scholarly journals Identification and validation of lncRNAs involved in m6A regulation for patients with ovarian cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jianfeng Zheng ◽  
Jialu Guo ◽  
Benben Cao ◽  
Ying Zhou ◽  
Jinyi Tong

Abstract Background Both N6-methyladenosine (m6A) modification and lncRNAs play an important role in the carcinogenesis and cancer inhibition of ovarian cancer (OC). However, lncRNAs involved in m6A regulation (LI-m6As) have never been reported in OC. Herein, we aimed to identify and validate a signature based on LI-m6A for OC. Methods RNA sequencing profiles with corresponding clinical information associated with OC and 23 m6A regulators were extracted from TCGA. The Pearson correlation coefficient (PCC) between lncRNAs and 23 m6A regulators (|PCC|> 0.4 and p < 0.01) was calculated to identify LI-m6As. The LI-m6As with significant prognostic value were screened based on univariate Cox regression analysis to construct a risk model by LASSO Cox regression. Gene Set Enrichment Analysis (GSEA) was implemented to survey the biological functions of the risk groups. Several clinicopathological characteristics were utilized to evaluate their ability to predict prognosis, and a nomogram was constructed to evaluate the accuracy of survival prediction. Besides, immune microenvironment, checkpoint, and drug sensitivity in the two risk groups were compared using comprehensive algorithms. Finally, real-time qPCR analysis and cell counting kit-8 assays were performed on an alternative lncRNA, CACNA1G-AS1. Results The training cohort involving 258 OC patients and the validation cohort involving 111 OC patients were downloaded from TCGA. According to the PCC between the m6A regulators and lncRNAs, 129 LI-m6As were obtained to perform univariate Cox regression analysis and then 10 significant prognostic LI-m6As were identified. A prognostic signature containing four LI-m6As (AC010894.3, ACAP2-IT1, CACNA1G-AS1, and UBA6-AS1) was constructed according to the LASSO Cox regression analysis of the 10 LI-m6As. The prognostic signature was validated to show completely opposite prognostic value in the two risk groups and adverse overall survival (OS) in several clinicopathological characteristics. GSEA indicated that differentially expressed genes in disparate risk groups were enriched in several tumor-related pathways. At the same time, we found significant differences in some immune cells and chemotherapeutic agents between the two groups. An alternative lncRNA, CACNA1G-AS1, was proven to be upregulated in 30 OC specimens and 3 OC cell lines relative to control. Furthermore, knockdown of CACNA1G‐AS1 was proven to restrain the multiplication capacity of OC cells. Conclusions Based on the four LI-m6As (AC010894.3, ACAP2-IT1, CACNA1G-AS1, and UBA6-AS1), the risk model we identified can independently predict the OS and therapeutic value of OC. CACNA1G‐AS1 was preliminarily proved to be a malignant lncRNA.

2021 ◽  
Author(s):  
Zhehong Li ◽  
Junqiang Wei ◽  
Honghong Zheng ◽  
Xintian Gan ◽  
Mingze Song ◽  
...  

Abstract Background: Hypoxia- and immune-status play an essential role in tumorigenesis and tumor development. This study sought to build a novel hypoxia- and immune-related signature to evaluate sarcoma patients' prognosis.Methods: Transcriptome data and clinicopathological characteristics of sarcoma patients were downloaded from the TARGET database. We grouped patients with three clusters by using t-SNE. We defined the three cluster as high-, medium-, and low-hypoxia clusters by K-M analysis and differential expression of target genes associated with the HIF-1 signaling pathway. Then we used the "limma" package to screen hypoxia-related differentially expressed genes (HRDEGs) in the high- and low-hypoxia clusters. We immediately assessed the immune status by using the single sample Gene Set Enrichment Analysis (ssGSEA) and divided the patients into high-, medium-, and low-immune clusters. Immune-related DEGs (IRDEGs) were filtered in the high- and low- immune groups. The intersection of HRDEGs and IRDEGs screened overlapping genes. We used a combination of Cox regression analysis and LASSO model to obtain prognosis-related genes and established a novel hypoxia- and immune-related prognostic signature for sarcoma patients. Combining clinicopathological characteristics of sarcoma patients, we evaluated the signature by univariate and multivariate Cox regression analysis. We further divided the patients into high- and low-risk groups based on the novel signature. Finally, we evaluated the differences in hypoxia status and the immune status in high- and low-risk groups.Results: We identified two genes associated with prognosis, CMA1 and IGDCC3. The novel Prognostic signature could be used as an independent prognostic factor for sarcoma patients. We distinguished patients more effectively by their different survival outcomes, immune cells' infiltration status, and immune-related markers.Conclusion: The hypoxia- and immune-related prognostic signature can be used to stratify the risk of sarcoma patients. Our study established a new prognostic signature and provides a potential prognostic markers for hypoxia- and immune-related therapy.


Author(s):  
Qianqian Wu ◽  
Sutian Jiang ◽  
Tong Cheng ◽  
Manyu Xu ◽  
Bing Lu

Hepatocellular carcinoma (HCC) is the second most lethal malignant tumor because of its significant heterogeneity and complicated molecular pathogenesis. Novel prognostic biomarkers are urgently needed because no effective and reliable prognostic biomarkers currently exist for HCC patients. Increasing evidence has revealed that pyroptosis plays a role in the occurrence and progression of malignant tumors. However, the relationship between pyroptosis-related genes (PRGs) and HCC patient prognosis remains unclear. In this study, 57 PRGs were obtained from previous studies and GeneCards. The gene expression profiles and clinical data of HCC patients were acquired from public data portals. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to establish a risk model using TCGA data. Additionally, the risk model was further validated in an independent ICGC dataset. Our results showed that 39 PRGs were significantly differentially expressed between tumor and normal liver tissues in the TCGA cohort. Functional analysis confirmed that these PRGs were enriched in pyroptosis-related pathways. According to univariate Cox regression analysis, 14 differentially expressed PRGs were correlated with the prognosis of HCC patients in the TCGA cohort. A risk model integrating two PRGs was constructed to classify the patients into different risk groups. Poor overall survival was observed in the high-risk group of both TCGA (p &lt; 0.001) and ICGC (p &lt; 0.001) patients. Receiver operating characteristic curves demonstrated the accuracy of the model. Furthermore, the risk score was confirmed as an independent prognostic indicator via multivariate Cox regression analysis (TCGA cohort: HR = 3.346, p &lt; 0.001; ICGC cohort: HR = 3.699, p &lt; 0.001). Moreover, the single-sample gene set enrichment analysis revealed different immune statuses between high- and low-risk groups. In conclusion, our new pyroptosis-related risk model has potential application in predicting the prognosis of HCC patients.


2021 ◽  
Vol 11 ◽  
Author(s):  
Yuancheng Huang ◽  
Zehong Yang ◽  
Chaoyuan Huang ◽  
Xiaotao Jiang ◽  
Yanhua Yan ◽  
...  

ObjectivesThe purpose of this study was to investigate the role of m6A-related lncRNAs in gastric adenocarcinoma (STAD) and to determine their prognostic value.MethodsGene expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) database. Correlation analysis and univariate Cox regression analysis were conducted to identify m6A-related prognostic lncRNAs. Subsequently, different clusters of patients with STAD were identified via consensus clustering analysis, and a prognostic signature was established by least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The clinicopathological characteristics, tumor microenvironment (TME), immune checkpoint genes (ICGs) expression, and the response to immune checkpoint inhibitors (ICIs) in different clusters and subgroups were explored. The prognostic value of the prognostic signature was evaluated using the Kaplan-Meier method, receiver operating characteristic curves, and univariate and multivariate regression analyses. Additionally, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Gene Ontology (GO) analysis were performed for biological functional analysis.ResultsTwo clusters based on 19 m6A-related lncRNAs were identified, and a prognostic signature comprising 14 m6A-related lncRNAs was constructed, which had significant value in predicting the OS of patients with STAD, clinicopathological characteristics, TME, ICGs expression, and the response to ICIs. Biological processes and pathways associated with cancer and immune response were identified.ConclusionsWe revealed the role and prognostic value of m6A-related lncRNAs in STAD. Together, our finding refreshed the understanding of m6A-related lncRNAs and provided novel insights to identify predictive biomarkers and immunotherapy targets for STAD.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Ouyang ◽  
Kaide Xia ◽  
Xue Yang ◽  
Shichao Zhang ◽  
Li Wang ◽  
...  

AbstractAlternative splicing (AS) events associated with oncogenic processes present anomalous perturbations in many cancers, including ovarian carcinoma. There are no reliable features to predict survival outcomes for ovarian cancer patients. In this study, comprehensive profiling of AS events was conducted by integrating AS data and clinical information of ovarian serous cystadenocarcinoma (OV). Survival-related AS events were identified by Univariate Cox regression analysis. Then, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to construct the prognostic signatures within each AS type. Furthermore, we established a splicing-related network to reveal the potential regulatory mechanisms between splicing factors and candidate AS events. A total of 730 AS events were identified as survival-associated splicing events, and the final prognostic signature based on all seven types of AS events could serve as an independent prognostic indicator and had powerful efficiency in distinguishing patient outcomes. In addition, survival-related AS events might be involved in tumor-related pathways including base excision repair and pyrimidine metabolism pathways, and some splicing factors might be correlated with prognosis-related AS events, including SPEN, SF3B5, RNPC3, LUC7L3, SRSF11 and PRPF38B. Our study constructs an independent prognostic signature for predicting ovarian cancer patients’ survival outcome and contributes to elucidating the underlying mechanism of AS in tumor development.


2021 ◽  
Author(s):  
Yan Li ◽  
Xiaoying Wang ◽  
Yue Han ◽  
Xun Li

Abstract Background: Long non-coding RNAs (lncRNAs) play an important role in angiogenesis, immune response, inflammatory response and tumor development and metastasis. m6 A (N6 - methyladenosine) is one of the most common RNA modifications in eukaryotes. The aim of our research was to investigate the potential prognostic value of m6A-related lncRNAs in ovarian cancer (OC).Methods: The data we need for our research was downloaded from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Pearson correlation analysis between 21 m6A regulators and lncRNAs was performed to identify m6A-related lncRNAs. Univariate Cox regression analysis was implemented to screen for lncRNAs with prognostic value. A least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression analyses was used to further reduct the lncRNAs with prognostic value and construct a m6A-related lncRNAs signature for predicting the prognosis of OC patients. Results: 275 m6A-related lncRNAs were obtained using pearson correlation analysis. 29 m6A-related lncRNAs with prognostic value was selected through univariate Cox regression analysis. Then, a seven m6A-related lncRNAs signature was identified by LASSO Cox regression. Each patient obtained a riskscore through multivariate Cox regression analyses and the patients were classified into high-and low-risk group using the median riskscore as a cutoff. Kaplan-Meier curve revealed that the patients in high-risk group have poor outcome. The receiver operating characteristic curve revealed that the predictive potential of the m6A-related lncRNAs signature for OC was powerful. The predictive potential of the m6A-related lncRNAs signature was successfully validated in the GSE9891, GSE26193 datasets and our clinical specimens. Multivariate analyses suggested that the m6A-related lncRNAs signature was an independent prognostic factor for OC patients. Moreover, a nomogram based on the expression level of the seven m6A-related lncRNAs was established to predict survival rate of patients with OC. Finally, a competing endogenous RNA (ceRNA) network associated with the seven m6A-related lncRNAs was constructed to understand the possible mechanisms of the m6A-related lncRNAs involed in the progression of OC.Conclusions: In conclusion, our research revealed that the m6A-related lncRNAs may affect the prognosis of OC patients and identified a seven m6A-related lncRNAs signature to predict the prognosis of OC patients.


Author(s):  
Wei Jiang ◽  
Jiameng Xu ◽  
Zirui Liao ◽  
Guangbin Li ◽  
Chengpeng Zhang ◽  
...  

ObjectiveTo screen lung adenocarcinoma (LUAC)-specific cell-cycle-related genes (CCRGs) and develop a prognostic signature for patients with LUAC.MethodsThe GSE68465, GSE42127, and GSE30219 data sets were downloaded from the GEO database. Single-sample gene set enrichment analysis was used to calculate the cell cycle enrichment of each sample in GSE68465 to identify CCRGs in LUAC. The differential CCRGs compared with LUAC data from The Cancer Genome Atlas were determined. The genetic data from GSE68465 were divided into an internal training group and a test group at a ratio of 1:1, and GSE42127 and GSE30219 were defined as external test groups. In addition, we combined LASSO (least absolute shrinkage and selection operator) and Cox regression analysis with the clinical information of the internal training group to construct a CCRG risk scoring model. Samples were divided into high- and low-risk groups according to the resulting risk values, and internal and external test sets were used to prove the validity of the signature. A nomogram evaluation model was used to predict prognosis. The CPTAC and HPA databases were chosen to verify the protein expression of CCRGs.ResultsWe identified 10 LUAC-specific CCRGs (PKMYT1, ETF1, ECT2, BUB1B, RECQL4, TFRC, COCH, TUBB2B, PITX1, and CDC6) and constructed a model using the internal training group. Based on this model, LUAC patients were divided into high- and low-risk groups for further validation. Time-dependent receiver operating characteristic and Cox regression analyses suggested that the signature could precisely predict the prognosis of LUAC patients. Results obtained with CPTAC, HPA, and IHC supported significant dysregulation of these CCRGs in LUAC tissues.ConclusionThis prognostic prediction signature based on CCRGs could help to evaluate the prognosis of LUAC patients. The 10 LUAC-specific CCRGs could be used as prognostic markers of LUAC.


2021 ◽  
Vol 12 ◽  
Author(s):  
Guomin Wu ◽  
Qihao Wang ◽  
Ting Zhu ◽  
Linhai Fu ◽  
Zhupeng Li ◽  
...  

This study aimed to establish a prognostic risk model for lung adenocarcinoma (LUAD). We firstly divided 535 LUAD samples in TCGA-LUAD into high-, medium-, and low-immune infiltration groups by consensus clustering analysis according to immunological competence assessment by single-sample gene set enrichment analysis (ssGSEA). Profile of long non-coding RNAs (lncRNAs) in normal samples and LUAD samples in TCGA was used for a differential expression analysis in the high- and low-immune infiltration groups. A total of 1,570 immune-related differential lncRNAs in LUAD were obtained by intersecting the above results. Afterward, univariate COX regression analysis and multivariate stepwise COX regression analysis were conducted to screen prognosis-related lncRNAs, and an eight-immune-related-lncRNA prognostic signature was finally acquired (AL365181.2, AC012213.4, DRAIC, MRGPRG-AS1, AP002478.1, AC092168.2, FAM30A, and LINC02412). Kaplan–Meier analysis and ROC analysis indicated that the eight-lncRNA-based model was accurate to predict the prognosis of LUAD patients. Simultaneously, univariate COX regression analysis and multivariate COX regression analysis were undertaken on clinical features and risk scores. It was illustrated that the risk score was a prognostic factor independent from clinical features. Moreover, immune data of LUAD in the TIMER database were analyzed. The eight-immune-related-lncRNA prognostic signature was related to the infiltration of B cells, CD4+ T cells, and dendritic cells. GSEA enrichment analysis revealed significant differences in high- and low-risk groups in pathways like pentose phosphate pathway, ubiquitin mediated proteolysis, and P53 signaling pathway. This study helps to treat LUAD patients and explore molecules related to LUAD immune infiltration to deeply understand the specific mechanism.


2020 ◽  
Author(s):  
Zhihao Wang ◽  
Kidane Siele Embaye ◽  
Qing Yang ◽  
Lingzhi Qin ◽  
Chao Zhang ◽  
...  

Abstract Background: Given that metabolic reprogramming has been recognized as an essential hallmark of cancer cells, this study sought to investigate the potential prognostic values of metabolism-related genes(MRGs) for hepatocellular carcinoma (HCC) diagnosis and treatment. Methods: The metabolism-related genes sequencing data of HCC samples with clinical information were obtained from the International Cancer Genome Consortium(ICGC) and The Cancer Genome Atlas (TCGA). The differentially expressed MRGs were identified by Wilcoxon rank sum test. Then, univariate Cox regression analysis were performed to identify metabolism-related DEGs that related to overall survival(OS). A novel metabolism-related prognostic signature was developed using the least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analyses . Furthermore, the signature was validated in the TCGA dataset. Finally, cox regression analysis was applied to identify the prognostic value and clinical relationship of the signature in HCC. Results: A total of 178 differentially expressed MRGs were detected between the ICGA dataset and the TCGA dataset. We found that 17 MRGs were most significantly associated with OS by using the univariate Cox proportional hazards regression analysis in HCC. Then, the Lasso and multivariate Cox regression analyses were applied to construct the novel metabolism-relevant prognostic signature, which consisted of six MRGs. The prognostic value of this prognostic model was further successfully validated in the TCGA dataset. Further analysis indicated that this signature could be an independent prognostic indicator after adjusting to other clinical factors. Six MRGs (FLVCR1, MOGAT2, SLC5A11, RRM2, COX7B2, and SCN4A) showed high prognostic performance in predicting HCC outcomes, and were further associated with tumor TNM stage, gender, age, and pathological stage. Finally, the signature was found to be associated with various clinicopathological features. Conclusions: In summary, our data provided evidence that the metabolism-based signature could serve as a reliable prognostic and predictive tool for overall survival in patients with HCC.


2020 ◽  
Author(s):  
Ze-bing Song ◽  
Guo-pei Zhang ◽  
shaoqiang li

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumor in the world which prognosis is poor. Therefore, a precise biomarker is needed to guide treatment and improve prognosis. More and more studies have shown that lncRNAs and immune response are closely related to the prognosis of hepatocellular carcinoma. The aim of this study was to establish a prognostic signature based on immune related lncRNAs for HCC.Methods: Univariate cox regression analysis was performed to identify immune related lncRNAs, which had negative correlation with overall survival (OS) of 370 HCC patients from The Cancer Genome Atlas (TCGA). A prognostic signature based on OS related lncRNAs was identified by using multivariate cox regression analysis. Gene set enrichment analysis (GSEA) and a competing endogenous RNA (ceRNA) network were performed to clarify the potential mechanism of lncRNAs included in prognostic signature. Results: A prognostic signature based on OS related lncRNAs (AC145207.5, AL365203.2, AC009779.2, ZFPM2-AS1, PCAT6, LINC00942) showed moderately in prognosis prediction, and related with pathologic stage (Stage I&II VS Stage III&IV), distant metastasis status (M0 VS M1) and tumor stage (T1-2 VS T3-4). CeRNA network constructed 15 aixs among differentially expressed immune related genes, lncRNAs included in prognostic signature and differentially expressed miRNA. GSEA indicated that these lncRNAs were involved in cancer-related pathways. Conclusion: We constructed a prognostic signature based on immune related lncRNAs which can predict prognosis and guide therapies for HCC.


2021 ◽  
Vol 12 ◽  
Author(s):  
Yudong Cao ◽  
Hecheng Zhu ◽  
Jun Tan ◽  
Wen Yin ◽  
Quanwei Zhou ◽  
...  

IntroductionGlioma is the most common primary cancer of the central nervous system with dismal prognosis. Long noncoding RNAs (lncRNAs) have been discovered to play key roles in tumorigenesis in various cancers, including glioma. Because of the relevance between immune infiltrating and clinical outcome of glioma, identifying immune-related lncRNAs is urgent for better personalized management.Materials and methodsSingle-sample gene set enrichment analysis (ssGSEA) was applied to estimate immune infiltration, and glioma samples were divided into high immune cell infiltration group and low immune cell infiltration group. After screening differentially expressed lncRNAs in two immune groups, least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to construct an immune-related prognostic signature. Additionally, we explored the correlation between immune infiltration and the prognostic signature.ResultsA total of 653 samples were appropriate for further analyses, and 10 lncRNAs were identified as immune-related lncRNAs in glioma. After univariate Cox regression and LASSO Cox regression analysis, six lncRNAs were identified to construct a prognostic signature for glioma, which could be taken as independent prognostic factors in both univariate and multivariate Cox regression analyses. Moreover, risk score was significantly correlated with all the 29 immune-related checkpoint expression (p &lt; 0.05) in ssGSEA except neutrophils (p = 0.43).ConclusionThe study constructed an immune-related prognostic signature for glioma, which contributed to improve clinical outcome prediction and guide immunotherapy.


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