ceRNA Network of lncRNA/miRNA as Circulating Prognostic Biomarkers in Non-Hodgkin Lymphomas: Bioinformatic Analysis and Assessment of Their Prognostic Value in an NHL Cohort

Research has been focusing on identifying novel biomarkers to better stratify non-Hodgkin lymphoma patients based on prognosis. Studies have demonstrated that lncRNAs act as miRNA sponges, creating ceRNA networks to regulate mRNA expression, and its deregulation is associated with lymphoma development. This study aimed to identify novel circulating prognostic biomarkers based on miRNA/lncRNA-associated ceRNA network for NHL. Herein, bioinformatic analysis was performed to construct ceRNA networks for hsa-miR-150-5p and hsa-miR335-5p. Then, the prognostic value of the miRNA–lncRNA pairs’ plasma levels was assessed in a cohort of 113 NHL patients. Bioinformatic analysis identified MALAT1 and NEAT1 as hsa-miR-150-5p and has-miR-335-5p sponges, respectively. Plasma hsa-miR-150-5p/MALAT1 and hsa-miR335-5p/NEAT1 levels were significantly associated with more aggressive and advanced disease. The overall survival and progression-free survival analysis indicated that hsa-miR-150-5p/MALAT1 and hsa-miR335-5p/NEAT1 pairs’ plasma levels were remarkably associated with NHL patients’ prognosis, being independent prognostic factors in a multivariate Cox analysis. Low levels of hsa-miR-150-5p and hsa-miR-335-5p combined with high levels of the respective lncRNA pair were associated with poor prognosis of NHL patients. Overall, the analysis of ceRNA network expression levels may be a useful prognostic biomarker for NHL patients and could identify patients who could benefit from more intensive treatments.

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Effect of an lncRNA-associated ceRNA regulatory network in MVI-positive hepatocellular carcinoma on their sensitivity to sorafenib.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16615 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16615-e16615

Author(s):

Zhiwen Luo ◽

Xinyu Bi

Keyword(s):

Hepatocellular Carcinoma ◽

Expression Profiles ◽

Recurrence Risk ◽

Vital Role ◽

Prognostic Biomarkers ◽

Protein Coding ◽

Functional Roles ◽

Cerna Network ◽

Mirna Sponges ◽

Regulate Protein

e16615 Background: Microvascular invasion (MVI) is a histological feature of hepatocellular carcinoma (HCC) related to aggressiveness. But different sensitivity to first line targeted drug, sorafenib, in MVI+ HCC has been observed. Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression; so lncRNAs are considered as a major part of competitive endogenous RNA (ceRNA) network and have attracted growing attention. We explored the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in MVI+ HCC, and ceRNA network’s potential impact on prognosis and sensitivity to sorafenib in MVI+ HCC patient. Methods: We studied the expression profiles, prognostic value of lncRNA, miRNA, and mRNA from MVI+ HCC patients, established a prognosis-related network of dysregulated ceRNAs and analyzed its role in sensitivity to sorafenib and radiomics features by bioinformatics methods. Results: A ceRNA network including 13 lncRNAs, 3 miRNAs, and 2 mRNAs specific to MVI+ HCC was established. 6 lncRNAs ( ARHGEF7-AS1, ATP2B2-IT1, LINC00330, MUC2, TLR8-AS1 and ZNF385D-AS1), 2 miRNAs ( hsa-mir-206 and hsa-mir-373) and two mRNAs ( PAX3, SIK1) were prognostic biomarkers for MVI+ HCC. PAX3 was an unfavorable prognostic gene (HR = 1.9, 95%CI 1.01 ~ 3.60), while SIK1 favored the prognosis (HR = 0.4, 95%CI 0.19 ~ 0.85). PAX3 as a stratification in recurrence predicting model was used to identify MVI+ HCC with high or low recurrence risk. Datamining into the dataset of phase 3 STORM trial showed no difference in the influence of PAX3 level on the outcome between sorafenib HCC group and placebo HCC group. However, deep datamining into GDSC dataset revealed our high PAX3 group in MVI+ HCC related to resistance to sorafenib ( P = 0.0039). Radiomics features were extracted from CT of MVI+ HCC, and texture analysis in MVI+ HCCs is ongoing. Conclusions: The proposed ceRNA network may help elucidate the regulatory mechanism by which lncRNAs function as ceRNAs and contribute to the pathogenesis of MVI in HCC. Importantly, the candidate lncRNAs, miRNAs, and mRNAs involved in the ceRNA network have shown to be potential therapeutic targets and prognostic biomarkers for MVI+ HCC. PAX3 might play a vital role in the mechanism of sorafenib resistance in MVI+ HCC, exclusively, this aggressive HCC subtype. The ongoing experiments on radiomics might add potent supports to identify sorafenib sensitive MVI+ HCC.

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E1 Detection as Prognosticator in Human Papillomavirus-Positive Head and Neck Cancers

The International Journal of Biological Markers ◽

10.5301/jbm.5000193 ◽

2016 ◽

Vol 31 (2) ◽

pp. 163-172

Author(s):

Daniela Vivenza ◽

Cristiana Lo Nigro ◽

Nerina Denaro ◽

Mirella Fortunato ◽

Martino Monteverde ◽

...

Keyword(s):

Head And Neck ◽

Prognostic Value ◽

Locally Advanced ◽

Progression Free Survival ◽

Good Prognosis ◽

Head And Neck Cancers ◽

P Value ◽

Formalin Fixed Paraffin Embedded ◽

Cox Analysis ◽

Dna Pcr

Purpose HPV-related locally advanced head and neck cancers (LA-HNCs) show a good prognosis. This study aimed to investigate the HPV prevalence in LA-HNCs and compare the prognostic value of E1, E6 and L1 genomic viral fragments and p16, individually and in combination, in order to find the best prognosticator in terms of overall survival (OS) and progression-free survival (PFS). Patients and Methods HPV16 was searched in 255 LA-HNC formalin-fixed paraffin-embedded tumor tissues, 89 oropharyngeal cancers (OPCs), and 166 non-OPCs by DNA-PCR with 3 primer pairs. p16 was analyzed by immunohistochemistry in 235 patients. Results The prevalence of positive samples decreased constantly from E6 to L1 and E1 in both OPCs and non-OPCs. Each LA-HNC patient highlighted variable positivity for each fragment. OPCs showed a higher prevalence of positive samples compared to non-OPCs. Positive coexistence of all the fragments was more common in OPCs (31.5%) than non-OPCs (4.2%), and E1 detection was always associated with E6 and L1. E1-positive OPCs showed improved OS (p = 0.012) and PFS (p = 0.036), while L1- or E6-positive ones did not. p16-positive patients were more prevalent in the OPC (29.8%) than the non-OPC group (7.3%) (p<0.0001) and its prognostic value was not superior to that of E1. However, the multivariate Cox analysis which included E1, L1, E6 status and p16 expression did not show a significant p value. Conclusions Though HPV16 positivity measured by DNA-PCR was higher for L1 and E6, they performed weakly as prognosticators; E1 might become a strong prognostic marker for OS and PFS in OPCs.

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Expression profile of SYNE3 and bioinformatic analysis of its prognostic value and functions in tumors

Journal of Translational Medicine ◽

10.1186/s12967-020-02521-7 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Liwei Liao ◽

Longshan Zhang ◽

Mi Yang ◽

Xiaoqing Wang ◽

Weiqiang Huang ◽

...

Keyword(s):

Prognostic Value ◽

Enrichment Analysis ◽

Bioinformatic Analysis ◽

Transcriptional Network ◽

The Cancer Genome Atlas ◽

Linc Complex ◽

Spectrin Repeat ◽

Tumor Invasiveness ◽

Cerna Network

Abstract Background Spectrin repeat containing nuclear envelope family member 3 (SYNE3) encodes an essential component of the linker of the cytoskeleton and nucleoskeleton (LINC) complex, namely nesprin-3. In a tumor, invasiveness and metastasis rely on the integrity of the LINC complex, while the role of SYNE3/nesprin-3 in cancer is rarely studied. Methods Here, we explored the expression pattern, prognostic value, and related mechanisms of SYNE3 through both experimental and bioinformatic methods. We first detected SYNE3 in BALB/c mice, normal human tissues, and the paired tumor tissues, then used bioinformatics databases to verify our results. We further analyzed the prognostic value of SYNE3. Next, we predicted miRNA targeting SYNE3 and built a competing endogenous RNA (ceRNA) network and a transcriptional network by analyzing data from the cancer genome atlas (TCGA) database. Interacting genes of SYNE3 were predicted, and we further performed GO and KEGG enrichment analysis on these genes. Besides, the relationship between SYNE3 and immune infiltration was also investigated. Results SYNE3 exhibited various expressions in different tissues, mainly located on nuclear and in cytoplasm sometimes. SYNE3 expression level had prognostic value in tumors, possibly by stabilizing nucleus, promoting tumor cells apoptosis, and altering tumor microenvironment. Additionally, we constructed a RP11-2B6.2-miR-149-5p-/RP11-67L2.2-miR-330-3p-SYNE3 ceRNA network and a SATB1-miR-149-5p-SYNE3 transcriptional network in lung adenocarcinoma to support the tumor-suppressing role of SYNE3. Conclusions Our study explored novel anti-tumor functions and mechanisms of SYNE3, which might be useful for future cancer therapy.

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Expression profile of SYNE3 and bioinformatic analysis of its prognostic value and functions in tumors

10.21203/rs.3.rs-17159/v1 ◽

2020 ◽

Author(s):

Liwei Liao ◽

Longshan Zhang ◽

Mi Yang ◽

Xiaoqing Wang ◽

Weiqiang Huang ◽

...

Keyword(s):

Prognostic Value ◽

Lung Squamous Cell Carcinoma ◽

Enrichment Analysis ◽

Bioinformatic Analysis ◽

Transcriptional Network ◽

The Cancer Genome Atlas ◽

Linc Complex ◽

Spectrin Repeat ◽

Cerna Network

Abstract Background: Spectrin repeat containing nuclear envelope family member 3 (SYNE3) encodes an important component of linker of cytoskeleton and nucleoskeleton (LINC) complex, namely nesprin-3. In tumor, invasiveness and metastasis rely on the integrity of LINC complex, while the role of SYNE3/nesprin-3 in cancer is rarely studied. Methods: Here, we explored the expression pattern, prognostic value and related mechanisms of SYNE3 through both experimental and bioinformatic methods. We first detected SYNE3 in BALB/c mice, normal human tissues and the paired tumor tissues, then used bioinformatic databases to verify our results. We further analyzed the prognostic value of SYNE3. Next, we predicted miRNA targeting SYNE3 and built a competing endogenous RNA (ceRNA) network and a transcriptional network by analyzing data from the cancer genome atlas (TCGA) database. Interacting genes of SYNE3 were predicted, and we further performed GO and KEGG enrichment analysis on these genes. Besides, the relationship of SYNE3 and immune infiltration was also investigated. Results: SYNE3 exhibited various expressions in different tissues, mainly located on nuclear and in cytoplasm sometimes. SYNE3 expression level had prognostic value in tumors, possibly by stablizing nucleus, promoting tumor cells apoptosis and altering tumor microenvironment. Additionally, we constructed a RP11-2B6.2-miR-149-5p-/LINC01094-miR-330-3p-SYNE3 ceRNA network and a SATB1-miR-149-5p-SYNE3 transcriptional network in lung squamous cell carcinoma to support the tumor-suppressing role of SYNE3. Conclusions: Our study explored novel anti-tumor functions and mechanisms of SYNE3, which might be useful for future cancer therapy.

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Identification of Tumor Microenvironment-Related Prognostic Biomarkers in Luminal Breast Cancer

Frontiers in Genetics ◽

10.3389/fgene.2020.555865 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yanyan Wang ◽

Mingzhi Zhu ◽

Feng Guo ◽

Yi Song ◽

Xunjie Fan ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Prognostic Value ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Luminal Breast Cancer ◽

Ppi Network ◽

Cerna Network ◽

Novel Biomarkers

Background: The tumor microenvironment (TME) has been reported to have significant value in the diagnosis and prognosis of cancers. This study aimed to identify key biomarkers in the TME of luminal breast cancer (BC).Methods: We obtained immune scores (ISs) and stromal scores (SSs) for The Cancer Genome Atlas (TCGA) luminal BC cohort from the online ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) portal. The relationships between ISs and SSs and the overall survival of luminal BC patients were assessed by the Kaplan-Meier method. The differentially expressed messenger RNAs (DEmRNAs) related to the ISs and SSs were subjected to functional enrichment analysis. Additionally, a competing endogenous RNA (ceRNA) network was constructed with differentially expressed microRNAs (DEmiRNAs) and long noncoding RNAs (DElncRNAs). Furthermore, a protein–protein interaction (PPI) network was established to analyze the DEmRNAs in the ceRNA network. Then, survival analysis of biomarkers involved in the ceRNA network was carried out to explore their prognostic value. Finally, these biomarkers were validated using the luminal BC dataset from the Gene Expression Omnibus (GEO) database.Results: The results showed that ISs were significantly associated with longer survival times of luminal BC patients. Functional enrichment analysis showed that the DEmRNAs were mainly associated with immune response, antigen binding, and the extracellular region. In the PPI network, the top 10 DEmRNAs were identified as hub genes that affected the TME of luminal BC. Finally, two DEmiRNAs, two DElncRNAs, and 17 DEmRNAs of the ceRNA network associated with the TME were shown to have prognostic value. Subsequently, the expression of 15 prognostic biomarkers was validated in one additional dataset (GSE81002). In particular, one lncRNA (GVINP1) and five mRNAs (CCDC69, DOCK2, IKZF1, JCHAIN, and NCKAP1L) were novel biomarkers.Conclusions: Our studies demonstrated that ISs were associated with the survival of luminal BC patients, and a set of novel biomarkers that might play a prognostic role in the TME of luminal BC was identified.

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Oncological Effects and Prognostic Value of AMAP1 in Gastric Cancer

Frontiers in Genetics ◽

10.3389/fgene.2021.675100 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiao Li ◽

Shan Tian ◽

Yingyun Guo ◽

Weiguo Dong

Keyword(s):

Gastric Cancer ◽

Prognostic Value ◽

Meta Analysis ◽

Progression Free Survival ◽

Bioinformatic Analysis ◽

Luciferase Assay ◽

Migration And Invasion ◽

Diagnostic Significance ◽

Poor Overall Survival ◽

Normal Tissues

PurposeWe examined the diagnostic significance, prognostic value, and potential function of AMAP1 in gastric cancer (GC).MethodsComprehensive bioinformatic analysis was conducted to investigate differential expression of AMAP1 mRNA and protein in GC. Meta-analyses were utilized to determine the overall prognostic correlation of AMAP1 mRNA in patients with GC. A panel of vitro assays was applied to assess target microRNA and AMAP1 protein in GC cell lines and tissues, respectively.ResultsAMAP1 mRNA and protein levels were upregulated in GC specimens, compared to matched normal tissues. AMAP1 mRNA exhibited promising results regarding differential diagnosis of GC and normal tissue. Meta-analysis based on the TCGA and GEO databases revealed that high AMAP1 mRNA abundance was associated with poor overall survival (HR = 1.42; 95% CI: 1.06–1.89) and was correlated with reduced progression-free survival (HR = 1.89; 95% CI: 1.51–2.36) in GC patients. Moreover, AMAP1 was negatively correlated with miR-192-3p (r = −0.3843; P < 0.0001). A dual-luciferase assay revealed that miR-192-3p targeted AMAP1. Levels of miR-192-3p were significantly higher in GC tissues and GC cells than in normal tissues and cells. Moreover, AMAP1 silencing resulted in reduced GC proliferation, migration, and invasion.ConclusionAMAP1 is a novel oncogene in GC and is negatively correlated with by miR-192-3p. AMAP1 may act as a diagnostic and prognostic marker of GC.

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The Prognostic Significance of Combined Pretreatment Fibrinogen and Neutrophil-Lymphocyte Ratio in Various Cancers: A Systematic Review and Meta-Analysis

Disease Markers ◽

10.1155/2020/4565379 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Rongqiang Liu ◽

Shiyang Zheng ◽

Qing Yuan ◽

Peiwen Zhu ◽

Biao Li ◽

...

Keyword(s):

Prognostic Value ◽

Meta Analysis ◽

Prognostic Significance ◽

Disease Free Survival ◽

Progression Free Survival ◽

Regression Analyses ◽

Free Survival ◽

Neutrophil Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Meta Regression

Purpose. The prognostic value of a new scoring system, termed F-NLR, that combines pretreatment fibrinogen level with neutrophil-lymphocyte ratio has been evaluated in various cancers. However, the results are controversial. The purpose of this study was to comprehensively analyze the prognostic value of F-NLR score in patients with cancers. Methods. An integrated search of relevant studies was conducted by screening the PubMed and Embase databases. Pooled hazard ratios, with 95% confidence intervals (CIs), for overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS) were calculated to estimate the prognostic significance of F-NLR score in patients with various tumors. A random effects model was used for comprehensive analysis, and subgroup and meta-regression analyses were used to explore sources of heterogeneity. Results. Thirteen articles reporting data from of 4747 patients were included in the study. Pooled analysis revealed that high F-NLR score was significantly associated with poor OS ( HR = 1.77 ; 95% CI, 1.51–2.08) and poor DFS/PFS ( HR = 1.63 ; 95% CI, 1.30–2.05). Subgroup and meta-regression analyses did not alter the prognostic role of F-NLR score in OS and DFS/PFS. Conclusions. Increased F-NLR score is significantly associated with poor prognosis in patients with cancers and can serve as an effective prognostic indicator.

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Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: Results of a phase 1 clinical trial

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa154 ◽

2020 ◽

Author(s):

Gary L Gallia ◽

Matthias Holdhoff ◽

Henry Brem ◽

Avadhut D Joshi ◽

Christine L Hann ◽

...

Keyword(s):

Dose Escalation ◽

Plasma Levels ◽

Phase 1 ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

High Grade ◽

Newly Diagnosed ◽

Kaplan Meier ◽

High Grade Gliomas ◽

Expansion Cohort

Abstract Background Mebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers. Methods A single center dose escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas (HGG) in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide. Dose escalation levels were 25, 50, 100 and 200 mg/kg/day of oral mebendazole. A 15-patient expansion cohort was conducted at the maximum tolerated dose of 200 mg/kg/day. Trough plasma levels of mebendazole were measured at 4, 8 and 16 weeks. Results Twenty-four patients (18 glioblastoma, 6 anaplastic astrocytoma) were enrolled with median age of 49.9 years. Four patients (at 200 mg/kg) developed elevated grade 3 ALT and/or AST after one month, which reversed with lower dosing or discontinuation. Plasma levels of mebendazole were variable but generally increased with dose. Kaplan Meier analysis showed a 21-month median survival with 43% of patients alive at two years and 25% at 3 and 4 years. Median progression free survival (PFS) from the date of diagnosis for 17 patients taking more than one month of mebendazole was 13.1 months (95% Confidence Interval: 8.8 to 14.6 months) but for seven patients who received less than one month of mebendazole PFS was 9.2 months (95% CI: 5.8 -13.0 months). Conclusion Mebendazole at doses up to 200 mg/kg demonstrated long-term safety and acceptable toxicity. Further studies are needed to determine mebendazole’s efficacy in patients with HGG.

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