Dysregulation Of RNA-binding Proteins Research Articles

AEP promotes aberrant RNA splicing through DDX3X cleavage in solid tumors.

Aberrant alternative splicing (AS) events have been identified in a variety of cancers. Although somatic mutations of splicing factors and dysregulation of RNA-binding proteins (RBPs) have been linked to AS and tumor malignancy, it remains unclear how upstream mechanisms contribute to cancer development via alternative gene splicing. In this issue of the JCI, Wenrui Zhang and colleagues identified the role of asparagine endopeptidase (AEP), an intracellular cysteine endopeptidase, in promoting solid tumor-associated RNA splicing. The authors demonstrated that tumor environmental factors such as oxygen and nutrient deprivation induce the activity of AEP in a HIF1A-dependent manner. The activated AEP, in turn, cleaves an RNA helicase DDX3X to promote its nuclear retention. The authors further showed that this DDX3X nuclear fraction engages with splicing machinery to induce AS events in several cancer cells. These findings suggest that targeting an AEP-dependent aberrant RNA splicing cascade may facilitate therapeutics for solid tumors.

Modulation of insulin secretion by RBFOX2-mediated alternative splicing

Insulin secretion is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Although the molecular components of insulin granule trafficking and secretion are well established, how they are regulated to rapidly fine-tune secretion in response to changing environmental conditions is not well characterized. Recent studies have determined that dysregulation of RNA-binding proteins (RBPs) and aberrant mRNA splicing occurs at the onset of diabetes. We demonstrate that the RBP, RBFOX2, is a critical regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis. Conditional mutation of Rbfox2 in the mouse pancreas results in decreased insulin secretion and impaired blood glucose homeostasis. Consistent with defects in secretion, we observe reduced insulin granule docking and corresponding splicing defects in the SNARE complex components. These findings identify an additional mechanism for modulating insulin secretion in both healthy and dysfunctional pancreatic β cells.

Identification of RNA-binding Proteins in Spinal Cord Injury: An In-silico Approach

Introduction: Gene expression is regulated by trans-acting factors such as microRNA, and RNA-binding proteins (RBPs). Dysregulation of RNA-binding proteins (RBPs) are found in neurological diseases. However, the role RBPs in spinal cord injury (SCI) have not been identified. The objective of this study was to identify RBPs by re-analyzing RNA-sequencing data from SCI mice model using the latest version of Tuxedo pipeline. Methods: Reads from transcriptomic sequence of acute, subacute, and control mice models, from the Sequence Read Archive (SRA) website, were uploaded to a scientific workflow system called usegalaxy.org. The reads were assessed for their quality using FastQC, before they were mapped to the mouse mm10 reference genome using HISAT2. The fragments were then aligned to full-length transcripts using Stringtie, followed by DESeq2 to find differentially expressed genes (false discovery rate of 0.05 and fold change of -1< x >1). Finally, to find functional annotations, the Protein Analysis through Evolutionary Relationship (PANTHER) and g:Profiler were used. Results: There were 24 RBP-coding genes identified in the acute injury, and 27 in the subacute injury. Four RBPs that were commonly expressed at high levels in both acute and subacute injury; Hnrnpm, Ptbp3, Rbfox3 and Znf385a. These proteins regulate alternative splicing, and RNA transport. Other RBP-coding genes with a role in inflammatory response and apoptosis were also discovered. Conclusion: Novel RBP-coding genes differentially expressed in SCI were discovered, suggesting their role in the pathophysiology of SCI. These findings contribute to a better understanding of the regulatory mechanisms employed by RBPs in SCI.

Surmounting Cancer Drug Resistance: New Perspective on RNA-Binding Proteins.

RNA-binding proteins (RBPs), being pivotal elements in both physiological and pathological processes, possess the ability to directly impact RNA, thereby exerting a profound influence on cellular life. Furthermore, the dysregulation of RBPs not only induces alterations in the expression levels of genes associated with cancer but also impairs the occurrence of post-transcriptional regulatory mechanisms. Consequently, these circumstances can give rise to aberrations in cellular processes, ultimately resulting in alterations within the proteome. An aberrant proteome can disrupt the equilibrium between oncogenes and tumor suppressor genes, promoting cancer progression. Given their significant role in modulating gene expression and post-transcriptional regulation, directing therapeutic interventions towards RBPs represents a viable strategy for combating drug resistance in cancer treatment. RBPs possess significant potential as diagnostic and prognostic markers for diverse cancer types. Gaining comprehensive insights into the structure and functionality of RBPs, along with delving deeper into the molecular mechanisms underlying RBPs in tumor drug resistance, can enhance cancer treatment strategies and augment the prognostic outcomes for individuals afflicted with cancer.

An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene.

Oncogenic RAS signaling reprograms gene expression through both transcriptional and post-transcriptional mechanisms. While transcriptional regulation downstream of RAS is relatively well characterized, how RAS post-transcriptionally modulates gene expression to promote malignancy remains largely unclear. Using quantitative RNA interactome capture analysis, we here reveal that oncogenic RAS signaling reshapes the RNA-bound proteomic landscape of pancreatic cancer cells, with a network of nuclear proteins centered around nucleolin displaying enhanced RNA-binding activity. We show that nucleolin is phosphorylated downstream of RAS, which increases its binding to pre-ribosomal RNA (rRNA), boosts rRNA production, and promotes ribosome biogenesis. This nucleolin-dependent enhancement of ribosome biogenesis is crucial for RAS-induced pancreatic cancer cell proliferation and can be targeted therapeutically to inhibit tumor growth. Our results reveal that oncogenic RAS signaling drives ribosome biogenesis by regulating the RNA-binding activity of nucleolin and highlight a crucial role for this mechanism in RAS-mediated tumorigenesis.

Upregulated SSB Is Involved in Hepatocellular Carcinoma Progression and Metastasis through the Epithelial-Mesenchymal Transition, Antiapoptosis, and Altered ROS Level Pathway.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high morbidity and mortality. Therefore, finding new diagnostic and therapeutic targets is vital for HCC patients. Recent studies have shown that dysregulation of RNA-binding proteins is often associated with cancer progression. Several studies have reported that the RNA-binding protein SSB can promote cancer occurrence and progression and is linked to tumor epithelial-mesenchymal transition (EMT), which could be a new diagnostic marker and therapeutic target. However, the expression and function of SSB in HCC remain to be elucidated. Therefore, this study is aimed at clarifying the expression and biological function of SSB in HCC through bioinformatics analysis combined with in vitro experiments. We found that SSB is highly expressed in HCC and is associated with the poor prognosis of HCC patients, and it can serve as an independent unfavorable prognostic factor. Knockdown of SSB can inhibit the growth of HCC cells in vitro, increase the level of apoptosis and the expression of pro-apoptosis-related proteins, and decrease the expression of antiapoptotic proteins. Meanwhile, SSB knockdown reduced HCC cell invasiveness, and the expression of EMT-related proteins changed significantly. We also found that the gene SSB was associated with the level of oxidative stress in liver cancer cells, and the level of intracellular reactive oxygen species (ROS) increased after knockdown of SSB. The results of bioinformatics analysis also showed that high expression of SSB may affect the effect of checkpoint blockade (ICB) therapy. In conclusion, we found that SSB is highly expressed in HCC and that upregulated SSB can promote the proliferation and metastasis of HCC through antiapoptotic, altered intracellular oxidative stress level, and EMT pathways, which can serve as a new diagnostic marker and therapeutic target, and patients with high SSB expression may not have obvious ICB therapy effect.

Post-Transcriptional Modification by Alternative Splicing and Pathogenic Splicing Variants in Cardiovascular Development and Congenital Heart Defects.

Advancements in genomics, bioinformatics, and genome editing have uncovered new dimensions in gene regulation. Post-transcriptional modifications by the alternative splicing of mRNA transcripts are critical regulatory mechanisms of mammalian gene expression. In the heart, there is an expanding interest in elucidating the role of alternative splicing in transcriptome regulation. Substantial efforts were directed toward investigating this process in heart development and failure. However, few studies shed light on alternative splicing products and their dysregulation in congenital heart defects (CHDs). While elegant reports showed the crucial roles of RNA binding proteins (RBPs) in orchestrating splicing transitions during heart development and failure, the impact of RBPs dysregulation or genetic variation on CHDs has not been fully addressed. Herein, we review the current understanding of alternative splicing and RBPs' roles in heart development and CHDs. Wediscuss the impact of perinatal splicing transition and its dysregulation in CHDs. We further summarize the discoveries made of causal splicing variants in key transcription factors that are implicated in CHDs. An improved understanding of the roles of alternative splicing in heart development and CHDs may potentially inform novel preventive and therapeutic advancements for newborn infants with CHDs.

Targeted Musashi1 knockdown leads to reduce tau pathology and improves cognitive function in aged P301L mouse model

AbstractBackgroundThe buildup of toxic tau species in the brain is thought to lead to the development of Alzheimer’s disease. While our current understanding of the mechanisms underlying this aggregation is limited, growing evidence has pointed to RNA‐binding proteins (RBPs) playing a role. The dysregulation of RBPs is associated with various neurodegenerative diseases. For example, during amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD), dysregulated TDP‐43 accumulates in the brain. Similarly, our recent studies showed that the RBP, Musashi‐1 (MSI1), may co‐aggregate with toxic tau oligomers in Alzheimer’s disease. Clarifying the connection between these two proteins may provide novel insights into the mechanisms behind toxic tau buildup in Alzheimer’s, allowing for new therapeutic targets in treatment development.MethodIn this study, we investigated the role of MSI1 on the aggregation and deposition of tau in aged (18‐months old) P301L mouse models, which express the P301L mutant form of tau. MSI1 expression was knocked down (KD) by performing intracerebroventricular injections of MSI1 antisense oligonucleotides into the hippocampus. The effects of MSI1 KD on tau accumulation and pathology were studied in the hippocampus, cortex, and cerebellum.ResultWestern blot and immunofluorescence (IF) analysis revealed a significant reduction in MSI1 and tau proteins levels and aggregation in the P301L mouse brain, mainly in the hippocampus. Furthermore, brain Co‐IF microscopy and Dot Blot analysis of the PBS‐ and Sarkosyl‐soluble fractions showed that there was a significant reduction of MSI1 and tau oligomeric species in the hippocampus, cortex, and cerebellum in MSI1 KD mice. In addition, phosphorylated tau forms (pSer422, pSer202/Thr205, pThr212/Ser214 and pThr231/Ser235) were significantly decreased in the cortex, cerebellum, and most prominently, in the hippocampus. Increase in synaptic marker Synaptophysin suggesting an increase of synaptogenesis. Behavioral tests, Novel Object Recognition (NOR) and Y‐Maze spontaneous alternations tests, MSI1‐KD mice showed significant improvements.ConclusionThese results suggest that MSI1 plays a major role in tau toxicity, revealing it as a possible target for treating Alzheimer’s disease.

Exploration and validation of the prognostic value of RNA-binding proteins in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Increasing evidence suggests that the dysregulation of RNA-binding proteins (RBPs) is involved in the development of various cancers. However, there is a paucity of studies investigating the roles of RBPs in HCC. Data on HCC samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases (available at: www.ncbi.nlm.nih.gov/geo), and data regarding human RBPs were integrated from SONAR, XRNAX, and CARIC results. We identified modules associated with prognosis using weighted gene co-expression network analysis (WGCNA) and performed functional enrichment analysis. Univariate and least absolute shrinkage and selection operator (LASSO) regression analyses were used to identify prognostic RBPs and establish a prediction model. According to the median risk score, we separated patients into high- and low-risk groups and investigated the differences in immune cell infiltration, somatic mutations, and gene set enrichment. Univariate and multivariate regression analyses were used to identify prognostic factors for HCC. A nomogram was constructed, and its performance was evaluated with calibration curves. Sixteen RBPs (MEX3A, TTK, MRPL53, IQGAP3, PFN2, IMPDH1, TCOF1, DYNC1LI1, EIF2B4, NOL10, GNL2, EIF1B, PSMD1, AHSA1, SEC61A1, and YBX1) were identified as prognostic genes, and a prognostic model was established. Survival analysis indicated that the model had good predictive performance and that a high-risk score was significantly related to a poor prognosis. Additionally, there were significant differences in immune cell infiltration, somatic mutations, and gene set enrichment between the high- and low-risk groups. Univariate and multivariate regression analyses indicated that the RBP-based signature was an independent prognostic factor for HCC. The nomogram based on 16 RBPs performed well in predicting the overall survival of HCC patients. The RBP-based signature is an independent prognostic factor for HCC, and this study could provide an innovative method for analyzing prognostic biomarkers and therapeutic targets for HCC.

Comprehensive landscape of the functions and prognostic value of RNA binding proteins in uterine corpus endometrial carcinoma.

Background: The dysregulation of RNA binding proteins (RBPs) is involved in tumorigenesis and progression. However, information on the overall function of RNA binding proteins in Uterine Corpus Endometrial Carcinoma (UCEC) remains to be studied. This study aimed to explore Uterine Corpus Endometrial Carcinoma-associated molecular mechanisms and develop an RNA-binding protein-associated prognostic model. Methods: Differently expressed RNA binding proteins were identified between Uterine Corpus Endometrial Carcinoma tumor tissues and normal tissues by R packages (DESeq2, edgeR) from The Cancer Genome Atlas (TCGA) database. Hub RBPs were subsequently identified by univariate and multivariate Cox regression analyses. The cBioPortal platform, R packages (ggplot2), Human Protein Atlas (HPA), and TIMER online database were used to explore the molecular mechanisms of Uterine Corpus Endometrial Carcinoma. Kaplan-Meier (K-M), Area Under Curve (AUC), and the consistency index (c-index) were used to test the performance of our model. Results: We identified 128 differently expressed RNA binding proteins between Uterine Corpus Endometrial Carcinoma tumor tissues and normal tissues. Seven RNA binding proteins genes (NOP10, RBPMS, ATXN1, SBDS, POP5, CD3EAP, ZC3H12C) were screened as prognostic hub genes and used to construct a prognostic model. Such a model may be able to predict patient prognosis and acquire the best possible treatment. Further analysis indicated that, based on our model, the patients in the high-risk subgroup had poor overall survival (OS) compared to those in the low-risk subgroup. We also established a nomogram based on seven RNA binding proteins. This nomogram could inform individualized diagnostic and therapeutic strategies for Uterine Corpus Endometrial Carcinoma. Conclusion: Our work focused on systematically analyzing a large cohort of Uterine Corpus Endometrial Carcinoma patients in the The Cancer Genome Atlas database. We subsequently constructed a robust prognostic model based on seven RNA binding proteins that may soon inform individualized diagnosis and treatment.

The Role of RNA-Binding Proteins in Hematological Malignancies.

Hematological malignancies comprise a plethora of different neoplasms, such as leukemia, lymphoma, and myeloma, plus a myriad of dysplasia, such as myelodysplastic syndromes or anemias. Despite all the advances in patient care and the development of new therapies, some of these malignancies remain incurable, mainly due to resistance and refractoriness to treatment. Therefore, there is an unmet clinical need to identify new biomarkers and potential therapeutic targets that play a role in treatment resistance and contribute to the poor outcomes of these tumors. RNA-binding proteins (RBPs) are a diverse class of proteins that interact with transcripts and noncoding RNAs and are involved in every step of the post-transcriptional processing of transcripts. Dysregulation of RBPs has been associated with the development of hematological malignancies, making them potential valuable biomarkers and potential therapeutic targets. Although a number of dysregulated RBPs have been identified in hematological malignancies, there is a critical need to understand the biology underlying their contribution to pathology, such as the spatiotemporal context and molecular mechanisms involved. In this review, we emphasize the importance of deciphering the regulatory mechanisms of RBPs to pinpoint novel therapeutic targets that could drive or contribute to hematological malignancy biology.

In silico study predicts a key role of RNA-binding domains 3 and 4 in nucleolin-miRNA interactions.

RNA binding proteins (RBPs) regulate many important cellular processes through their interactions with RNA molecules. RBPs are critical for posttranscriptional mechanisms keeping gene regulation in a fine equilibrium. Conversely, dysregulation of RBPs and RNA metabolism pathways is an established hallmark of tumorigenesis. Human nucleolin (NCL) is a multifunctional RBP that interacts with different types of RNA molecules, in part through its four RNA binding domains (RBDs). Particularly, NCL interacts directly with microRNAs (miRNAs) and is involved in their aberrant processing linked with many cancers, including breast cancer. Nonetheless, molecular details of the NCL-miRNA interaction remain obscure. In this study, we used an in silico approach to characterize how NCL targets miRNAs and whether this specificity is imposed by a definite RBD-interface. Here, we present structural models of NCL-RBDs and miRNAs, as well as predict scenarios of NCL-miRNA interactions generated using docking algorithms. Our study suggests a predominant role of NCL RBDs 3 and 4 (RBD3-4) in miRNA binding. We provide detailed analyses of specific motifs/residues at the NCL-substrate interface in both these RBDs and miRNAs. Finally, we propose that the evolutionary emergence of more than two RBDs in NCL in higher organisms coincides with its additional role/s in miRNA processing. Our study shows that RBD3-4 display sequence/structural determinants to specifically recognize miRNA precursor molecules. Moreover, the insights from this study can ultimately support the design of novel antineoplastic drugs aimed at regulating NCL-dependent biological pathways with a causal role in tumorigenesis.

Immune-Related RNA-Binding Protein-Based Signature With Predictive and Prognostic Implications in Patients With Lung Adenocarcinoma.

Background: Dysregulation of RNA-binding proteins (RBPs) in cancers is associated with immune and cancer development. Here, we aimed to profile immune-related RBPs in lung adenocarcinoma (LUAD) and construct an immune-related RBP signature (IRBPS) to predict the survival and response to immunotherapy. Methods: A correlation analysis was performed to establish a co-expression network of RBPs and immune-related genes (IRGs) to characterize immune-related RBPs in the TCGA–LUAD cohort (n = 497 cases). Then, a combination of the Random survival forest (RSF) and Cox regression analysis was performed to screen the RBPs and establish IRBPS. This was followed by independent validation of IRBPS in GSE72094 (n = 398 cases), GSE31210, (n = 226 cases), and GSE26939 (n = 114 cases). Differences between the low- and high-risk groups were compared in terms of gene mutations, tumor mutation burden, tumor-infiltrating lymphocytes, and biomarkers responsive to immunotherapy. Results: DDX56, CTSL, ZC3H12D, and PSMC5 were selected and used to construct IRBPS. The high-risk scores of patients had a significantly worse prognosis in both training and testing cohorts (p < 0.0001 and p < 0.05, respectively), and they tended to be older and have an advanced TNM stage. Furthermore, IRBPS was a prognostic factor independent of age, gender, smoking history, TNM stage, and EGFR mutation status (p = 0.002). In addition, high-risk scores of IRBPS were significantly correlated with tumor-infiltrating lymphocytes (p < 0.05). They also had a high level of PD-L1 protein expression (p < 0.01), number of neoantigens (p < 0.001), and TMB (p < 0.001), implying the possible prediction of IRBPS in the immunotherapy of LUAD. Conclusion: The currently established IRBPS encompassing immune-related RBPs might serve as a promising tool to predict survival, reflect the immune microenvironment, and predict the efficacy of immunotherapy among LUAD patients.

FXR1 can bind with the CFIm25/CFIm68 complex and promote the progression of urothelial carcinoma of the bladder by stabilizing TRAF1 mRNA

RNA-binding proteins (RBPs) are key regulators of gene expression. RBP dysregulation is reported to play essential roles in tumorigenesis. However, the role of RBPs in urothelial carcinoma of the bladder (UCB) is only starting to be unveiled. Here, we comprehensively assessed the mRNA expression landscape of 104 RBPs from two independent UCB cohorts, Sun Yat-sen University Cancer Center (SYSUCC) and The Cancer Genome Atlas (TCGA). Fragile X-related gene 1 (FXR1) was identified as a novel cancer driver gene in UCB. FXR1 overexpression was found to be related to the poor survival rate in the SYSUCC and TCGA cohorts. Functionally, FXR1 promotes UCB proliferation and tumorigenesis. Mechanistically, FXR1 serves as a platform to recruit CFIm25 and CFIm68, forming a novel 3′ processing machinery that functions in sequence-specific poly(A) site recognition. FXR1 affects the 3′ processing of Tumor necrosis factor receptor-associated factor 1 (TRAF1) mRNA, which leads to nuclear stabilization. The novel regulatory relationship between FXR1 and TRAF1 can enhance cell proliferation and suppress apoptosis. Our data collectively highlight the novel regulatory role of FXR1 in TRAF1 3′ processing as an important determinant of UCB oncogenesis. Our study provides new insight into RBP function and provides a potential therapeutic target for UCB.

Development and Validation of a Prognostic Model of RNA-Binding Proteins in Colon Adenocarcinoma: A Study Based on TCGA and GEO Databases.

BackgroundPrevious studies reported that dysregulation of RNA-binding proteins (RBPs) is significantly associated with the development of cancer. However, there are few studies to date on the role of RBPs in colon adenocarcinoma (COAD).MethodsRNA sequencing and clinical data for COAD patients were downloaded from The Cancer Genome Atlas (TCGA) database to identify differentially expressed (DE) RBPs between COAD tissue and normal colon tissue, and then the expression and prognostic significance of these RBPs were investigated in detail by systematic bioinformatics analysis. qRT-PCR was used to validate the expressions of prognosis-related RBP-encoding genes.ResultsSeven RBPs (RPL10L, ERI1, POP1, CAPRIN2, TDRD7, SNIP1 and PPARGC1A) were identified as hub genes associated with prognosis by a series of regression analyses, and were then used to construct a prognostic model. Further analysis based on this model indicated that the overall survival (OS) of the high-risk groups was lower than that of the low-risk groups. In this prognostic model, the area under the ROC curve (AUC) was 0.694, 0.709 and 0.665 for the TCGA cohort at 1, 3 and 5 years, respectively, while the AUC was 0.671, 0.633 and 0.601 for the GEO combined cohort at 1, 3 and 5 years, respectively, indicating the good predictive ability of the model. We also built a nomogram based on the 7 RBPs in the TCGA cohort, and the model showed good discriminatory ability for COAD.ConclusionWe screened seven prognosis-related genes in COAD patients based on RBP-related genes, validated the expressions of the seven prognosis-related RBP-encoding genes by qRT-PCR and constructed a prognosis-related nomogram for patients with COAD.

The Function and Prognostic Value of RNA-Binding Proteins in Colorectal Adenocarcinoma Were Analyzed Based on Bioinformatics of Smart Medical Big Data.

Colon cancer is the third most frequent cancer in the world and is mainly adenocarcinoma in terms of pathological type. It has been confirmed that the dysregulation of RNA-binding proteins (RBPs) significantly participates in the occurrence and development of numerous malignant tumors. Therefore, we analyzed the RBPs associated with colon adenocarcinoma (COAD) to assess their possible biological effects and prognostic value. A total of 398 COAD tissue datasets and 39 normal tissue datasets were retrieved from the TCGA data resource and screened out the RBPs, which are differentially expressed between tumor tissues and nontumor tissues. Then, bioinformatics analyses based on smart medical big data were conducted on these RBPs. Overall, 181 differentially expressed RBPs were uncovered, consisting of 121 upregulated RBPs and 60 downregulated RBPs. Finally, we selected 7 prognostic-related RBPs with research prospects and constructed a prognostic model according to the median risk score. There were remarkable differences in OS between the high-risk and low-risk groups. In addition, the performance of the prognostic model was evaluated and verified with other COAD patient data in the TCGA database. The results showed that the area under the ROC curve (AUC) for the train group was 0.744 and the one for the test group was 0.661, confirming that the model assesses patients' prognosis to some extent. And based on 7 hub RBPs, we constructed a nomogram as a reference for evaluating the survival rate of COAD patients.

Therapeutic targeting of RNA-binding protein by RNA-PROTAC

Therapeutic targeting of RNA-binding protein by RNA-PROTAC

A New RBPs-Related Signature Predicts the Prognosis of Colon Adenocarcinoma Patients.

The dysregulation of RNA binding proteins (RBPs) is closely related to tumorigenesis and development. However, the role of RBPs in Colon adenocarcinoma (COAD) is still poorly understood. We downloaded COAD’s RNASeq data from the Cancer Genome Atlas (TCGA) database, screened the differently expressed RBPs in normal tissues and tumor, and constructed a protein interaction network. COAD patients were randomly divided into a training set (N = 315) and a testing set (N = 132). In the training set, univariate Cox analysis identified 12 RBPs significantly related to the prognosis of COAD. By multivariate COX analysis, we constructed a prognostic model composed of five RBPs (CELF4, LRRFIP2, NOP14, PPARGC1A, ZNF385A) based on the lowest Akaike information criterion. Each COAD patient was scored according to the model formula. Further analysis showed that compared with the low-risk group, the overall survival rate (OS) of patients in the high-risk group was significantly lower. The area under the curve of the time-dependent receiver operator characteristic (ROC) curve was 0.722 in the training group and 0.738 in the test group, which confirmed a good prediction feature. In addition, a nomogram was constructed based on clinicopathological characteristics and risk scores. C-index and calibration curve proved the accuracy in predicting the 1-, 3-, and 5-year survival rates of COAD patients. In short, we constructed a superior prognostic and diagnostic signature composed of five RBPs, which indicates new possibilities for individualized treatment of COAD patients.

RNA-Binding Proteins and the Complex Pathophysiology of ALS.

Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have identified disease-causing mutations and accelerated the unveiling of complex molecular pathogenic mechanisms, which may be important for understanding the disease and developing therapeutic strategies. Many disease-related genes encode RNA-binding proteins, and most of the disease-causing RNA or proteins encoded by these genes form aggregates and disrupt cellular function related to RNA metabolism. Disease-related RNA or proteins interact or sequester other RNA-binding proteins. Eventually, many disease-causing mutations lead to the dysregulation of nucleocytoplasmic shuttling, the dysfunction of stress granules, and the altered dynamic function of the nucleolus as well as other membrane-less organelles. As RNA-binding proteins are usually components of several RNA-binding protein complexes that have other roles, the dysregulation of RNA-binding proteins tends to cause diverse forms of cellular dysfunction. Therefore, understanding the role of RNA-binding proteins will help elucidate the complex pathophysiology of ALS. Here, we summarize the current knowledge regarding the function of disease-associated RNA-binding proteins and their role in the dysfunction of membrane-less organelles.

A Prognostic Model Based on RNA Binding Protein Predicts Clinical Outcomes in Hepatocellular Carcinoma Patients.

Dysregulation of RNA binding proteins (RBPs) is closely associated with tumor events. However, the function of RBPs in hepatocellular carcinoma (HCC) has not been fully elucidated. The RNA sequences and relevant clinical data of HCC were retrieved from the The Cancer Genome Atlas (TCGA) database to identify distinct RBPs. Subsequently, univariate and multivariate cox regression analysis was performed to evaluate the overall survival (OS)-associated RBPs. The expression levels of prognostic RBP genes and survival information were analyzed using a series of bioinformatics tool. A total of 365 samples with 1,542 RBPs were included in this study. One hundred and eighty-seven differently RBPs were screened, including 175 up-regulated and 12 down-regulated. The independent OS-associated RBPs of NHP2, UPF3B, and SMG5 were used to develop a prognostic model. Survival analysis showed that low-risk patients had a significantly longer OS and disease-free survival (DFS) when compared to high-risk patients (HR: 2.577, 95% CI: 1.793–3.704, P < 0.001 and HR: 1.599, 95% CI: 1.185–2.159, P = 0.001, respectively). The International Cancer Genome Consortium (ICGC) database was used to externally validate the model, and the OS of low-risk patients were found to be longer than that of high-risk patients (P < 0.001). The Nomograms of OS and DFS were plotted to help in clinical decision making. These results showed that the model was effective and may help in prognostic stratification of HCC patients. The prognostic prediction model based on RBPs provides new insights for HCC diagnosis and personalized treatment.