Construction and validation of somatic mutation-derived long noncoding RNAs signatures of genomic instability to predict prognosis of hepatocellular carcinoma

BACKGROUND Long non-coding RNAs(LncRNAs)have been found to be a potential prognostic factor for cancers,including hepatocellular carcinoma(HCC).Some LncRNAs have been confirmed as potential indicators to quantify genomic instability(GI).Nevertheless,GI-LncRNAs remain largely unexplored.This study established a GI-derived LncRNA signature(GILncSig)that can predict the prognosis of HCC patients.AIM To establish a GILncSig that can predict the prognosis of HCC patients.METHODS Identification of GI-LncRNAs was conducted by combining LncRNA expression and somatic mutation profiles.The GI-LncRNAs were then analyzed for functional enrichment.The GILncSig was established in the training set by Cox regression analysis,and its predictive ability was verified in the testing set and TCGA set.In addition,we explored the effects of the GILncSig and TP53 on prognosis.RESULTS A total of 88 GI-LncRNAs were found,and functional enrichment analysis showed that their functions were mainly involved in small molecule metabolism and GI.The GILncSig was constructed by 5 LncRNAs(miR210HG,AC016735.1,AC116351.1,AC010643.1,LUCAT1).In the training set,the prognosis of high-risk patients was significantly worse than that of low-risk patients,and similar results were verified in the testing set and TCGA set.Multivariate Cox regression analysis and stratified analysis confirmed that the GILncSig could be used as an independent prognostic factor.Receiver operating characteristic curve analysis of the GILncSig showed that the area under the curve(0.773)was higher than the two LncRNA signatures published recently.Furthermore,the GILncSig may have a better predictive performance than TP53 mutation status alone.CONCLUSION We established a GILncSig that can predict the prognosis of HCC patients,which will help to guide prognostic evaluation and treatment decisions.

Lipid metabolism-related long noncoding RNAs:A potential prognostic biomarker for hepatocellular carcinoma

The incidence rates of hepatocellular carcinoma(HCC)have increased in recent decades.Despite advancements in therapy and early diagnosis improving shortterm prognosis,long-term outcomes remain poor.Long noncoding RNAs(lncRNAs)and lipid metabolism play crucial roles in the development and progression of HCC.Enhanced lipid synthesis promotes HCC progression,and lncRNAs can reprogram the expression of lipogenic enzymes.Consequently,lipid metabolism-related(LMR)-lncRNAs regulate lipid anabolism,accelerating the onset and progression of HCC.This suggests that LMR-lncRNAs could serve as novel prognostic biomarkers and therapeutic targets.

Curcumin inhibits the growth and invasion of gastric cancer by regulating long noncoding RNA AC022424.2

BACKGROUND Gastric cancer,characterized by a multifactorial etiology and high heterogeneity,continues to confound researchers in terms of its pathogenesis.Curcumin,a natural anticancer agent,exhibits therapeutic promise in gastric cancer.Its effects include promoting cell apoptosis,curtailing tumor angiogenesis,and enhancing sensitivity to radiation and chemotherapy.Long noncoding RNAs(lncRNAs)have garnered significant attention as biomarkers for early screening,diagnosis,treatment,and drug response because of their remarkable specificity and sensitivity.Recent investigations have revealed an association between aberrant lncRNA expression and early diagnosis,clinical staging,metastasis,drug sensitivity,and prognosis in gastric cancer.A profound understanding of the intricate mechanisms through which lncRNAs influence gastric cancer develop-ment can provide novel insights for precision treatment and tailored management of patients with gastric cancer.This study aimed to unravel the potential of curcumin in suppressing the malignant behavior of gastric cancer cells by upregu-lating specific lncRNAs and modulating gastric cancer onset and progression.AIM To identify lncRNAs associated with curcumin treatment and investigate the role of lncRNA AC022424.2 in the effects of curcumin on gastric cancer cell apoptosis,proliferation,and invasion.Furthermore,these findings were validated in clinical samples.METHODS The study employed CCK-8 assays to assess the impact of curcumin on gastric cancer cell proliferation,flow cytometry to investigate its effects on apoptosis,and scratch and Transwell assays to evaluate its influence on the migration and invasion of BGC-823 and MGC-803 cells.Western blotting was used to gauge changes in the protein expression levels of CDK6,CDK4,Bax,Bcl-2,caspase-3,P65,and the PI3K/Akt/mTOR pathway in gastric cancer cell lines after curcumin treatment.Differential expression of lncRNAs before and after curcumin treatment was assessed using lncRNA sequencing and validated using quantitative reverse transcription polymerase chain reaction(qRT-PCR)in BGC-823 and MGC-803 cells.AC022424.2-1 knockdown BGC-823 and MGC-803 cells were generated to scrutinize the impact of lncRNA AC022424.2 on apoptosis,proliferation,migration,and invasion of gastric cancer cells.Western blotting was performed to ascertain changes in the expression of proteins implicated in the PI3K/Akt/mTOR and NF-κB signaling pathways.RT-PCR was employed to measure lncRNA AC022424.2 expression in clinical gastric cancer tissues and to correlate its expression with clinical pathological characteristics.RESULTS Curcumin induced apoptosis and hindered proliferation,migration,and invasion of gastric cancer cells in a dose-and time-dependent manner.LncRNA AC022424.2 was upregulated after curcumin treatment,and its knockdown enhanced cancer cell aggressiveness.LncRNA AC022424.2 may have affected cancer cells via the PI3K/Akt/mTOR and NF-κB signaling pathways.LncRNA AC022424.2 downregulation was correlated with lymph node metastasis,making it a potential diagnostic and prognostic marker.CONCLUSION Curcumin has potential anticancer effects on gastric cancer cells by regulating lncRNA AC022424.2.This lncRNA plays a significant role in cancer cell behavior and may have clinical implications in diagnosis and prognosis evaluation.The results of this study enhance our understanding of gastric cancer development and precision treatment.

Integrating disulfidptosis-related long noncoding RNAs in colorectal cancer prognosis:A path to precision medicine

This commentary explores the burgeoning field of disulfidptosis-related long noncoding RNAs(lncRNAs)in the prognosis and therapeutic targeting of colorectal cancer(CRC).By evaluating recent research,including the pivotal study"Predicting colorectal cancer prognosis based on long noncoding RNAs of disulfidptosis genes"by Wang et al,this analysis underscores the critical role of lncRNAs in deciphering the molecular complexities of CRC.Highlighting the innovative methodologies and significant findings,I discuss the implications for patient survival,therapeutic response,and the potential of lncRNAs as biomarkers for precision medicine.The integration of bioinformatics,clinical databases,and molecular biology in these studies offers a promising avenue for advancing CRC treatment strategies and improving patient outcomes.

Prognostic value of the long noncoding RNA AFAP1-AS1 in cancers

Objective This meta-analysis explored whether the expression of actin filament-associated protein 1 antisense RNA 1(AFAP1-AS1)is related to the prognosis and clinicopathological features of patients with cancer.Methods PubMed,EMBASE,and Cochrane Library were systematically searched.Hazard ratios(HRs)with 95%confidence intervals(CIs)were used to assess the prognostic value based on overall survival(OS),disease-free survival(DFS),and progression-free survival(PFS).Odds ratios(ORs)with 95%CIs were used to determine the relationships between AFAP1-AS1 and clinicopathological features,such as large tumor size(LTS),high tumor stage(HTS),poor histological grade(PHG),lymph node metastasis(LNM),and distant metastasis(DM).Results Thirty-five eligible articles and 3433 cases were analyzed.High AFAP1-AS1 expression,compared to low AFAP1-AS1 expression,correlated with significantly shorter OS(HR=2.15,95%CI=1.97-2.34,P<0.001),DFS(HR=1.37,95%CI=1.19-1.57,P<0.001),and PFS(HR=1.97,95%CI=1.56-2.50,P<0.001)in patients with cancer.In various cancers,elevated AFAP1-AS1 expression was significantly associated with LTS(OR=2.76,95%CI=2.16-3.53,P<0.001),HTS(OR=2.23,95%CI=1.83-2.71,P<0.001),and PHG(OR=1.39,95%CI=1.08-1.79,P=0.01)but not LNM(OR=1.59,95%CI=0.88-2.85,P=0.12)or DM(OR=1.81,95%CI=0.90-3.66,P=0.10).Conclusion High AFAP1-AS1 expression was associated with prognostic and clinicopathological features,suggesting that AFAP1-AS1 is a prognostic biomarker for human cancers.

Long noncoding RNA steroid receptor RNA activator 1 inhibits proliferation and glycolysis of esophageal squamous cell carcinoma

BACKGROUND The clinical effects and detailed roles of long non-coding RNA(LncRNA)steroid receptor RNA activator 1(SRA1)in esophageal squamous cell carcinoma(ESCC)remain ambiguous.In the present study,the complementary sites between lncRNA SRA1,miRNA-363-5p,and phospholysine phosphohistidine inorganic pyrophosphate phosphatase(LHPP)predicted via bioinformatics analysis stimulated us to hypothesize that miRNA-363-5p/LHPP axis might be required for SRA1-mediated ESCC progression.AIM To investigate the molecular events of SRA1 in the malignant behavior in ESCC.METHODS Thirty-eight ESCC tissues and paired adjacent normal tissues were acquired.SRA1 expression was detected in ESCC tissues and cell lines using quantitative reverse transcription-polymerase chain reaction.Cell counting Kit-8 assay,transwell invasion assay,glycolysis assay,and xenograft tumor model were performed to address the malignant biological behaviors of ESCC cells after the introduction of SRA1.The t-test and theχ2 test were used for comparison between groups.Survival curve analysis was performed using the Kaplan-Meier method.RESULTS SRA1 downregulation was identified in ESCC.ESCC patients exhibiting a low SRA1 expression faced shorter overall survival than those with a high SRA1 expression.The introduction of SRA1 inhibited cell proliferation,glucose uptake,and lactate production in ESCC.In vivo,the growth of ESCC was hindered by SRA1 overexpression.Then,SRA1 overexpresses the LHPP by inhibiting miRNA-363-5p.Lastly,the introduction of small interfering RNA si-LHPP or miRNA-363-5p mimic could abrogate the inhibition roles triggered by SRA1.CONCLUSION SRA1 inhibits the oncogenicity of ESCC via miRNA-363-5p/LHPP axis.The SRA1/miRNA-363-5p/LHPP pathway may be a therapeutic target for ESCC.

Exploring prognostic potential of long noncoding RNAs in colorectal cancer based on a competing endogenous RNA network

BACKGROUND Colorectal cancer(CRC)is one of the most prevalent tumors worldwide.Recently,long noncoding RNAs(lncRNAs)have been shown to influence tumorigenesis and tumor progression by acting as competing endogenous RNAs(ceRNAs).It is difficult to extract prognostic lncRNAs and useful bioinformation from most ceRNA networks constructed previously.AIM To construct a prognostic related ceRNA regulatory network and lncRNA related signature based on risk score in CRC.METHODS RNA transcriptome profile and clinical information of 506 CRC patients were downloaded from the Cancer Genome Atlas database.R packages and Perl program were used for data processing.Cox regression analysis was used for prognostic model construction.Quantitative real-time polymerase chain reaction was used to detect the expression of lncRNAs.RESULTS A prognostic-related ceRNA network was constructed,including 9 lncRNAs,44 mRNAs,and 30 miRNAs.In addition,a four-lncRNA model was constructed using multivariate Cox regression analysis,which could be an independent prognostic model in CRC.The risk score for each patient was calculated,and the 506 patients were divided into high and low-risk groups(253 for each group)based on the median risk score.The results of the survival analysis showed that patients with a high-risk score had a poor survival rate.Furthermore,the predictive value of the four-lncRNA model was evaluated in GSE38832.Patient survival probabilities could be better predicted when combing the risk score and clinical features.Gene Set Enrichment Analysis results verified that a number of cancer-related signaling pathways were enriched with a high-risk score in CRC.Finally,we validated a novel lncRNA(LINC00488)using quantitative real-time polymerase chain reaction in 22 paired CRC patient tumor tissues compared to adjacent non-tumor tissues.CONCLUSION The four-lncRNA model could give better predictive value for CRC patients.Our understanding of the lncRNA-related ceRNA regulatory mechanism could provide a potential diagnostic indicator for CRC patients.

Role of long noncoding RNA-mediated competing endogenous RNA regulatory network in hepatocellular carcinoma

Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are noncodingRNAs (ncRNAs) that occupy over 90% of the human genome, and their mainfunction is to directly or indirectly regulate messenger RNA (mRNA) expressionand participate in the tumorigenesis and progression of malignances. Inparticular, some lncRNAs can interact with miRNAs as competing endogenousRNAs (ceRNAs) to modulate mRNA expression. Accordingly, these RNAmolecules are interrelated and coordinate to form a dynamic lncRNA-mediatedceRNA regulatory network. Mounting evidence has revealed that lncRNAs thatact as ceRNAs are closely related to tumorigenesis. To date, numerous studieshave established many different regulatory networks in hepatocellular carcinoma(HCC), and perturbations in these ceRNA interactions may result in the initiationand progression of HCC. Herein, we emphasize recent advances concerning thebiological function of lncRNAs as ceRNAs in HCC, with the aim of elucidating themolecular mechanism underlying these HCC-related RNA molecules andproviding novel insights into the diagnosis and treatment of HCC.

Long noncoding RNA protein-disulfide isomerase-associated 3 regulated high glucose-induced podocyte apoptosis in diabetic nephropathy through targeting miR-139-3p

BACKGROUND Podocyte apoptosis plays a vital role in proteinuria pathogenesis in diabetic nephropathy(DN).The regulatory relationship between long noncoding RNAs(lncRNAs)and podocyte apoptosis has recently become another research hot spot in the DN field.AIM To investigate whether lncRNA protein-disulfide isomerase-associated 3(Pdia3)could regulate podocyte apoptosis through miR-139-3p and revealed the underlying mechanism.METHODS Using normal glucose or high glucose(HG)-cultured podocytes,the cellular functions and exact mechanisms underlying the regulatory effects of lncRNA Pdia3 on podocyte apoptosis and endoplasmic reticulum stress(ERS)were explored.LncRNA Pdia3 and miR-139-3p expression were measured through quantitative real-time polymerase chain reaction.Relative cell viability was detected through the cell counting kit-8 colorimetric assay.The podocyte apoptosis rate in each group was measured through flow cytometry.The interaction between lncRNA Pdia3 and miR-139-3p was examined through the dual luciferase reporter assay.Finally,western blotting was performed to detect the effect of lncRNA Pdia3 on podocyte apoptosis and ERS via miR-139-3p.RESULTS The expression of lncRNA Pdia3 was significantly downregulated in HG-cultured podocytes.Next,lncRNA Pdia3 was involved in HG-induced podocyte apoptosis.Furthermore,the dual luciferase reporter assay confirmed the direct interaction between lncRNA Pdia3 and miR-139-3p.LncRNA Pdia3 overexpression attenuated podocyte apoptosis and ERS through miR-139-3p in HG-cultured podocytes.CONCLUSION Taken together,this study demonstrated that lncRNA Pdia3 overexpression could attenuate HG-induced podocyte apoptosis and ERS by acting as a competing endogenous RNA of miR-139-3p,which might provide a potential therapeutic target for DN.

Differentially expressed long noncoding RNAs and regulatory mechanism of LINC02407 in human gastric adenocarcinoma

BACKGROUND Long noncoding RNAs(lncRNAs)have been identified to play important roles in the development and progression of various tumors,including gastric cancer(GC).However,the molecular role of lncRNAs in GC progression remains unclear.AIM To investigate the differential expression of lncRNAs in human GC and elucidate the function and regulatory mechanism of LINC02407.METHODS The Cancer Genome Atlas database was used to investigate the involvement of lncRNAs in GC.Quantitative real-time polymerase chain reaction was used to estimate the relative expression level of LINC02407 in GC tissues and cells.Functional experiments including CCK8 assay,apoptosis assay,wound healing assay,and transwell assay were used to investigate the effect of LINC02407 on GC cells.Some microRNAs were predicted and verified via bioinformatics analysis and the luciferase reporter system.Predictive analysis and Western blot assay were used to analyze the expression of related proteins.RESULTS Many differentially expressed lncRNAs were identified in GC,and some of them including LINC02407 can affect the survival.LINC02407 was upregulated in tumor tissues compared with adjacent tissues.HGC-27 cells showed the highest LINC02407 expression and HaCaT cells exhibited the lowest expression.Different experiment groups were constructed using LINC02407 overexpressing plasmids and related siRNAs.The results of functional experiments showed that LINC02407 can promote the proliferation,migration,and invasion of GC cells but inhibit apoptosis.Luciferase reporter assay showed that hsa-miR-6845-5p and hsa-miR-4455 was downstream regulated by LINC02407.Western blot analysis showed that adhesion G protein-coupled receptor D1(ADGRD1)was regulated by the LINC02407-miR-6845-5p/miR-4455-ADGRD1 pathways.CONCLUSION LINC02407 plays a role in GC through the LINC02407-miR-6845-5p/miR-4455-ADGRD1 pathways,and thus,it may be an important oncogene and has potential value in GC diagnosis and treatment.

Upregulation of long noncoding RNA W42 promotes tumor development by binding with DBN1 in hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)is a malignancy found globally.Accumulating studies have shown that long noncoding RNAs(lncRNAs)play critical roles in HCC.However,the function of lncRNA in HCC remains poorly understood.AIM To understand the effect of lncRNA W42 on HCC and dissect the underlying molecular mechanisms.METHODS We measured the expression of lncRNA W42 in HCC tissues and cells(Huh7 and SMMC-7721)by quantitative reverse transcriptase polymerase chain reaction.Receiver operating characteristic curves were used to assess the sensitivity and specificity of lncRNA W42 expression.HCC cells were transfected with pcDNA3.1-lncRNA W42 or shRNA-lncRNA W42.Cell functions were detected by cell counting Kit-8(CCK-8),colony formation,flow cytometry and Transwell assays.The interaction of lncRNA W42 and DBN1 was confirmed by RNA immunoprecipitation and RNA pull down assays.An HCC xenograft model was used to assess the role of lncRNA W42 on tumor growth in vivo.The Kaplan-Meier curve was used to evaluate the overall survival and recurrence-free survival after surgery in patients with HCC.RESULTS In this study,we identified a novel lncRNA(lncRNA W42),and investigated its biological functions and clinical significance in HCC.LncRNA W42 expression was upregulated in HCC tissues and cells.Overexpression of lncRNA W42 notably promoted the proliferative and invasion of HCC,and inhibited cell apoptosis.LncRNA W42 directly bound to DBN1 and activated the downstream pathway.LncRNA W42 knockdown suppressed HCC xenograft tumor growth in vivo.The clinical investigation revealed that HCC patients with high lncRNA W42 expression exhibited shorter survival times.CONCLUSION In vitro and in vivo results suggested that the novel lncRNA W42,which is upregulated in HCC,may serve as a potential candidate prognostic biomarker and therapeutic target in HCC patients.

Expression and regulatory network of long noncoding RNA in rats after spinal cord hemisection injury

Long noncoding RNAs(lncRNAs)participate in a variety of biological processes and diseases.However,the expression and function of lncRNAs after spinal cord injury has not been extensively analyzed.In this study of right side hemisection of the spinal cord at T10,we detected the expression of lncRNAs in the proximal tissue of T10 lamina at different time points and found 445 lncRNAs and 6522 mRNA were differentially expressed.We divided the differentially expressed lncRNAs into 26 expression trends and analyzed Profile 25 and Profile 2,the two expression trends with the most significant difference.Our results showed that the expression of 68 lncRNAs in Profile 25 rose first and remained high 3 days post-injury.There were 387 mRNAs co-expressed with the 68 lncRNAs in Profile 25.The co-expression network showed that the co-expressed genes were mainly enriched in cell division,inflammatory response,FcγR-mediated cell phagocytosis signaling pathway,cell cycle and apoptosis.The expression of 56 lncRNAs in Profile2 first declined and remained low after 3 days post-injury.There were 387 mRNAs co-expressed with the 56 lncRNAs in Profile 2.The co-expression network showed that the co-expressed genes were mainly enriched in the chemical synaptic transmission process and in the signaling pathway of neuroactive ligand-receptor interaction.The results provided the expression and regulatory network of the main lncRNAs after spinal cord injury and clarified their co-expressed gene enriched biological processes and signaling pathways.These findings provide a new direction for the clinical treatment of spinal cord injury.

Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis

BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues,but its role in HCC progression is unclear.Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.AIM To study the role of ultrasound microbubbles(UTMBs)mediated HAND2-AS1 in the progression of HCC,in order to provide a new reference for the treatment of HCC.METHODS In vitro,we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs,and detected cell proliferation,apoptosis,invasion and epithelial-mesenchymal transition(EMT)by cell counting kit-8 assay,flow cytometry,Transwell invasion assay and Western blotting,respectively.In addition,we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior.Next,the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2(TIMP2)overexpression vector,and we detected cell proliferation,apoptosis,invasion and EMT.In vivo,we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.RESULTS We found that UTMBs carrying HAND2-AS1 restricted cell proliferation,invasion,and EMT,encouraged apoptosis,and HAND2-AS1 silencing eliminated the effect of UTMBs.Additionally,miR-873-5p targets the gene HAND2-AS1,which also targets the 3’UTR of TIMP2.And miR-873-5p mimic counteracted the impact of HAND2-AS1.Further,miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs.We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase(MMP)2/MMP9.In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.CONCLUSION LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.

Analysis of long noncoding RNA-associated competing endogenous RNA network in glucagon-like peptide-1 receptor agonist-mediated protection inβcells

BACKGROUND Long noncoding RNAs(lncRNAs)and mRNAs are widely involved in various physiological and pathological processes.The use of glucagon-like peptide-1 receptor agonists(GLP-1RAs)is a novel therapeutic strategy that could promote insulin secretion and decrease the rate ofβ-cell apoptosis in type 2 diabetes mellitus(T2DM)patients.However,the specific lncRNAs and mRNAs and their functions in these processes have not been fully identified and elucidated.AIM To identify the lncRNAs and mRNAs that are involved in the protective effect of GLP-1RA inβcells,and their roles.METHODS Rat gene microarray was used to screen differentially expressed(DE)lncRNAs and mRNAs inβcells treated with geniposide,a GLP-1RA.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to assess the underlying functions of DE mRNAs.Hub mRNAs were filtered using the STRING database and the Cytoscape plugin,CytoHubba.In order to reveal the regulatory relationship between lncRNAs and hub mRNAs,their co-expression network was constructed based on the Pearson coefficient of DE lncRNAs and mRNAs,and competing endogenous RNA(ceRNA)mechanism was explored through miRanda and TargetScan databases.RESULTS We identified 308 DE lncRNAs and 128 DE mRNAs with a fold change filter of≥1.5 and P value<0.05.GO and KEGG pathway enrichment analyses indicated that the most enriched terms were G-protein coupled receptor signaling pathway,inflammatory response,calcium signaling pathway,positive regulation of cell proliferation,and ERK1 and ERK2 cascade.Pomc,Htr2a,and Agtr1a were screened as hub mRNAs using the STRING database and the Cytoscape plugin,CytoHubba.This result was further verified using SwissTargetPrediction tool.Through the co-expression network and competing endogenous(ceRNA)mechanism,we identified seven lncRNAs(NONRATT027738,NONRATT027888,NONRATT030038,etc.)co-expressed with the three hub mRNAs(Pomc,Htr2a,and Agtr1a)based on the Pearson coefficient of the expression levels.These lncRNAs regulated hub mRNA functions by competing with six miRNAs(rno-miR-5132-3p,rno-miR-344g,rno-miR-3075,etc.)via the ceRNA mechanism.Further analysis indicated that lncRNA NONRATT027738 interacts with all the three hub mRNAs,suggesting that it is at a core position within the ceRNA network.CONCLUSION We have identified key lncRNAs and mRNAs,and highlighted here how they interact through the ceRNA mechanism to mediate the protective effect of GLP-1RA inβcells.

Plasma long noncoding RNA expression profile identified by microarray in patients with Crohn's disease

AIM: To investigate the expression pattern of plasma long noncoding RNAs (lncRNAs) in Chrohn&#x02019;s disease (CD) patients.METHODS: Microarray screening and qRT-PCR verification of lncRNAs and mRNAs were performed in CD and control subjects, followed by hierarchy clustering, GO and KEGG pathway analyses. Significantly dysregulated lncRNAs were categorized into subgroups of antisense lncRNAs, enhancer lncRNAs and lincRNAs. To predict the regulatory effect of lncRNAs on mRNAs, a CNC network analysis was performed and cross linked with significantly changed lncRNAs. The overlapping lncRNAs were randomly selected and verified by qRT-PCR in a larger cohort.RESULTS: Initially, there were 1211 up-regulated and 777 down-regulated lncRNAs as well as 1020 up-regulated and 953 down-regulated mRNAs after microarray analysis; a heat map based on these results showed good categorization into the CD and control groups. GUSBP2 and {'type':'entrez-nucleotide','attrs':{'text':'AF113016','term_id':'6642755','term_text':'AF113016'}}AF113016 had the highest fold change of the up- and down-regulated lncRNAs, whereas TBC1D17 and CCL3L3 had the highest fold change of the up- and down-regulated mRNAs. Six (SNX1, CYFIP2, CD6, CMTM8, STAT4 and IGFBP7) of 10 mRNAs and 8 ({'type':'entrez-nucleotide','attrs':{'text':'NR_033913','term_id':'299890801','term_text':'NR_033913'}}NR_033913, {'type':'entrez-nucleotide','attrs':{'text':'NR_038218','term_id':'333360887','term_text':'NR_038218'}}NR_038218, {'type':'entrez-nucleotide','attrs':{'text':'NR_036512','term_id':'302393555','term_text':'NR_036512'}}NR_036512, {'type':'entrez-nucleotide','attrs':{'text':'NR_049759','term_id':'388240827','term_text':'NR_049759'}}NR_049759, {'type':'entrez-nucleotide','attrs':{'text':'NR_033951','term_id':'300068996','term_text':'NR_033951'}}NR_033951, {'type':'entrez-nucleotide','attrs':{'text':'NR_045408','term_id':'354548835','term_text':'NR_045408'}}NR_045408, {'type':'entrez-nucleotide','attrs':{'text':'NR_038377','term_id':'335334999','term_text':'NR_038377'}}NR_038377 and {'type':'entrez-nucleotide','attrs':{'text':'NR_039976','term_id':'337756399','term_text':'NR_039976'}}NR_039976) of 14 lncRNAs showed the same change trends on the microarray and qRT-PCR results with statistical significance. Based on the qRT-PCR verified mRNAs, 1358 potential lncRNAs with 2697 positive correlations and 2287 negative correlations were predicted by the CNC network.CONCLUSION: The plasma lncRNAs profiles provide preliminary data for the non-invasive diagnosis of CD and a resource for further specific lncRNA-mRNA pathway exploration.

Expression profiles of long noncoding RNAs in retinopathy of prematurity

Long noncoding RNA(lncRNA)regulates the proliferation and migration of human retinal endothelial cells,as well as retinal neovascularization in diabetic retinopathy.Based on similarities between the pathogenesis of retinopathy of prematurity(ROP)and diabetic retinopathy,lncRNA may also play a role in ROP.Seven-day-old mice were administered 75±2% oxygen for 5 days and normoxic air for another 5 days to establish a ROP model.Expression of lncRNA and mRNA in the retinal tissue of mice was detected by high-throughput sequencing technology,and biological functions of the resulted differentially expressed RNAs were evaluated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses.The results showed that compared with the control group,57 lncRNAs were differentially expressed,including 43 upregulated and 14 downregulated,in the retinal tissue of ROP mice.Compared with control mice,42 mRNAs were differentially expressed in the retinal tissue of ROP mice,including 24 upregulated and 18 downregulated mRNAs.Differentially expressed genes were involved in ocular development and related metabolic pathways.The differentially expressed lncRNAs may regulate ROP in mice via microRNAs and multiple signaling pathways.Our results revealed that these differentially expressed lncRNAs may be therapeutic targets for ROP treatment.This study was approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University on February 25,2016(approval No.2016PS074K).

Epigenetic regulation by long noncoding RNAs in osteo-/adipogenic differentiation of mesenchymal stromal cells and degenerative bone diseases

Bone is a complex tissue that undergoes constant remodeling to maintain homeostasis,which requires coordinated multilineage differentiation and proper proliferation of mesenchymal stromal cells(MSCs).Mounting evidence indicates that a disturbance of bone homeostasis can trigger degenerative bone diseases,including osteoporosis and osteoarthritis.In addition to conventional genetic modifications,epigenetic modifications(i.e.,DNA methylation,histone modifications,and the expression of noncoding RNAs)are considered to be contributing factors that affect bone homeostasis.Long noncoding RNAs(lncRNAs)were previously regarded as‘transcriptional noise’with no biological functions.However,substantial evidence suggests that lncRNAs have roles in the epigenetic regulation of biological processes in MSCs and related diseases.In this review,we summarized the interactions between lncRNAs and epigenetic modifiers associated with osteo-/adipogenic differentiation of MSCs and the pathogenesis of degenerative bone diseases and highlighted promising lncRNA-based diagnostic and therapeutic targets for bone diseases.

Metastasis-associated long noncoding RNAs in gastrointestinal cancer: Implications for novel biomarkers and therapeutic targets

Long non-coding RNAs(lnc RNAs), a newly discovered class of nc RNA molecules, have been widely accepted as crucial regulators of various diseases including cancer. Increasing numbers of studies have demonstrated that lnc RNAs are involved in diverse physiological and pathophysiological processes, such as cell cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Aberrant expression of lnc RNAs frequently occurs in gastrointestinal cancer and plays emerging roles in cancer metastasis. In this review, we focus on and outline the regulatory functions of recently identified metastasis-associated lnc RNAs, and evaluate the p o t e n t i a l r o l e s o f l n c R N A s a s n o v e l d i a g n o s t i c biomarkers and therapeutic targets in gastrointestinal cancer.

Identification of key long noncoding RNAs and their biological functions in hepatocellular carcinoma

Long noncoding RNAs(lncRNAs)are vital regulators in tumorigenesis and metastasis.However,the pathological role of lncRNAs in hepatocellular carcinoma(HCC)is still unclear.In this study,we filtered out three lncRNAs from The Cancer Genome Atlas(TCGA)data that were screened for basic expression and clinical research.We selected lncRNA-NEAT1 for further study to explore its function in HCC progression and its regulatory mechanism.We identified three differentially expressed lncRNAs(DElncRNAs)in tumor and adjacent normal tissues from the TCGA library using data mining methods:lncRNA-NEAT1,lncRNA-MAGI2-AS3 and lncRNA-HCG11.Their basic expression levels were detected by qPCR.Then,we selected lncRNA-NEAT1 as a potentially important lncRNA to verity its biological function and mechanism in HCC cell lines.lncRNA-NEAT1,lncRNA-MAGI2-AS3 and lncRNA-HCG11 were overexpressed in liver cancer tissues and cell lines.We found that silencing NEAT1 in vitro can inhibit the proliferation of HuH-7 and Li-7 cells,inhibit cell migration,and induce apoptosis as well as significantly increase the level of miR-16-5p.We also confirmed that miR-16-5p has a significant correlation with Bcl-2.When NEAT1 is silenced,the expression of Bcl-2 decreases.Inhibiting miR-16-5p can restore Bcl-2 to its original level.We conclude that miR-16-5p1/lncRNA NEAT1 plays a crucial role in regulating the delivery of Bcl-2 in HCC.Overall,the miR-16-5p/lncRNA-NEAT1/Bcl-2 signaling axis may be a promising target for HCC treatment.

Emerging role of long noncoding RNAs in recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)remains one of the most frequent types of liver cancer and is characterized by a high recurrence rate.Recent studies have proposed that long non-coding RNAs(lncRNAs)are potential biomarkers in several recurrent tumor types.It is now well understood that invasion,migration,and metastasis are important factors for tumor recurrence.Moreover,some of the known risk factors for HCC may affect the expression levels of several types of lncRNAs and thus affect the recurrence of liver cancer through lncRNA regulation.In this paper,we review the biological functions,molecular mechanisms,and roles of lncRNAs in HCC and summarize current knowledge about lncRNAs as potential biomarkers in recurrent HCC.