To identify a lncRNA signature to predict survival of breast cancer (BRCA) patients. A total of 1222 BRCA case and control datasets were downloaded from the TCGA database. The weighted gene co-expression network analysis of differentially expressed mRNAs was performed to generate the modules associated with BRCA overall survival status and further construct a hub on competing endogenous RNA (ceRNA) network. LncRNA signatures for predicting survival of BRCA patients were generated using univariate survival analyses and a multivariate Cox hazard model analysis and validated and characterized for prognostic performance measured using receiver operating characteristic (ROC) curves. A prognostic score model of eight lncRNAs signature was identified as Prognostic score = (0.121 × EXPAC007731.1) + (0.108 × EXPAL513123.1) + (0.105 × EXPC10orf126) + (0.065 × EXPWT1-AS) + (− 0.126 × EXPADAMTS9-AS1) + (− 0.130 × EXPSRGAP3-AS2) + (0.116 × EXPTLR8-AS1) + (0.060 × EXPHOTAIR) with median score 1.088. Higher scores predicted higher risk. The lncRNAs signature was an independent prognostic factor associated with overall survival. The area under the ROC curves (AUC) of the signature was 0.979, 0.844, 0.99 and 0.997 by logistic regression, support vector machine, decision tree and random forest models, respectively, and the AUCs in predicting 1- to 10-year survival were between 0.656 and 0.748 in the test dataset from TCGA database. The eight-lncRNA signature could serve as an independent biomarker for prediction of overall survival of BRCA. The lncRNA-miRNA-mRNA ceRNA network is a good tool to identify lncRNAs that is correlated with overall survival of BRCA.

An eight-lncRNA signature predicts survival of breast cancer patients: a comprehensive study based on weighted gene co-expression network analysis and competing endogenous RNA network

Exosomal long non‐coding RNAs (lncRNAs) serve as excellent candidate biomarkers for clinical applications. The expression of differentiation antagonizing non‐protein coding RNA (DANCR) has been shown to be decreased in breast cancer (BC) tissues and cell lines. However, the clinical value of circulating exosomal DANCR in BC has not been explored.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jcla.24186

High serum exosomal long non‐coding RNA DANCR expression confers poor prognosis in patients with breast cancer

Long noncoding RNAs (lncRNAs) exert crucial biological functions by regulating miRNAs, which are implicated in cancer progression and tumorigenesis. A previous study has indicated that lncRNA linc02544 expression is upregulated in lung adenocarcinoma, whereas, the role of linc02544 in LUSC is elusive.The differential linc02544 expression in LUSC tissues and adjacent non-tumor tissues were evaluated with RT-qPCR. Kaplan-Meier curve was conducted to evaluate the clinical prognostic significance of linc02544. Then cellular experiments were performed to assess the influence of linc02544 in LUSC proliferation, invasion, and migration, and a western blot assay was used to measure the metastasis-related protein levels. The downstream miRNAs were verified using the LncBase Experimental v.2 database and dual-luciferase reporter assay.Linc02544 was overexpressed in LUSC tissues from positive lymph node metastasis-positive and TNM high-stage patients. Low linc02544 expression was associated with a longer survival rate. Downregulation of linc02544 by si-linc02544 restrained cell growth capacities, migration, and invasion abilities. Expression of MMP-2, MMP-9, and vimentin was decreased while E-cadherin was increased in si-linc02544 cells compared with that in untreated cells. Mechanistically, we identified that linc02544 acted as a sponge of miR-138-5p, which expression had a negative correlation. E2F3 was a potential target of miR-138-5p, CONCLUSIONS: Notably, high linc02544 expression was associated with severe clinical parameters and was a putative prognostic predictor for patients with LUSC. Downregulation of linc02544 may weaken the LUSC cell proliferation, migration, and invasion by regulating miR-138-5p/E2F3, which maybe serve as a biomarker for the prognosis and target treatment of LUSC. 

/pdf/upregulation-of-long-noncoding-rna-linc02544-and-its-iav7g4ao.pdf

Upregulation of long noncoding RNA linc02544 and its association with overall survival rate and the influence on cell proliferation and migration in lung squamous cell carcinoma

Simple Summary Through their regulatory activity of gene expression, microRNAs have been heavily implicated in the genesis of cancer. They can act both as promoters (oncogenes) and suppressors of tumorigenesis. They can work within cells but also be secreted and uptaken by cells. While in certain instances, microRNAs appear to unequivocally act as oncogenes or tumor suppressor genes, in other instances, their activity appears to be tissue or context-dependent, in seemingly contradictory reports. MiR-22 has been extensively studied because of its powerful and diverse biological activities and has been attributed to both oncogenic and tumor-suppressive abilities. In this article, we critically analyzed this vast literature and reassessed the status of the miR-22 genetic locus in human cancer. We conclude that, when studied in immunocompetent model systems, miR-22 invariably acts as a tumor-promoting miRNA in view of its ability to impact the cancer immune microenvironment. Abstract MiR-22 was first identified as a proto-oncogenic microRNA (miRNA) due to its ability to post-transcriptionally suppress the expression of the potent PTEN (Phosphatase And Tensin Homolog) tumor suppressor gene. miR-22 tumorigenic role in cancer was subsequently supported by its ability to positively trigger lipogenesis, anabolic metabolism, and epithelial-mesenchymal transition (EMT) towards the metastatic spread. However, during the following years, the picture was complicated by the identification of targets that support a tumor-suppressive role in certain tissues or cell types. Indeed, many papers have been published where in vitro cellular assays and in vivo immunodeficient or immunosuppressed xenograft models are used. However, here we show that all the studies performed in vivo, in immunocompetent transgenic and knock-out animal models, unanimously support a proto-oncogenic role for miR-22. Since miR-22 is actively secreted from and readily exchanged between normal and tumoral cells, a functional immune dimension at play could well represent the divider that allows reconciling these contradictory findings. In addition to a critical review of this vast literature, here we provide further proof of the oncogenic role of miR-22 through the analysis of its genomic locus vis a vis the genetic landscape of human cancer.

/pdf/an-immunocompetent-environment-unravels-the-proto-oncogenic-1squ50pv.pdf

An Immunocompetent Environment Unravels the Proto-Oncogenic Role of miR-22

Background Liver hepatocellular carcinoma (LIHC) has a poor prognosis worldwide. Polycomb group factor 1 (PCGF1) was recently reported to play a tumor suppressive role in cancers. However, the molecular mechanism and competitive endogenous ribonucleic acid (ceRNA) regulatory networks of PCGF1 in LIHC are still unclear. Methods We constructed a PCGF1 ceRNA regulatory network in LIHC and identified potential prognostic markers, especially for tumor immunity. We identified the gene expression profiles and conducted correlation and survival analyses of PCGF1 and the related RNAs. We also explored the clinicopathological features and diagnostic and prognostic values of PCGF1 and constructed a nomogram to predict 1-, 3-, and 5-year survival. Based on a variety of bioinformatics tools, we confirmed the PCGF1-related signaling pathways in LIHC. Finally, the role of PCGF1 in immune cell infiltration was also analyzed. Results We found that PCGF1 was overexpressed in LIHC (P<0.001) and was linked to a poor prognosis in terms of overall survival (OS, P=0.029), the progress-free interval (PFI, P=0.002), and disease-free survival (DFS, P=0.02). Hsa-miR-22-3p was highly negatively correlated with PCGF1. Further, 3 upstream long non-coding RNAs (lncRNAs) (i.e., AC016405.3, BX284668.6, and MIR4435-2HG) were confirmed to further research. PCGF1 was positively associated with pathologic tumor stages (P=0.001), histologic grade (P=0.030), alpha fetoprotein (AFP) level (P=0.030), and vascular invasion (P=0.022). The area under the curve of PCGF1 was 0.983 [confidence interval (CI): 0.972–0.994]. In the multivariate analyses, high PCGF1 expression remained an independent factor associated with OS [hazards ratio (HR): 1.696, P=0.027], DSS (HR: 2.139, P=0.024), and the PFI (HR: 1.512, P=0.034). We found that PCGF1 was involved in some malignancy-associated signaling pathways and plays a role in regulating the immune response. Conclusions We confirmed the upstream ceRNA regulatory network of PCGF1 in LIHC. PCGF1 has an oncogenic effect and correlates with tumor immunity.

/pdf/the-non-coding-rna-ncrna-mediated-high-expression-of-1bmezrzw.pdf

The non-coding RNA (ncRNA)-mediated high expression of polycomb group factor 1 (PCGF1) is a prognostic biomarker and is correlated with tumor immunity infiltration in liver hepatocellular carcinoma

Background Increasing studies reported that long non-coding RNAs are involved in regulating breast cancer (BRCA) progression. However, the specific roles and mechanisms of lncRNAs in BRCA remain largely unknown. Here, we sought to explore the functions and mechanisms of AC016405.3 in BRCA progression. Methods Bioinformatic analysis for AC016405.3, miR-22-3p, and ERBB3 were performed on starBase. The expressions of AC016405.3, miR-22-3p, and ERBB3 were examined by RT-qPCR. The functions of AC016405.3 on the proliferation, migration, and invasion of cells were evaluated by conducting CCK-8, colony formation, wound-healing, and Transwell assays. The subcellular distribution of AC016405.3 in BRCA cells was identified by performing fluorescence in situ hybridization (FISH) and subcellular fractionation techniques. Dual-luciferase assay was applied to validate the interactions of miR-22-3p with AC016405.3 or ERBB3. The interaction between ERBB3 and miR-22-3p was also tested by Anti-Ago2 RNA immunoprecipitation (RIP) assay. Results The results showed that AC016405.3 is highly expressed in BRCA tissues as well as cells and positively correlated with poor prognosis in BRCA patients. Silencing AC016405.3 obviously repressed the malignant behaviors of BRCA cells. Mechanistically, AC016405.3 functioned as a competing endogenous RNA (ceRNA) for miR-22-3p in the cytoplasm and sponged miR-22-3p to release its suppression of ERBB3. Rescue experiments revealed that the suppression role induced by AC016405.3 depletion on malignant behaviors of BRCA cells could be obviously counter by inhibiting miR-22-3p or overexpressing ERBB3. Conclusion AC016405.3 promotes BRCA progression by the derepression of ERBB3 via sponging miR-22-3p, which may represent a potential target for BRCA treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcla.23952

AC016405.3 functions as an oncogenic long non-coding RNA by regulating ERBB3 via sponging miR-22-3p in breast cancer

Long non-coding RNAs (lncRNAs) have been demonstrated to be aberrantly expressed in several types of tumor, and dysregulated lncRNAs are suggested to play a prognostic role in breast cancer (BC). Estrogen receptor (ER) status is a prognostic factor in patients with ER-negative BC, which is associated with poor prognosis. Thus, the present study developed a prognostic lncRNA signature specifically for ER-negative BC, in order to predict the risk of post-surgery relapse and improve patient prognosis. A gene expression profile containing 1,631 lncRNAs was obtained by investigating and integrating publicly available cohorts of BC. Subsequently, a nine-lncRNA signature was developed and validated in two independent cohorts via the Cox regression model. Using the nine-lncRNA signature, patients in the discovery cohort were divided into high- and low-risk groups, with significantly different disease-free survival [DFS; hazard ratio (HR)=2.718, 95% confidence interval (CI)=2.115-3.494, P<0.0001]. Receiver operating characteristic curve analyses demonstrated that the area under the curve reached 0.908. Similar results were obtained in the two independent cohorts (HR=1.499, 95% CI=0.950-2.365, P=0.04; HR=1.262, 95% CI=1.056-1.510, P=0.01), respectively. Furthermore, the nine lncRNAs were demonstrated to play important roles in the cell invasion and metastasis of different types of tumor. The differentially expressed genes (DEGs) identified between the high- and low-risk groups were consistently high in the discovery and validation cohorts. Functional analysis indicated that these DEGs, as well as genes co-expressed with the nine lncRNAs, were involved in cancer-associated signaling pathways, all of which provide further evidence for the predictive ability of the nine-lncRNA signature. Overall, the present study developed a novel prognostic biomarker for ER-negative BC.

https://www.spandidos-publications.com/10.3892/ol.2020.11391/download

Jie Wang

Papers

AC016405.3 functions as an oncogenic long non-coding RNA by regulating ERBB3 via sponging miR-22-3p in breast cancer

Development of a nine-lncRNA signature as a novel prognostic marker of estrogen receptor-negative breast cancer.