Search Results (61)

Uterine fibroids (leiomyomas) are benign tumors whose growth is influenced by estrogen and progesterone. This study aimed to compare the profiles of differentially expressed long non-coding RNAs (lncRNAs) in fibroids from postmenopausal and premenopausal women to identify hormone-responsive lncRNAs. RNA sequencing was performed on six pairs of fibroid (Fib) and adjacent myometrium (Myo) tissues from postmenopausal women. Out of 7876 normalized lncRNAs, 3684 were differentially expressed (≥1.5-fold), with 1702 upregulated and 1982 downregulated in Fib. Comparative analysis with a previously published premenopausal dataset identified 741 lncRNAs that were altered based on their menopausal status, including 62 lncRNAs that were uniquely dysregulated in postmenopausal samples. Overall, 9 lncRNAs were selected for validation by PCR in an expanded cohort of 31 postmenopausal and 84 premenopausal paired samples. Several lncRNAs, including LINC02433, LINC01449, SNHG12, H19, and HOTTIP, were upregulated in premenopausal Fib but not in postmenopausal ones, while ZEB2-AS1 displayed the opposite pattern. CASC15 and MIAT were elevated in Fib from both groups, although the increase was less pronounced in the postmenopausal group. LINC01117 was significantly downregulated in postmenopausal Fib, with no change observed in premenopausal samples. Additionally, analysis based on MED12 mutation status revealed that lncRNAs such as LINC01449, CASC15, and MIAT showed limited or reduced differential expression (mutation-positive vs. mutation-negative) in postmenopausal patients compared to the premenopausal group. These findings indicate that lncRNA expression in fibroids is modulated by menopausal status, likely reflecting hormonal influence. Hormone-responsive lncRNAs may play key roles in fibroid pathogenesis and represent potential targets for therapeutic intervention. Full article

Long non-coding RNAs (lncRNAs) could alter the tumor immune microenvironment and regulate the expression of immune checkpoints (ICPs) by regulating target genes in tumors. However, only a few lncRNAs have precise functions in immunity and potential for predicting ICP inhibitors (ICI) response. Here, we developed a computational multi-step framework that leverages interaction network-based analysis to identify cancer- and immune-context ICP-related lncRNAs (NetLnc). Based on bulk and single-cell RNA sequencing data, these lncRNAs were significantly correlated with immune cell infiltration and immune expression signature. Specific hub ICP-related lncRNAs such as BANCR, MIAT, and SNHG15 could predict three- and five-year prognosis of melanoma in independent datasets. We also validated that some NetLnc-based predictions could better effectively predict ICI response compared to single molecules using three kinds of machine learning algorithms following independent datasets. Taken together, this study presents the use of a network-based framework to efficiently select ICP-related lncRNAs, which contributes to a comprehensive understanding of lncRNA functions and accelerates the discovery of lncRNA-based biomarkers in ICI treatment. Full article

Prostate cancer (PCa) is the most frequently diagnosed malignancy in the male genitourinary tract. However, the regulatory mechanism of competitive endogenous RNAs (ceRNAs) in PCa remains unclear. In this study, we first performed immune scores of mRNA data from 481 PCa samples using single-sample Gene Set Enrichment Analysis (ssGSEA). Based on the immune scores, we then evaluated the tumor immune microenvironment and analyzed 28 types of immune cells in PCa, we constructed a comprehensive network with four lncRNAs (MEG3, PCAT1, SNHG19, TRG-AS1), three miRNAs (hsa-miR-488-3p, hsa-miR-210-5p, hsa-miR-137), and twenty-seven mRNAs (including H2AFJ, THBS1, HPGD). Among the 28 immune cell types, seven immune cell types were found to be significantly associated with clinical characteristics. These network nodes have prognostic significance in multiple cancers and play critical roles in malignancy development, indicating the network’s predictive capability. We also observed a strong correlation (r = 0.6) between T-helper type 1 (Th1) cells and lncRNA network modules. The network connectivity highlights the association between immune therapy biomarkers for PCa, particularly those related to H2AFJ, THBS1, and HPGD. These findings provide valuable insights into the ceRNA regulatory network and its implications for immune-based therapies in PCa. Full article

Abstract: Our work aimed to evaluate and differentiate the role of ten lncRNA genes (GAS5, HAND2-AS1, KCNK15-AS1, MAGI2-AS3, MEG3, SEMA3B-AS1, SNHG6, SSTR5-AS1, ZEB1-AS1, and ZNF667-AS1) in the development and progression of epithelial ovarian cancer (EOC). A representative set of clinical samples was used: 140 primary tumors from patients without and with metastases and 59 peritoneal metastases. Using MS-qPCR, we demonstrated an increase in methylation levels of all ten lncRNA genes in tumors compared to normal tissues (p < 0.001). Using RT-qPCR, we showed downregulation and an inverse relationship between methylation and expression levels for ten lncRNAs (r_s < −0.5). We further identified lncRNA genes that were specifically hypermethylated in tumors from patients with metastases to lymph nodes (HAND2-AS1), peritoneum (KCNK15-AS1, MEG3, and SEMA3B-AS1), and greater omentum (MEG3, SEMA3B-AS1, and ZNF667-AS1). The same four lncRNA genes involved in peritoneal spread were associated with clinical stage and tumor extent (p < 0.001). Interestingly, we found a reversion from increase to decrease in the hypermethylation level of five metastasis-related lncRNA genes (MEG3, SEMA3B-AS1, SSTR5-AS1, ZEB1-AS1, and ZNF667-AS1) in 59 peritoneal metastases. This reversion may be associated with partial epithelial–mesenchymal transition (EMT) in metastatic cells, as indicated by a decrease in the level of the EMT marker, CDH1 mRNA (p < 0.01). Furthermore, novel mRNA targets and regulated miRNAs were predicted for a number of the studied lncRNAs using the NCBI GEO datasets and analyzed by RT-qPCR and transfection of SKOV3 and OVCAR3 cells. In addition, hypermethylation of SEMA3B-AS1, SSTR5-AS1, and ZNF667-AS1 genes was proposed as a marker for overall survival in patients with EOC. Full article

Metastasis suppressor 1 (MTSS1) has been reported to play important roles in suppressing cancer progression. In this study, we investigated the underlying mechanism that regulates MTSS1 expression. We showed that in breast cancer cells, lncRNA-SNHG15-induced cell invasion and proliferation was accompanied with the decreased expression of MTSS1 mRNA. Further study revealed that SNHG15 mediated MTSS1 repression through blocking its promoter activity. Mechanistically, SNHG15 complexes with DDX5 and RTF1 and interacts with the core promoter of the MTSS1 gene to interfere with RNA-Pol-II-directed transcriptional initiation. Association with DDX5 stabilizes SNHG15 while binding to RTF1 allows SNHG15 to carry RTF1 to the core promoter, where RTF1 forms a complex with PNA pl II to enhance transcriptional pausing. Our findings revealed a molecular mechanism by which SNHG15 serves as a regulator to suppresses MTSS1 transcription via interaction with the gene core promoter. Full article

The ovary is a major determinant of female reproductive health. Ovarian functions are mainly related to the primordial follicle pool, which is gradually lost with aging. Ovarian aging and reproductive dysfunctions share oxidative stress as a common underlying mechanism. ROS signaling is essential for normal ovarian processes, yet it can contribute to various ovarian disorders when disrupted. Therefore, balance in the redox system is crucial for proper ovarian functions. In the present study, by focusing on mRNAs and ncRNAs described in the ovary and taking into account only validated ncRNA interactions, we built an ovarian antioxidant ceRNA network, named OvAnOx ceRNA, composed of 5 mRNAs (SOD1, SOD2, CAT, PRDX3, GR), 10 miRNAs and 5 lncRNAs (XIST, FGD5-AS1, MALAT1, NEAT1, SNHG1). Our bioinformatic analysis indicated that the components of OvAnOx ceRNA not only contribute to antioxidant defense but are also involved in other ovarian functions. Indeed, antioxidant enzymes encoded by mRNAs of OvAnOx ceRNA operate within a regulatory network that impacts ovarian reserve, follicular dynamics, and oocyte maturation in normal and pathological conditions. The OvAnOx ceRNA network represents a promising tool to unravel the complex dialog between redox potential and ovarian signaling pathways involved in reproductive health, aging, and diseases. Full article

As a representative item of chemical carcinogen, MNNG is closely associated with the onset of gastric cancer (GC), where N6-methyladonosine (m6A) RNA methylation is recognized as a critical epigenetic event. In our previous study, we found that the m6A modification by methyltransferase METTL3 was up-regulated in MNNG-exposed malignant GES-1 cells (MC cells) compared to control cells in vitro, and long non-coding RNA SNHG7 as a downstream target of the METTL3. However, the functional role of METTL3 in mediating the SNHG7 axis in MNNG-induced GC remains unclear. In the present study, we continuously investigate the functional role of METTL3 in mediating the SNHG7 axis in MNNG-induced GC. RIP-PCR and m6A-IP-qPCR were used to examine the molecular mechanism underlying the METTL3/m6A/SNHG7 axis in MNNG-induced GC. A METTL3 knockout mice model was constructed and exposed by MNNG. Western blot analysis, IHC analysis, and RT-qPCR were used to measure the expression of METTL3, SNHG7, and EMT markers. In this study, we demonstrated that in MNNG-induced GC tumorigenesis, the m6A modification regulator METTL3 facilitates cellular EMT and biological functions through the m6A/SNHG7 axis using in vitro and in vivo models. In conclusion, our study provides novel insights into critical epigenetic molecular events vital to MNNG-induced gastric carcinogenesis. These findings suggest the potential therapeutic targets of METTL3 for GC treatment. Full article

Background/Objectives: In recent times, epigenetics alterations in Hidradenitis suppurativa (HS) have been explored and exploited translationally to guide investigation of new therapeutic approaches. On the other hand, long noncoding RNAs (LncRNAs), main regulators of the epigenetic status of the human genome, have been scarcely investigated, notwithstanding their potential relevance in broad pathogenesis comprehension. Here, we aim to explore the methylation pattern of lncRNAs in HS. Methods: In this case-control study, 24 HS patients and age-, sex- and BMI-matched controls were analyzed to characterize the methylome of lncRNA genes in peripheral blood cells. Gene ontology analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein–protein interaction (PPI) network, and MCODE analysis were performed. Results: A set of fifteen lncRNA genes exhibited significantly differential methylation patterns, with ten of them showing hypomethylation and five displaying hypermethylation at specific CpG sites. The hypomethylated lncRNA genes were DLEU2, MESTIT1, CASC2, TUG1, KCNQ1DN, PSORS1C3, PCA3, DSCR8, RFPL1S, and PVT1, while the hypermethylated ones were HAR1A, FAM66B, SNHG9, HCG9, and HCP5. These lncRNA genes have been linked to various important biological processes, including cell proliferation, apoptosis, inflammation, chronic inflammatory skin diseases, and wound healing. Their altered methylation status suggests potential roles in regulating these processes, and may contribute to HS pathogenesis and healing mechanisms. Conclusions: This study revealed an interesting dysregulation pattern of definite lncRNAs in the methylome which is linked to both the development of HS and its comorbidities. Epigenetically altered lncRNAs genes could represent useful biomarkers, and could help in guiding innovative treatment strategies. Full article

Chromosomal instability is a hallmark of colorectal carcinogenesis and produces an accumulation of different forms of aneuploidies or broad copy number aberrations. Colorectal cancer is characterized by gain-type broad copy number aberrations, specifically in Chr20, Chr8q, Chr13 and Chr7, but their roles and mechanisms in cancer progression are not fully understood. It has been suggested that broad copy number gains might contribute to tumor development through the so-called caricature transcriptomic effect. We intend to investigate the impact of broad copy number gains on long non-coding RNAs’ expression in colorectal cancer, given their well-known role in oncogenesis. The influence of such chromosomal aberrations on lncRNAs’ transcriptome profile was investigated by SNP and transcriptome arrays in our series of colorectal cancer samples and cell lines. The correlation between aneuploidies and transcriptomic profiles led us to obtain a class of Over-UpT lncRNAs, which are transcripts upregulated in CRC and further overexpressed in colon tumors bearing specific chromosomal aberrations. The identified lncRNAs can contribute to a wide interaction network to establish the cancer driving effect of gain-type aneuploidies. Full article

Clear-cell renal-cell carcinoma (ccRCC) is a silent-development pathology with a high rate of metastasis in patients. The activity of coding genes in metastatic progression is well known. New studies evaluate the association with non-coding genes, such as competitive endogenous RNA (ceRNA). This study aims to build a ceRNA network and a gene signature for ccRCC associated with metastatic development and analyze their biological functions. Using data from The Cancer Genome Atlas (TCGA), we constructed the ceRNA network with differentially expressed genes, assembled nine preliminary gene signatures from eight feature selection techniques, and evaluated the classification metrics to choose a final signature. After that, we performed a genomic analysis, a risk analysis, and a functional annotation analysis. We present an 11-gene signature: SNHG15, AF117829.1, hsa-miR-130a-3p, hsa-mir-381-3p, BTBD11, INSR, HECW2, RFLNB, PTTG1, HMMR, and RASD1. It was possible to assess the generalization of the signature using an external dataset from the International Cancer Genome Consortium (ICGC-RECA), which showed an Area Under the Curve of 81.5%. The genomic analysis identified the signature participants on chromosomes with highly mutated regions. The hsa-miR-130a-3p, AF117829.1, hsa-miR-381-3p, and PTTG1 were significantly related to the patient’s survival and metastatic development. Additionally, functional annotation resulted in relevant pathways for tumor development and cell cycle control, such as RNA polymerase II transcription regulation and cell control. The gene signature analysis within the ceRNA network, with literature evidence, suggests that the lncRNAs act as “sponges” upon the microRNAs (miRNAs). Therefore, this gene signature presents coding and non-coding genes and could act as potential biomarkers for a better understanding of ccRCC. Full article

Small nucleolar RNAs (snoRNAs) constitute a class of intron-derived non-coding RNAs ranging from 60 to 300 nucleotides. Canonically localized in the nucleolus, snoRNAs play a pivotal role in RNA modifications and pre-ribosomal RNA processing. Based on the types of modifications they involve, such as methylation and pseudouridylation, they are classified into two main families—box C/D and H/ACA snoRNAs. Recent investigations have revealed the unconventional synthesis and biogenesis strategies of snoRNAs, indicating their more profound roles in pathogenesis than previously envisioned. This review consolidates recent discoveries surrounding snoRNAs and provides insights into their mechanistic roles in cancer. It explores the intricate interactions of snoRNAs within signaling pathways and speculates on potential therapeutic solutions emerging from snoRNA research. In addition, it presents recent findings on the long non-coding small nucleolar RNA host gene (lncSNHG), a subset of long non-coding RNAs (lncRNAs), which are the transcripts of parental SNHGs that generate snoRNA. The nucleolus, the functional epicenter of snoRNAs, is also discussed. Through a deconstruction of the pathways driving snoRNA-induced oncogenesis, this review aims to serve as a roadmap to guide future research in the nuanced field of snoRNA–cancer interactions and inspire potential snoRNA-related cancer therapies. Full article

The objective of this study was to elucidate the expression of long non-coding RNA (lncRNA) in leiomyomas (Lyo) and paired myometrium (Myo) and explore the impact of race and MED12 mutation. Fold change analysis (Lyo/paired Myo) indicated the expression of 63 lncRNAs was significantly altered in the mutated group but not in the non-mutated Lyo. Additionally, 65 lncRNAs exhibited an over 1.5-fold change in the Black but not the White group. Fifteen differentially expressed lncRNAs identified with next-generation sequencing underwent qRT-PCR confirmation. Compared with Myo, the expression of TPTEP1, PART1, RPS10P7, MSC-AS1, SNHG12, CA3-AS1, LINC00337, LINC00536, LINC01436, LINC01449, LINC02433, and LINC02624 was significantly higher, while the expression of ZEB2-AS1, LINC00957, and LINC01186 was significantly lower. Comparison of normal Myo with diseased Myo showed significant differences in the expression of several lncRNAs. Analysis based on race and Lyo MED12 mutation status indicated a significantly higher expression of RPS10P7, SNHG12, LINC01449, LINC02433, and LINC02624 in Lyo from Black patients. The expression of TPTEP1, PART1, RPS10P7, MSC-AS1, LINC00337, LINC00536, LINC01436, LINC01449, LINC02433, and LINC02624 was higher, while LINC01186 was significantly lower in the MED12-mutated group. These results indicate that Lyo are characterized by aberrant lncRNA expression, which is further impacted by race and Lyo MED12 mutation status. Full article

As a representative example of an environmental chemical carcinogen, MNNG exposure is closely associated with the onset of gastric cancer (GC) where N6-methyladenosine (m6A) RNA methylation tends to be the critical epigenetic event. However, the effect of m6A modification on long non-coding RNAs (lncRNAs) in MNNG-induced GC onset is still unclear. To address the above issue, based on the Methylated RNA immunoprecipitation sequencing (MeRIP-seq) data of MNNG-induced malignant cells (MCs) and GC cells, we comprehensively analyzed the MNNG exposure-associated vital lncRNAs. MeRIP-seq analysis identified 1432 lncRNA transcripts in the MC cell, and 3520 lncRNA transcripts were found to be m6A modified in the GC cell, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that MNNG exposure could spark cellular localization change, which might be the critical cellular note variation for malignant transformation. We demonstrated that METTL3 is responsible for N6 methylation of lncRNAs and identified SNHG7 as a downstream target of METTL3. More importantly, we observed that SNHG7 was progressively up-regulated during gastric carcinogenesis by MNNG exposure. Finally, we investigated SNHG7 expression in different stages of GC malignancies and found that elevated SNHG7 expression correlated with advanced clinical features and poor prognosis in GC. In conclusion, our study found for the first time that METTL3 regulates the m6A methylation level of lncRNA SNHG7 and its expression in MNNG exposure-induced GC, suggesting that SNHG7 as a predictive biomarker or therapeutic target for GC. Full article

Although, by definition, long noncoding RNAs (lncRNAs) are not translated, they are sometimes associated with ribosomes. In fact, some estimates suggest the existence of more than 50 K lncRNA molecules that could encode for small peptides. We examined the effects of an ethanol and Poly-ADP Ribose Polymerase (PARP) inhibitor (ABT-888) on ribosome-bound lncRNAs. Mice were administered via intraperitoneal injection (i.p.) either normal saline (CTL) or ethanol (EtOH) twice a day for four consecutive days. On the fourth day, a sub-group of mice administered with ethanol also received ABT-888 (EtOH+ABT). Ribosome-bound lncRNAs in CaMKIIα-expressing pyramidal neurons were measured using the Translating Ribosome Affinity Purification (TRAP) technique. Our findings show that EtOH altered the attachment of 107 lncRNA transcripts, while EtOH+ABT altered 60 lncRNAs. Among these 60 lncRNAs, 49 were altered by both conditions, while EtOH+ABT uniquely altered the attachment of 11 lncRNA transcripts that EtOH alone did not affect. To validate these results, we selected eight lncRNAs (Mir124-2hg, 5430416N02Rik, Snhg17, Snhg12, Snhg1, Mir9-3hg, Gas5, and 1110038B12Rik) for qRT-PCR analysis. The current study demonstrates that ethanol-induced changes in lncRNA attachment to ribosomes can be mitigated by the addition of the PARP inhibitor ABT-888. Full article

Long noncoding RNAs (lncRNAs) may contribute to the formation of psoriatic lesions. The present study’s objective was to identify long lncRNA genes that are differentially expressed in patient samples of psoriasis through computational analysis techniques. By using previously published RNA sequencing data from psoriatic and healthy patients (n = 324), we analysed the differential expression of lncRNAs to determine transcripts of heightened expression. We computationally screened lncRNA transcripts as annotated by GENCODE across the human genome and compared transcription in psoriatic and healthy samples from two separate studies. We observed 54 differentially expressed genes as seen in two independent datasets collected from psoriasis and healthy patients. We also identified the differential expression of LINC01215 and LINC1206 associated with the cell cycle pathway and psoriasis pathogenesis. SH3PXD2A-AS1 was identified as a participant in the STAT3/SH3PXD2A-AS1/miR-125b/STAT3 positive feedback loop. Both the SH3PXD2A-AS1 and CERNA2 genes have already been recognised as part of the IFN-γ signalling pathway regulation. Additionally, EPHA1-AS1, CYP4Z2P and SNHG12 gene upregulation have all been previously linked to inflammatory skin diseases. Differential expression of various lncRNAs affects the pathogenesis of psoriasis. Further characterisation of lncRNAs and their functions are important for developing our understanding of psoriasis. Full article