Dysregulation Of RNAs Research Articles

Cardiorenal syndrome: clinical diagnosis, molecular mechanisms and therapeutic strategies.

As the heart and kidneys are closely connected by the circulatory system, primary dysfunction of either organ usually leads to secondary dysfunction or damage to the other organ. These interactions play a major role in the pathogenesis of a clinical entity named cardiorenal syndrome (CRS). The pathophysiology of CRS is complicated and involves multiple body systems. In early studies, CRS was classified into five subtypes according to the organs associated with the vicious cycle and the acuteness and chronicity of CRS. Increasing evidence shows that CRS is associated with a variety of pathological mechanisms, such as haemodynamics, neurohormonal changes, hypervolemia, hypertension, hyperuraemia and hyperuricaemia. In this review, we summarize the classification and currently available diagnostic biomarkers of CRS. We highlight the recently revealed molecular pathogenesis of CRS, such as oxidative stress and inflammation, hyperactive renin‒angiotensin‒aldosterone system, maladaptive Wnt/β-catenin signalling pathway and profibrotic TGF‒β1/Smad signalling pathway, as well as other pathogeneses, such as dysbiosis of the gut microbiota and dysregulation of noncoding RNAs. Targeting these CRS-associated signalling pathways has new therapeutic potential for treating CRS. In addition, various chemical drugs, natural products, complementary therapies, blockers, and agonists that protect against CRS are summarized. Since the molecular mechanisms of CRS remain to be elucidated, no single intervention has been shown to be effective in treating CRS. Pharmacologic therapies designed to block CRS are urgently needed. This review presents a critical therapeutic avenue for targeting CRS and concurrently illuminates challenges and opportunities for discovering novel treatment strategies for CRS.

Global dysregulation of circular RNAs in frontal cortex and whole blood from DM1 and DM2.

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular disorders associated with expansions of microsatellites, respectively, in DMPK and CNBP. Their pathogenesis is linked to the global aberrant alternative splicing (AAS) of many genes and marks mostly muscular and neuronal tissues, while blood is the least affected. Recent data in DM1 skeletal muscles indicated that abnormalities in RNA metabolism also include global upregulation of circular RNAs (circRNAs). CircRNAs are a heterogeneous group considered splicing errors and by-products of canonical splicing. To elucidate whether circRNA dysregulation is an inherent feature of the myotonic environment, we perform their analysis in the frontal cortex and whole blood of DM1 and DM2 patients. We find a global elevation of circRNAs in both tissues, and its magnitude is neither correlated with the differences in their parental gene expression nor is associated with AAS published earlier. Aberrantly spliced cassette exons of linear transcripts affected in DM1 and DM2 are not among the circularized exons, which unique genomic features prerequisite back-splicing. However, the blueprint of the AAS of linear RNAs is found in a variety of circRNA isoforms. The heterogeneity of circRNAs also originates from the utilization of exonic and intronic cryptic donors/acceptors in back splice junctions, and intron-containing circRNAs are more characteristic of the blood. Overall, this study reveals circRNA dysregulation in various tissues from DM1 and DM2; however, their levels do not correlate with the AAS in linear RNAs, suggesting a potential independent regulatory mechanism underlying circRNA upregulation in myotonic dystrophy.

M6A-related genes ALKBH5 and RBMX as prognostic and progression biomarkers in Chinese oral squamous cell carcinoma patients

ObjectiveN6-methyladenosine (m6A) RNA dysregulation is crucial for cancer development. The study aimed to explore the effects of m6A modification in oral squamous cell carcinoma (OSCC) and its potential as a biomarker and therapeutic target. DesignWe first analyzed m6A-related gene expression and its impact on OSCC prognosis and progression using the TCGA database. Subsequently, a Chinese cohort of 134 samples was used for validation. Bioinformatics analysis was conducted with TCGA data, and m6A levels were measured in the validation cohort using a quantification kit. Survival analysis was performed to study the relationship between m6A-related genes and OSCC prognosis in the Chinese population. The expression of m6A-related genes was assessed by using quantitative real-time PCR, Western blot analysis, and immunohistochemistry. ResultsIn the TCGA database, we found dysregulated expressions of METTL14, ALKBH5, YTHDF2, HNRNPC, LRPPRC, HNRNPA2B1, IGF2BP2, and RBMX in OSCC. Based on this, we observed significantly elevated total m6A content in OSCC tissues compared to normal controls in the validation cohort. Among the m6A candidate genes, only ALKBH5 and RBMX upregulation were found to be independent prognostic risk factors for poor OSCC survival in the Chinese population. And the inclusion of these two genes had a higher area under the curve for 3-year (0.705, 0.826), and 5-year (0.715, 0.788) overall survival compared to the model that only considered clinical parameters. ConclusionsWe found the upregulation of m6A status in OSCC, of which, ALKBH5 and RBMX may serve as promising diagnostic and prognostic biomarkers for Chinese patients with OSCC.

Clinical Impact of Cellular Senescence and RNA Dysregulation in HCC Is Associated With MASLD and HCV-SVR.

The incidence of hepatocellular carcinoma (HCC) associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatitis C virus sustained virologic response (HCV-SVR) are increasing. However, the mechanisms driving HCC development in these patients remain unclear. This study aimed to evaluate the role of cellular senescence and RNA editing in HCC by examining cyclin-dependent kinase inhibitor 2A (p16) and adenosine deaminase acting on RNA (ADAR1) expression. HCC specimens from patients with MASLD or HCV-SVR were analyzed by immunohistochemistry to assess p16 and ADAR1 expression. Statistical analyses were conducted using the Chi-squared test, Fisher's exact test, and Mann-Whitney U-test. Survival analyses were performed using the Kaplan-Meier method, the log-rank test, and Cox regression analysis. Among 122 patients, 59 (48.4%) had MASLD and 63 (51.6%) had HCV-SVR. p16 expression was observed in 69 cases (57.0%) in the noncancerous areas and 53 cases (44.5%) in the cancerous areas. ADAR1 expression was positive in 28 cases (23.5%) in the cancerous areas and significantly associated with p16 expression in the cancerous areas (p=0.039). Patients with p16 expression in the noncancerous areas were older (p=0.045) and had elevated serum ALT levels (p=0.024). p16 expression in the cancerous areas were correlated with a shorter recurrence-free survival (HR=1.65, 95%CI=1.00-2.73, p=0.046). Cellular senescence and RNA editing may play a key role in MASLD- and HCV-SVR-related HCC. p16 expression in the cancerous areas may serve as a prognostic biomarker for surgical outcomes.

Dysregulation of transposable elements and PIWI-interacting RNAs in myelodysplastic neoplasms

BackgroundMyelodysplastic neoplasms (MDS) are heterogeneous hematopoietic disorders characterized by ineffective hematopoiesis and genome instability. Mobilization of transposable elements (TEs) is an important source of genome instability leading to oncogenesis, whereas small PIWI-interacting RNAs (piRNAs) act as cellular suppressors of TEs. However, the roles of TEs and piRNAs in MDS remain unclear.MethodsIn this study, we examined TE and piRNA expression through parallel RNA and small RNA sequencing of CD34+ hematopoietic stem cells from MDS patients.ResultsComparative analysis of TE and piRNA expression between MDS and control samples revealed several significantly dysregulated molecules. However, significant differences were observed between lower-risk MDS (LR-MDS) and higher-risk MDS (HR-MDS) samples. In HR-MDS, we found an inverse correlation between decreased TE levels and increased piRNA expression and these TE and piRNA levels were significantly associated with patient outcomes. Importantly, the upregulation of PIWIL2, which encodes a key factor in the piRNA pathway, independently predicted poor prognosis in MDS patients, underscoring its potential as a valuable disease marker. Furthermore, pathway analysis of RNA sequencing data revealed that dysregulation of the TE‒piRNA axis is linked to the suppression of processes related to energy metabolism, the cell cycle, and the immune response, suggesting that these disruptions significantly affect cellular activity.ConclusionsOur findings demonstrate the parallel dysregulation of TEs and piRNAs in HR-MDS patients, highlighting their potential role in MDS progression and indicating that the PIWIL2 level is a promising molecular marker for prognosis.Graphical

Organoid modeling identifies USP3-AS1 as a novel promoter in colorectal cancer liver metastasis through increasing glucose-driven histone lactylation.

Dysregulation of long non-coding RNAs (lncRNAs) is common in colorectal cancer liver metastasis (CRLM). Emerging evidence links lncRNAs to multiple stages of metastasis from initial migration to colonization of distant organs. In this study we investigated the role of lncRNAs in metabolic reprogramming during CRLM using patient-derived organoid (PDO) models. We established five pairs of PDOs from primary tumors and matched liver metastatic lesions, followed by microarray analysis. We found that USP3-AS1 was significantly upregulated in CRLM-derived PDOs compared to primary tumors. High level of USP3-AS1 was positively associated with postoperative liver metastasis and negatively correlated with the prognosis of colorectal cancer (CRC) patients. Overexpression of USP3-AS1 significantly enhanced both sphere formation efficiency and liver metastasis in PDOs. Gene set enrichment analysis revealed that USP3-AS1 upregulation significantly enriched glycolysis and MYC signaling pathways. Metabolomics analysis confirmed that USP3-AS1 promoted glycolysis in PDOs, whereas glycolysis inhibition partially attenuated the effects of USP3-AS1 overexpression on PDO growth and liver metastasis. We revealed that USP3-AS1 stabilized MYC via post-translational deubiquitination, thereby promoting glycolysis. We demonstrated that USP3-AS1 increased the stability of USP3 mRNA, resulting in higher USP3 protein expression. The elevated USP3 protein then interacted with MYC and promoted its stability by deubiquitination. The USP3-AS1-MYC-glycolysis regulatory axis modulated liver metastasis by promoting H3K18 lactylation and CDC27 expression in CRC. In conclusion, USP3-AS1 is a novel promoter of CRLM by inducing histone lactylation.

LncRNA SERPINB9P1 Mitigates Cerebral Injury Induced by Oxygen‒Glucose Deprivation/Reoxygenation by Interacting with HSPA2.

Dysregulation of long non-coding RNAs (lncRNAs) is implicated in the pathophysiology of ischemic stroke (IS). However, the molecular mechanism of the lncRNA SERPINB9P1 in IS remains unclear. Our study aimed to explore the role and molecular mechanism of the lncRNA SERPINB9P1 in IS. This study revealed downregulation of the lncRNA SERPINB9P1 in the peripheral blood of IS patients, which was corroborated by the GSE140275 dataset. Furthermore, high lncRNA SERPINB9P1 expression was associated with lower National Institutes of Health Stroke Scale (NIHSS) scores and favorable outcome. Clinically, lncRNA SERPINB9P1 expression was correlated with inflammation and coagulation parameters in IS patients. Furthermore, lncRNA SERPINB9P1 silencing inhibited cell viability, induced apoptosis and inflammatory response under oxygen-glucose deprivation/reperfusion ; however, these effects were reversed upon its overexpression. Additionally, Chromatin Isolation by RNA Purification and mass spectrometry (CHIRP-MS) and western blot confirmed that the lncRNA SERPINB9P1 was involved in the pathological process of IS through binding to heat shock protein 2 (HSPA2). HSPA2 was upregulated in IS patients, and its protein interaction network was significantly enriched in IS-related pathways. In conclusion, the lncRNA SERPINB9P1 may ameliorate neurological injury in IS patients by interacting with the HSPA2 protein and engaging in IS-related pathways, providing new insights into treatment strategies for IS.

A deep learning model for characterizing protein-RNA interactions from sequences at single-base resolution.

Protein-RNA interactions play pivotal roles in regulating transcription, translation, and RNA metabolism. Characterizing these interactions offers key insights into RNA dysregulation mechanisms. Here, we introduce Reformer, a deep learning model that predicts protein-RNA binding affinity from sequence data. Trained on 225 enhanced cross-linking and immunoprecipitation sequencing (eCLIP-seq) datasets encompassing 155 RNA-binding proteins across three cell lines, Reformer achieves high accuracy in predicting binding affinity at single-base resolution. The model uncovers binding motifs that are often undetectable through traditional eCLIP-seq methods. Notably, the motifs learned by Reformer are shown to correlate with RNA processing functions. Validation via electrophoretic mobility shift assays confirms the model's precision in quantifying the impact of mutations on RNA regulation. In summary, Reformer improves the resolution of RNA-protein interaction predictions and aids in prioritizing mutations that influence RNA regulation.

Accurate identification of snoRNA targets using variational graph autoencoder to advance the redevelopment of traditional medicines.

Existing studies indicate that dysregulation or abnormal expression of small nucleolar RNA (snoRNA) is closely associated with various diseases, including lung cancer. Furthermore, these diseases often involve multiple targets, making the redevelopment of traditional medicines highly promising. Accurate prediction of potential snoRNA therapeutic targets is essential for early disease intervention and the redevelopment of traditional medicines. Additionally, researchers have developed artificial intelligence (AI)-based methods to screen and predict potential snoRNA therapeutic targets, thereby advancing traditional drug redevelopment. However, existing methods face challenges such as imbalanced datasets and the dominance of high-degree nodes in graph neural networks (GNNs), which compromise the accuracy of node representations. To address these challenges, we propose an AI model based on variational graph autoencoders (VGAEs) that integrates decoupling and Kolmogorov-Arnold Network (KAN) technologies. The model reconstructs snoRNA-disease graphs by learning snoRNA and disease representations, accurately identifying potential snoRNA therapeutic targets. By decoupling similarity from node degree, the model mitigates the dominance of high-degree nodes, enhances prediction accuracy in scenarios like lung cancer, and leverages KAN technology to improve adaptability and flexibility to new data. Case studies revealed that snoRNA SNORA21 and SNORD33 are abnormally expressed in lung cancer patients and are strong candidates for potential therapeutic targets. These findings validate the proposed model's effectiveness in identifying therapeutic targets for diseases like lung cancer, supporting early screening and treatment, and advancing the redevelopment of traditional medicines. Data and experimental findings are archived in: https://github.com/shmildsj/data.

Trinucleotide Repeat Expansion and RNA Dysregulation in Fragile X Syndrome: Emerging Therapeutic Approaches.

Fragile X Syndrome (FXS) is characterized by intellectual impairment caused by CGG repeat expansion in the FMR1 gene. When repeats exceed 200, they induce DNA methylation of the promoter and the repeat region, resulting in transcriptional silencing of the FMR1 gene and the subsequent loss of FMRP protein. In the past decade or so, research has focused on the role of FMRP as an RNA-binding protein involved in translation inhibition in the brain in FXS model mice, particularly by slowing or stalling ribosome translocation on mRNA. More recent advances have shown that FMRP has a profound role in RNA splicing, at least in some cases by modulating the translation of splicing factor mRNAs. In a surprise, the human FMR1 gene is transcribed in most cases even with a full CGG expansion. However, much of the FMR1 that is produced is mis-spliced, which can be corrected by splice-switching antisense oligonucleotide (ASO) administration. Other recent findings suggest that inhibition of multiple kinases can demethylate the FMR1 gene and induce the formation of an R-loop in the CGG repeat region, leading to contraction of the repeat and FMRP restoration. These insights are paving the way for possible future therapeutic approaches for this disorder. We highlight the importance of FMRP restoration by ASO-mediated splice switching or CGG repeat modulation as key advances that may lead to successful treatments for FXS.

The diagnostic and predictive potential of lncRNA CASC2 targeting miR-155 in systemic lupus erythematosus patients with nephritis complication

Lupus nephritis (LN) is a serious problem that results from systemic lupus erythematosus (SLE) complications. Recent studies have highlighted that non-coding RNA (ncRNA) dysregulation is a notable feature in patients with SLE. As a result, this research was designed to investigate lncRNA CASC2 and miR-155 levels as non-invasive diagnostic biomarkers in SLE patients, including those with and without nephritis, and to investigate their effectiveness in assessing disease severity and predicting LN. Our study included 60 patients with SLE who were subclassified into (30 non-LN and 30 LN groups), along with 30 control subjects. Quantification of lncRNA CASC2 and miR-155 in serum samples from the Egyptian population was carried out with real-time polymerase chain reaction (RT-PCR). The disease activity index (SLEDAI) for SLE was evaluated, and the analysis of the receiver operating characteristic (ROC) curve was implemented. Increased levels of lncRNA CASC2 were observed in SLE patients compared to healthy controls, with even higher levels observed in the LN group versus the non-LN patients’ group. Conversely, miR-155 was noted to be down-regulated in SLE patients relative to controls, and its levels were lower in the LN group relative to the non-LN patients’ group. The elevated expression of lncRNA CASC2 and reduced expression of miR-155 were both correlated to the severity of the disease. The current study illustrated that both lncRNA CASC2 and miR-155 could act as valuable non-invasive diagnostic biomarkers for SLE and predicting LN among SLE patients, as well as their abilities to detect the disease severity and progression.

Altered blood and keratinocyte microRNA/transfer RNA fragment profiles related to fibromyalgia syndrome and its severity.

Fibromyalgia syndrome (FMS) is a debilitating widespread chronic pain condition of unclear pathophysiology. We studied small noncoding RNAs as potential classifiers and mediators of FMS. Blood and keratinocyte microRNAs (miRs) and transfer RNA fragments (tRFs) were profiled by small RNA-sequencing within a comprehensively phenotyped female cohort of 53 patients with FMS vs 34 healthy controls (hCOs) and 15 patients with major depression and chronic physical pain (disease controls). Small RNAs were quantified via RNA-sequencing and candidates validated via qRT-PCR. MicroRNAs and tRFs were tested for association with FMS symptoms and their potential regulatory roles. miR and tRF profiles were altered in FMS compared to hCO in whole blood (n = 69; n = 22) and keratinocytes (n = 41; n = 55). Receiver operating characteristic analysis of blood miR candidates hsa-miR-148a-3p and hsa-miR-182-5p, and tRF candidate tRF-21-WB8647O5D levels separated FMS from hCO. In blood, hsa-miR-182-5p and hsa-miR-576-5p upregulation was validated via qRT-PCR, showing even higher expression in disease control, while TRF-20-40KK5Y93 was selectively increased in FMS. MicroRNAs in blood and keratinocytes were associated with how widespread pain manifested in patients. Keratinocyte tRFs correlated with loss of skin innervation. In blood, altered small RNAs were linked to immune and RNA processes, whereas in keratinocytes, adhesion and epithelial functions were targeted. Modulated tRFs shared sequence motifs in patients with FMS, which may promote concerted pathway regulation. Our findings show miRs/tRFs as key small RNAs dysregulation in FMS pathophysiology and open new perspectives for FMS diagnostics, symptom monitoring, and clinical management.

Depletion of the RNA binding protein QKI and circular RNA dysregulation in T-cell acute lymphoblastic leukemia.

Not available.

Targeting TSPEAR-AS2 suppresses tumor growth and interferon signaling in esophageal cancer

Dysregulation of long non-coding RNAs (lncRNAs) and interferon signaling contributes to tumorigenesis and progression; however, their crosstalk in tumor biology remains poorly understood. Here, we showed that TSPEAR-AS2, an lncRNA mediated by METTL1, activates the interferon signaling pathway in esophageal cancer (ESCA). Clinically, we conducted a pan-cancer investigation and identified TSPEAR-AS2 as a novel ESCA-related lncRNA that predicts a worse patient prognosis. The high expression of TSPEAR-AS2 was validated in multiple ESCA cohorts, demonstrating that this lncRNA had good diagnostic performance. METTL1, an RNA N7-methylguanosine (m7G) methyltransferase, was positively correlated with TSPEAR-AS2 expression in ESCA tissues, and METTL1 was found to induce TSPEAR-AS2 expression in ESCA cells. Functionally, the up-regulation of TSPEAR-AS2 promoted proliferation, cell cycle progression, migration, and stemness in ESCA cells, whereas its knockdown attenuated these malignant phenotypes. Furthermore, both TSPEAR-AS2 deficiency and antisense oligonucleotide (ASO)-based intratumoral intervention could significantly suppress tumor growth in vivo. Mechanistically, quantitative proteomic analysis revealed that TSPEAR-AS2 ablation altered the expression of functional proteins related to interferon signaling pathways, such as HLA-E, IRF3, and IFITs. These findings identify a previously unrecognized role of the METTL1/TSPEAR-AS2/interferon signaling axis in ESCA development and suggest that TSPEAR-AS2 is a potential prognostic indicator and therapeutic vulnerability for this malignancy.

Exosomal mRNA Signatures as Predictive Biomarkers for Risk and Age of Onset in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and memory loss. While the precise causes of AD remain unclear, emerging evidence suggests that messenger RNA (mRNA) dysregulation contributes to AD pathology and risk. This study examined exosomal mRNA expression profiles of 15 individuals diagnosed with AD and 15 healthy controls from Barranquilla, Colombia. Utilizing advanced bioinformatics and machine learning (ML) techniques, we identified differentially expressed mRNAs and assessed their predictive power for AD diagnosis and AD age of onset (ADAOO). Our results showed that ENST00000331581 (CADM1) and ENST00000382258 (TNFRSF19) were significantly upregulated in AD patients. Key predictors for AD diagnosis included ENST00000311550 (GABRB3), ENST00000278765 (GGTLC1), ENST00000331581 (CADM1), ENST00000372572 (FOXJ3), and ENST00000636358 (ACY1), achieving > 90% accuracy in both training and testing datasets. For ADAOO, ENST00000340552 (LIMK2) expression correlated with a delay of ~12.6 years, while ENST00000304677 (RNASE6), ENST00000640218 (HNRNPU), ENST00000602017 (PPP5D1), ENST00000224950 (STN1), and ENST00000322088 (PPP2R1A) emerged as the most important predictors. ENST00000304677 (RNASE6) and ENST00000602017 (PPP5D1) showed promising predictive accuracy in unseen data. These findings suggest that mRNA expression profiles may serve as effective biomarkers for AD diagnosis and ADAOO, providing a cost-efficient and minimally invasive tool for early detection and monitoring. Further research is needed to validate these results in larger, diverse cohorts and explore the biological roles of the identified mRNAs in AD pathogenesis.

Circ_0068655 silencing ameliorates hypoxia-induced human cardiomyocyte injury by regulating apoptotic and inflammatory responses.

There is growing evidence suggesting that the dysregulation of circular RNAs (circRNAs) plays a significant role in various myocardial disorders, including myocardial ischemia (MI). This study aimed to explore the function of hsa_circ_0068655 (circ_0068655) in hypoxia-induced cardiomyocyte injury. Human AC16 cardiomyocyte cells were cultured under anaerobic condition to induce an in vitro model of MI. Cell apoptosis was assessed by Annexin V-fluorescein isothiocyanate staining and caspase-3 and caspase-9 activity assays. Cell proliferation was analyzed by 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assay. Inflammation was evaluated by enzyme-linked immunosorbent assays. Circ_0068655, miR-370-3p and BCL-2-like 11 (BCL2L11) expression were detected by real-time quantitative polymerase chain reaction or western blotting. The target interactions among circ_0068655, miR-370-3p and BCL2L11 were predicted using bioinformatics tools and validated using dual-luciferase reporter assays and RNA immunoprecipitation assays. Hypoxia treatment led to upregulated expression of circ_0068655 and BCL2L11, and downregulated expression of miR-370-3p in AC16 cells. This treatment also resulted in reduced cell viability, increased apoptosis rate, elevated caspase-9/3 activities and cleavage, and enhanced production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Notably, knockdown of circ_0068655 alleviated these detrimental effects. In addition, circ_0068655 silencing-mediated effects were restored by decreasing miR-370-3p expression in hypoxia-treated AC16 cells. Moreover, ectopic BCL2L11 expression remitted the effects of miR-370-3p overexpression on hypoxia-treated AC16 cells. Mechanistically, circ_0068655 was found to act as a sponge for miR-370-3p, thereby regulating BCL2L11 expression. Circ_0068655 silencing ameliorated hypoxia-induced human cardiomyocyte injury through the miR-370-3p/BCL2L11 axis.

Dysregulation of Transposable Elements and Piwi-Interacting RNAs in Myelodysplastic Neoplasms

Dysregulation of Transposable Elements and Piwi-Interacting RNAs in Myelodysplastic Neoplasms

The dysregulation and clinical relevance of lncRNAs MYOSLID and SFTA1P in colorectal cancer patients.

Colorectal cancer (CRC) is a very common cancer worldwide. CRC is characterized by some changes in the expression of oncogenic and tumor suppressor genes. These changes are associated with dysregulation of non-coding RNAs, including long non-coding RNAs (lncRNAs). LncRNAs are heterogeneous non-coding molecules without open reading frames. LncRNAs have been established as regulators in the development of CRC and clinical biomarkers for the CRC detection. In this project, we investigated the expression changes of two new lncRNAs named SFTA1P and MYOSLID in CRC patients. 30 samples of CRC tissue and 30 samples of normal tissue adjacent to the cancer tissue were obtained from patients. RNA extraction from tissue samples was performed using RNAX plus. ExcelRT™ Reverse Transcription Kit (SymBio, Korea) was used for cDNA synthesis. RealQ Plus 2x Master Mix Green Without ROX™ was used to perform a quantitative PCR (qPCR). REST, and SPSS software were used for statistical analysis. Our result demonstrated that lncRNAs MYOSLID and SFTA1P were significantly up-regulated in tumor tissues compared to healthy tissues with a fold change of 13.43 and 5.33 (P < 0.05) respectively. Based on the analysis of ROC curve, MYOSLID (AUC = 0.946, P < 0.0001, SE =0.0035) and SFTA1P (AUC = 0.800, P < 0.0001, SE = 0.059) were indicated as potential clinical hallmarks for CRC patients. According to the results obtained from this research, lncRNAs SFTA1P and MYOSLID can be suggested as molecular biomarkers for the CRC diagnosis.

MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination.

Muscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of Myotonic Dystrophy type 1 (DM1). In DM1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease. While attention to MBNL proteins has focused on their functions in skeletal muscle, new evidence suggests that their importance extends to motor neurons (MNs), pivotal cellular components in the control of motor skills and movement. To address this question, we generated conditional double knockout mice in which Mbnl1 and Mbnl2 were specifically deleted in motor neurons (MN-dKO). Adult MN-dKO mice develop gait coordination deficits associated with structural and ultrastructural defects in the neuromuscular junction, indicating that MBNL activity in MNs is crucial for the maintenance of the neuromuscular junction. In addition, transcriptome analysis performed on the spinal cord of MN-dKO mice identified mis-splicing events in genes associated with synaptic transmission and neuromuscular junction homeostasis. In summary, our results highlight the complex roles and regulatory mechanisms of MBNL proteins in MNs for muscle function and locomotion. This work provides valuable insights into fundamental aspects of RNA biology and offers promising avenues for therapeutic intervention in DM1 as well as a range of diseases associated with RNA dysregulation.

Circ_0060927 promotes colorectal cancer development by sponging miR-331-3p and upregulating TBX2

BackgroundThe dysregulation of circular RNAs (circRNAs) is closely associated with the pathogenesis of colorectal cancer (CRC). The present study aimed to elucidate the biological function and mechanism of circ_0060927 in CRC. Methods5-ethynyl-2’-deoxyuridine, Cell Counting Kit-8 (CCK-8), flow cytometry and transwell assays, as well as Xenograft tumor models were adopted for in vitro and in vivo analyses. The interaction between microRNA-331–3p (miR-331–3p) and circ_0060927 or T-box transcription factor 2 (TBX2) was verified by the dual-luciferase reporter and RNA pull-down assays. ResultsCirc_0060927 deficiency inhibited cell proliferation, autophagy, migration, and invasion and increased cell apoptosis and necrosis in CRC cells, as well as inhibited tumor growth in vivo. Circ_0060927 could bind to miR-331–3p, and circ_0060927 regulated CRC cell behaviors via sponging miR-331–3p. TBX2 was targeted by miR-331–3p, and miR-331–3p targeted TBX2 to exert the anti-cancer role in CRC cells. Mechanically, circ_0060927 regulated TBX2 expression by sequestering miR-331–3p in CRC cells. ConclusionCirc_0060927 downregulation inhibited CRC progression by regulating the miR-331–3p/TBX2 axis, which might offer a potential treatment target for CRC.