 90% in predicting the single and double-stranded content of transcripts and identifies a general enrichment of double-stranded regions caused by A-to-I in long intergenic noncoding RNAs (lincRNAs). For the individual cases of NEAT1, NORAD, and XIST, we investigated the relationship between A-to-I editing and interactions with RNA-binding proteins using available CLIP data and catRAPID predictions. We found that A-to-I editing is linked to the alteration of interaction sites with proteins involved in phase separation, which suggests that RNP assembly can be influenced by A-to-I. CROSSalive is available at http://service.tartaglialab.com/new_submission/crossalive.

LincRNAs and snoRNAs in Breast Cancer Cell Metastasis: The Unknown Players.

Simple SummaryRecent advances in research have led to earlier diagnosis and more targeted therapies against breast cancer, which has reduced breast cancer related mortality. However, the majority of breast cancer-related deaths are due to metastasis of cancer cells to other sites of the body, a process that has not been fully elucidated. Among the many factors and genes implicated in the regulation of the metastatic process, RNAs that do not code for a specific protein (non-coding RNAs) are emerging as crucial players. This review focuses on the role of long intergenic noncoding RNAs (lincRNAs) and small nucleolar RNAs (snoRNAs) in breast cancer cell metastasis. Both are subclasses of non-coding RNAs that function as regulatory molecules in processes such as cell proliferation, apoptosis, epithelial-to-mesenchymal transition, migration, and invasion, all of which are severely disrupted in aggressive cancer cells that are able to form metastasis in distal sites. In the current review, we identify the most important lincRNAs and snoRNAs that have been recently associated with breast cancer metastasis both through in vitro and in vivo experiments.Recent advances in research have led to earlier diagnosis and targeted therapies against breast cancer, which has resulted in reduced breast cancer-related mortality. However, the majority of breast cancer-related deaths are due to metastasis of cancer cells to other organs, a process that has not been fully elucidated. Among the factors and genes implicated in the metastatic process regulation, non-coding RNAs have emerged as crucial players. This review focuses on the role of long intergenic noncoding RNAs (lincRNAs) and small nucleolar RNAs (snoRNAs) in breast cancer cell metastasis. LincRNAs are transcribed between two protein-coding genes and are longer than 200 nucleotides, they do not code for a specific protein but function as regulatory molecules in processes such as cell proliferation, apoptosis, epithelial-to-mesenchymal transition, migration, and invasion while most of them are highly elevated in breast cancer tissues and seem to function as competing endogenous RNAs (ceRNAs) inhibiting relevant miRNAs that specifically target vital metastasis-related genes. Similarly, snoRNAs are 60–300 nucleotides long and are found in the nucleolus being responsible for the post-transcriptional modification of ribosomal and spliceosomal RNAs. Most snoRNAs are hosted inside intron sequences of protein-coding and non-protein-coding genes, and they also regulate metastasis-related genes affecting related cellular properties.

Allelic expression imbalance in articular cartilage and subchondral bone refined genome-wide association signals in osteoarthritis.

To present an unbiased approach to identify positional transcript single nucleotide polymorphisms (SNPs) of osteoarthritis (OA) risk loci by allelic expression imbalance (AEI) analyses using RNA sequencing of articular cartilage and subchondral bone from OA patients. RNA sequencing from 65 articular cartilage and 24 subchondral bone from OA patients was used for AEI analysis. AEI was determined for all genes present in the 100 regions reported by the genome-wide association studies (GWAS) catalog that were also expressed in cartilage or bone. The count fraction of the alternative allele (φ) was calculated for each heterozygous individual with the risk SNP or with the SNP in linkage disequilibrium (LD) with it (r2 > 0.6). Furthermore, a meta-analysis was performed to generate a meta-φ (null hypothesis median φ = 0.49) and P-value for each SNP. We identified 30 transcript SNPs (28 in cartilage and two in subchondral bone) subject to AEI in 29 genes. Notably, 10 transcript SNPs were located in genes not previously reported in the GWAS catalog, including two long intergenic non-coding RNAs (lincRNAs), MALAT1 (meta-φ = 0.54, FDR = 1.7×10-4) and ILF3-DT (meta-φ = 0.6, FDR = 1.75×10-5). Moreover, 12 drugs were interacting with seven genes displaying AEI, of which seven drugs have been already approved. By prioritizing proxy transcript SNPs that mark AEI in cartilage and/or subchondral bone at loci harbouring GWAS signals, we present an unbiased approach to identify the most likely functional OA risk-SNP and gene. We identified 10 new potential OA risk genes ready for further translation towards underlying biological mechanisms.

LINC00665 affects the malignant biological behavior of ovarian cancer via the miR-148b-3p/KLF5

This study investigated the expression and clinical significance of long intergenic noncoding RNA 00665 (LINC00665) in ovarian cancer (OC), as well as its effect on the malignant biological behavior of OC cells. The expression of LINC00665, miR-148b-3p, and Krüppel-like factor 5 (KLF5) in OC tissues and cells were determined by RT-qPCR. Western blot was used to detect the protein expression of KLF5. The expression patterns of LINC00665 in nuclear and cytoplasm fractions were undertaken using RT-qPCR. In addition, CCK-8 assay, clone formation assay, transwell, scratch test, and flow cytometry were respectively used to detect the cell activity, proliferation, invasiveness, healing of cells, and apoptosis rate of OC cells. Furthermore, the interactions between LINC00665 and miR-148b-3p and between miR-148b-3p and KLF5 were verified by the luciferase reporter assay, and the correlations among these three genes were analyzed. LINC00665 expression was upregulated both in OC cell lines and tissues. Si-LINC00665 inhibited cell proliferation, invasion, and migration and induced apoptosis to a certain extent. The subcellular fraction assay revealed LINC00665 to be located mainly in the cytoplasm. miR-148b-3p was a target of LINC00665, and KLF5 was directly targeted by miR-148b-3p. Si-LINC00665 inhibited KLF5 expression, miR-148b-3p inhibitor promoted KLF5 expression, and si-KLF5 inhibited LINC00665 expression. Interestingly, the expression of LINC00665 was reversely associated with miR-148b-3p expression but positively correlated with KLF5. Furthermore, miR-148b-3p expression was negatively correlated with KLF5. In addition, si-KLF5 inhibited the malignant biological behavior of OC cells, whereas miR-148b-3p inhibitor had the opposite effect. Most importantly, the si-LINC00665 could reverse the promotion effect of the miR-148b-3p inhibitor on the malignant biological behavior of OC cells. LINC00665 can be used as an effective prognostic indicator of OC, which has the potential to be a new therapeutic target.

Regulator of G Protein Signaling 20 Correlates with Long Intergenic Non-Coding RNA (lincRNAs) Harboring Oncogenic Potential and Is Markedly Upregulated in Hepatocellular Carcinoma.

Simple SummaryClinical and molecular advances have improved knowledge and treatment prospects for cancer, yet hepatocellular carcinoma (HCC), the most common form of liver cancer, still ranks significantly higher in terms of the global cancer burden. Herein, we investigated the role of RGS20 as a potential prognostic marker in 28 different cancers with a particular focus on HCC.Hepatocellular carcinoma (HCC) is at the forefront of the global cancer burden, and biomarkers for HCC are constantly being sought. Interestingly, RGS (Regulators of G protein signaling) proteins, which negatively regulate GPCR signaling, have been associated with various cancers, with some members of the RGS family being associated with liver cancer as well. Considering this, we investigated the role of RGS20 as a potential prognostic marker in 28 different cancer types with special emphasis on HCC. By using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data, our analysis revealed that (a) RGS20 was strongly upregulated in tumor tissue compared with adjacent normal tissue of HCC patients; (b) RGS20 was strongly associated with some important clinical parameters such as alpha-fetoprotein and tumor grade in the HCC patients; (c) besides HCC (p < 0.001), RGS20 was found to be an important factor for survival in four other cancers (clear renal cell carcinoma: p < 0.001, lung adenocarcinoma: p = 0.004, mesothelioma: p = 0.039, ovarian serous cystadenocarcinoma: p = 0.048); (d) RGS20 was found to be significantly associated with some tumor-related signaling pathways and long intergenic non-coding RNAs (lincRNAs: LINC00511, PVT1, MIR4435-2HG, BCYRN1, and MAPKAPK5-AS1) that exhibit oncogenic potential. Taken together, we showed that RGS20 correlates with a few HCC-associated lincRNAs harboring oncogenic potential and is markedly upregulated in HCC patients. Our analysis further supports the putative function of RGS proteins, particularly RGS20, in cancer.

The Conservation of Long Intergenic Non-Coding RNAs and Their Response to Verticillium dahliae Infection in Cotton.

Long intergenic non-coding RNAs (lincRNAs) have been demonstrated to be vital regulators of diverse biological processes in both animals and plants. While many lincRNAs have been identified in cotton, we still know little about the repositories and conservativeness of lincRNAs in different cotton species or about their role in responding to biotic stresses. Here, by using publicly available RNA-seq datasets from diverse sources, including experiments of Verticillium dahliae (Vd) infection, we identified 24,425 and 17,713 lincRNAs, respectively, in Gossypium hirsutum (Ghr) and G. barbadense (Gba), the two cultivated allotetraploid cotton species, and 6933 and 5911 lincRNAs, respectively, in G. arboreum (Gar) and G. raimondii (Gra), the two extant diploid progenitors of the allotetraploid cotton. While closely related subgenomes, such as Ghr_At and Gba_At, tend to have more conserved lincRNAs, most lincRNAs are species-specific. The majority of the synthetic and transcribed lincRNAs (78.2%) have a one-to-one orthologous relationship between different (sub)genomes, although a few of them (0.7%) are retained in all (sub)genomes of the four species. The Vd responsiveness of lincRNAs seems to be positively associated with their conservation level. The major functionalities of the Vd-responsive lincRNAs seem to be largely conserved amongst Gra, Ghr, and Gba. Many Vd-responsive Ghr-lincRNAs overlap with Vd-responsive QTL, and several lincRNAs were predicted to be endogenous target mimicries of miR482/2118, with a pair being highly conserved between Ghr and Gba. On top of the confirmation of the feature characteristics of the lincRNAs previously reported in cotton and other species, our study provided new insights into the conservativeness and divergence of lincRNAs during cotton evolution and into the relationship between the conservativeness and Vd responsiveness of lincRNAs. The study also identified candidate lincRNAs with a potential role in disease response for functional characterization.

Long Intergenic Non-Coding RNA LINC00885 Promotes Tumorigenesis of Cervical Cancer by Upregulating MACC1 Expression Through Serving as a Competitive Endogenous RNA for microRNA-432-5p [Expression of Concern

Expression of Concern for the article Long Intergenic Non-Coding RNA LINC00885 Promotes Tumorigenesis of Cervical Cancer by Upregulating MACC1 Expression Through Serving as a Competitive Endogenous RNA for microRNA-432-5p

Host-Directed Targeting of LincRNA-MIR99AHG Suppresses Intracellular Growth of Mycobacterium tuberculosis.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) kills 1.6 million people worldwide every year, and there is an urgent need for targeting host-pathogen interactions as a strategy to reduce mycobacterial resistance to current antimicrobials. Non-coding RNAs are emerging as important regulators of numerous biological processes and avenues for exploitation in host-directed therapeutics. Although long non-coding RNAs (lncRNAs) are abundantly expressed in immune cells, their functional role in gene regulation and bacterial infections remains under-studied. Here, we identify an immunoregulatory long intergenic non-coding RNA, lincRNA-MIR99AHG, which is upregulated in mouse and human macrophages upon IL-4/IL-13 stimulation and downregulated after clinical Mtb HN878 strain infection and in peripheral blood mononuclear cells (PBMC) from active TB patients. To evaluate the functional role of lincRNA-MIR99AHG, we employed antisense LNA GapmeR-mediated antisense oligonucleotide (ASO) lncRNA knockdown experiments. Knockdown of lincRNA-MIR99AHG with ASOs significantly reduced intracellular Mtb growth in mouse and human macrophages and reduced proinflammatory cytokine production. In addition, in vivo treatment of mice with MIR99AHG ASOs reduced the mycobacterial burden in the lung and spleen. Further, in macrophages, lincRNA-MIR99AHG is translocated to the nucleus and interacts with high affinity to hnRNPA2/B1 following IL-4/IL-13 stimulation and Mtb HN878 infection. Together, these findings identify lincRNA-MIR99AHG as a positive regulator of inflammation and macrophage polarization to promote Mtb growth and a possible target for adjunctive host-directed therapy against TB.

Long intergenic noncoding RNA LINC01287 drives the progression of cervical cancer via regulating miR-513a-5p/SERP1.

Cervical cancer is one of the most frequent types of cancer in women, which is characterized by high invasion and metastatic tendency in its advanced stage. Emerging evidence indicated that long non-coding RNAs (LncRNAs) are involved in the pathogenesis of cervical cancer. LINC01287 has been reported to play crucial regulatory roles in the pathogenesis and progression of multiple cancers. However, up until now, whether LINC01287 is associated with the initiation and development of cervical cancer remains largely unknown. In the present study, expression levels of LINC01287, miR-513a-5p and stress-associated endoplasmic reticulum protein 1 (SERP1) mRNA were quantified utilizing qRT-PCR. A series of functional experiments including CCK-8 assay, colony formation assay, transwell assay, flow cytometry, and tumor xenograft growth of cervical cancer cells were performed for studying the effects of LINC01287. The luciferase reporter assay, pull-down assay, and western blot were used to confirm the downstream targets of LINC01287 and miR-513a-5p. The results demonstrate that LINC01287 was highly expressed in cervical cancer tissue samples and cell lines. High LINC01287 predicts a poor prognosis for cervical cancer patients. Additional gain- and loss-of-function experiments demonstrated that silencing LINC01287 inhibited cervical cancer cells proliferation, colony formation, migration, apoptosis in vitro and retarded tumor growth and metastasis in vivo. Furthermore, the dual-luciferase reporter gene system and RNA pulldown assay validated that LINC01287 positively regulated SERP1 expressions by sponging miR-513a-5p, and LINC01287 inhibited cervical cancer progression by regulating miR-513a-5p/SERP1 axis. In conclusion, the current study first identified that LINC01287/miR-513a-5p/SERP1 axis played an important role in cervical cancer progression. LINC01287 might be a prognostic biomarker and a target for new therapies in patients with cervical cancer.

N6-Methyladenosine-modified lncRNA LINREP promotes Glioblastoma progression by recruiting the PTBP1/HuR complex.

Glioblastoma multiforme (GBM) is acknowledged as the most aggressive primary brain tumor in adults. It is typically characterized by the high heterogeneity which corresponds to extensive genetic mutations and complex alternative splicing (AS) profiles. Known as a major repressive splicing factor in AS, polypyrimidine tract-binding protein 1 (PTBP1) is involved in the exon skipping events of multiple precursor mRNAs (pre-mRNAs) in GBM. However, precise mechanisms that modulate the expression and activity of PTBP1 remain to be elucidated. In present study, we provided evidences for the role of a long intergenic noncoding RNA (LINREP) implicated in the regulation of PTBP1-induced AS. LINREP interacted with PTBP1 and human antigen R (HuR, ELAVL1) protein complex and protected PTBP1 from the ubiquitin-proteasome degradation. Consequently, a broad spectrum of PTBP1-induced spliced variants was generated by exon skipping, especially for the skipping of reticulon 4 (RTN4) exon 3. Interestingly, LINREP also promoted the dissociation of nuclear UPF1 from PTBP1, which increased the binding of PTBP1 to RTN4 transcripts, thus enhancing the skipping of RTN4 exon 3 to some extent. Besides, HuR recruitment was essential for the stabilization of LINREP via a manner dependent on N6-methyladenosine (m6A) formation and identification. Taken together, our results demonstrated the functional significance of LINREP in human GBM for its dual regulation of PTBP1-induced AS and its m6A modification modality, implicating that HuR/LINREP/PTBP1 axis might serve as a potential therapeutic target for GBM.