• fatty acid metabolism
• gastric cancer
• immunotherapy
• multi-omics technologies
• single-cell transcriptomics

• National Key Research and Development Program of China
• National Natural Science Foundation of China

• CircRNAs
• gastrointestinal cancers
• lncRNAs
• miRNAs
• non-coding RNAs
• senescence

• Cancer
• Cell biology
• Immunology
• Molecular biology
• Stem cells research
• Transcriptomics;

• Genomic analysis
• Immunology
• Oncology
• Transcriptomics

• CLLU1
• Gastric cancer
• Network module
• miR-200 and miR-183 families

• autophagy-related genes
• gastric cancer
• immunotherapy
• oxidative stress
• prognostic signature

• NLGN1-AS1
• Wnt/β-catenin pathway
• clear cell renal cell carcinoma
• long noncoding RNA
• proliferation

• Humans
• Carcinoma, Renal Cell/genetics
• Carcinoma, Renal Cell/pathology
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• beta Catenin/metabolism
• Cell Proliferation/genetics
• Wnt Signaling Pathway/genetics
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Kidney Neoplasms/genetics
• Kidney Neoplasms/pathology
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Frizzled Receptors/genetics
• Frizzled Receptors/metabolism

Ten-eleven translocation proteins (TET1-3) are dioxygenases that oxidize 5-methyldeoxycytosine, thus taking part in passive and active demethylation. TETs have shown to be involved in immune cell development, affecting from self-renewal of stem cells and lineage commitment to terminal differentiation. In fact, dysfunction of TET proteins have been vastly associated with both myeloid and lymphoid leukemias. Recently, there has been accumulating evidence suggesting that TETs regulate immune cell function during innate and adaptive immune responses, thereby modulating inflammation. In this work, we pursue to review the current and recent evidence on the mechanistic aspects by which TETs regulate immune cell maturation and function. We will also discuss the complex interplay of TET expression and activity by several factors to modulate a multitude of inflammatory processes. Thus, modulating TET enzymes could be a novel pharmacological approach to target inflammation-related diseases and myeloid and lymphoid leukemias, when their activity is dysregulated.

• DNA-hydroxymethylation
• DNA-methylation
• TETs
• dioxygenases
• epigenetics
• immune cell regulation
• inflammation

Background: Iron is an essential nutrient involved in the redox cycle and the formation of free radicals. The reprogramming of iron metabolism is the main link to tumor cell survival. Ferroptosis is an iron-dependent form of regulated cell death associated with cancer; the characteristics of ferroptosis in cancers are still uncertain. This study aimed to explore the application value and gender difference of ferroptosis in prognosis and immune prediction to provide clues for targeted therapy of gastric cancer.

Methods: We comprehensively evaluated the ferroptosis levels of 1,404 gastric cancer samples from six independent GC cohorts based on ferroptosis-related specific genes and systematically correlated ferroptosis with immune cell infiltrating and gender characteristics. The ferroptosis score was constructed to quantify the ferroptosis levels of individual tumors using principal component analysis (PCA) algorithms.

Results: We identified two distinct ferroptosis subtypes in gastric cancer, namely Subtype-A and Subtype-B. We found that male patients in Subtype-B had the worst prognosis in contrast with the other groups. Three sex hormone receptors (AR, ER, and PR) in Subtype-B tumor patients were higher than in Subtype-A tumor patients in GC, while the HER2 displayed an opposite trend. We developed a risk model termed ferroptosis score to evaluate ferroptosis levels within individual tumors. The low-ferroptosis score group was characterized by activation of immune cells and increased mutation burden, which is also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. The patients with a low-ferroptosis score showed a high microsatellite instability status (MSI-H) and had a higher response to immunotherapy. Furthermore, the patients with low-ferroptosis scores have a lower estimated IC50 in the several chemotherapy drugs, including paclitaxel, gemcitabine, and methotrexate.

Conclusions: We revealed that sex hormone receptors and immune cell infiltration were markedly different between ferroptosis subtypes in GC patients. The results suggested that gender difference may be critical when the ferroptosis-related strategy is applied in GC treatment. Further, ferroptosis levels were identified with an extreme variety of prognosis and tumor immune characteristics, which might benefit GC individualized treatment.

• ferroptosis
• gastric cancer
• gender difference
• immune infiltration
• subtypes

• miR-125a-5p
• Hippo pathway
• TAZ
• gastric cancer
• prognosis

• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Animals
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic
• Hippo Signaling Pathway/genetics
• Humans
• Male
• Mice, Nude
• MicroRNAs/genetics
• Receptor, EphA2/genetics
• Receptor, EphA2/metabolism
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• TEA Domain Transcription Factors/genetics
• TEA Domain Transcription Factors/metabolism
• Transcriptional Coactivator with PDZ-Binding Motif Proteins/genetics
• Transcriptional Coactivator with PDZ-Binding Motif Proteins/metabolism
• Xenograft Model Antitumor Assays
• Mice

• 202102310117 Key R & D and promotion projects of Henan Province in 2019
• 2015JJ4049 Natural Scientific Foundation of Hunan province
• 81172297 National Natural Scientific Foundation of China
• 81472692 National Natural Scientific Foundation of China
• 20B320029 Key scientific research projects of colleges and universities in Henan Province

• BAG4
• Gastric cancer
• Invasion
• Metastasis
• PI3K/AKT/NF-κB signaling

• Adaptor Proteins, Signal Transducing/antagonists & inhibitors
• Adaptor Proteins, Signal Transducing/genetics
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation/genetics
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• NF-kappa B/genetics
• Neoplasm Invasiveness/genetics
• Neoplasm Invasiveness/pathology
• Oncogene Protein v-akt/genetics
• Phosphatidylinositol 3-Kinases/genetics
• Signal Transduction/genetics
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Transcription Factor RelA/genetics
• Zinc Finger E-box-Binding Homeobox 1/genetics

The EMT (epithelial-to-mesenchymal-transition) subtype of gastric cancer (GC) is associated with poor treatment responses and unfavorable clinical outcomes. Despite the broad physiological roles of the micro-RNA (miR)-200 family, they largely serve to maintain the overall epithelial phenotype. However, during late-stage gastric tumorigenesis, members of the miR-200 family are markedly suppressed, resulting in the transition to the mesenchymal state and the acquisition of invasive properties. As such, the miR-200 family represents a robust molecular marker of EMT, and subsequently, disease severity and prognosis. Most reports have studied the effect of single miR-200 family member knockdown. Here, we employ a multiplex CRISPR/Cas9 system to generate a complete miR-200 family knockout (FKO) to investigate their collective and summative role in regulating key cellular processes during GC pathogenesis. Genetic deletion of all miR-200s in the human GC cell lines induced potent morphological alterations, G1/S cell cycle arrest, increased senescence-associated β-galactosidase (SA-β−Gal) activity, and aberrant metabolism, collectively resembling the senescent phenotype. Coupling RNA-seq data with publicly available datasets, we revealed a clear separation of senescent and non-senescent states amongst FKO cells and control cells, respectively. Further analysis identified key senescence-associated secretory phenotype (SASP) components in FKO cells and a positive feedback loop for maintenance of the senescent state controlled by activation of TGF-β and TNF-α pathways. Finally, we showed that miR-200 FKO associated senescence in cancer epithelial cells significantly recruited stromal cells in the tumor microenvironment. Our work has identified a new role of miR-200 family members which function as an integrated unit serving to link senescence with EMT, two major conserved biological processes.

Warburg phenomenon refers to the development of unique metabolic patterns during the growth of tumor cells. This study stratified gastric cancer into prognostic metabolic subgroups according to changes in gene expressions related to glycolysis and cholesterol synthesis. The RNA-seq expression data, single nucleotide variants (SNV), short insertions and deletions (InDel) mutation data, copy number variation (CNV) data and clinical follow-up information data of gastric cancer tissues were downloaded from The Cancer Genome Atlas (TCGA) database. ConsensusClusterPlus was used to stratify the metabolic subtypes of gastric cancer. Four metabolic subtypes (Cholesterogenic, Glycolytic, Mixed and Quiescent) of gastric cancer were identified, and patients with cholesterogenic tumors had the longest disease-specific survival (DSS). Genome-wide analysis showed that aberrant amplification of TP53 and MYC in gastric cancer was associated with abnormal cholesterol anabolic metabolism. The mRNA levels of mitochondrial pyruvate carriers 1 and 2 (MPC1/2) differed among the four subtypes. Tumors in the glycolytic group showed a higher PDCD1. A genomic signature based on tumor metabolism of different cancer types was established. This study showed that genes related to glucose and lipid metabolism play an important role in gastric cancer and facilitate a personalized treatment of gastric cancer.

• Gastric cancer
• bioinformatics
• cholesterol
• glycolysis
• metabolism
• subtype

• Colorectal cancer
• Consensus molecular subtypes
• Gastric cancer
• Pancreatic cancer

• Carcinoma, Pancreatic Ductal/genetics
• Gastrointestinal Neoplasms/diagnosis
• Gastrointestinal Neoplasms/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasm Recurrence, Local
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/genetics

There is a male preponderance in gastric cancer (GC), which suggests a role of androgen and androgen receptor (AR). However, the mechanism of AR signaling in GC especially in female patients remains obscure. We sought to identify the AR signaling pathway that might be related to prognosis and examine the potential clinical utility of the AR antagonist for treatment. Deep learning and gene set enrichment analysis was used to identify potential critical factors associated with gender bias in GC (n = 1390). Gene expression profile analysis was performed to screen differentially expressed genes associated with AR expression in the Tianjin discovery set (n = 90) and TCGA validation set (n = 341). Predictors of survival were identified via lasso regression analyses and validated in the expanded Tianjin cohort (n = 373). In vitro and in vivo experiments were established to determine the drug effect. The GC gender bias was attributable to sex chromosome abnormalities and AR signaling dysregulation. The candidates for AR-related gene sets were screened, and AR combined with miR-125b was associated with poor prognosis, particularly among female patients. AR was confirmed to directly regulate miR-125b expression. AR-miR-125b signaling pathway inhibited apoptosis and promoted proliferation. AR antagonist, bicalutamide, exerted anti-tumor activities and induced apoptosis both in vitro and in vivo, using GC cell lines and female patient-derived xenograft (PDX) model. We have shed light on gender differences by revealing a hormone-regulated oncogenic signaling pathway in GC. Our preclinical studies suggest that AR is a potential therapeutic target for this deadly cancer type, especially in female patients.

• long non-coding rnas
• non-small-cell lung cancer

• A549 Cells
• Animals
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/therapy
• Cell Line, Tumor
• Female
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic
• Gene Ontology
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/therapy
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• MicroRNAs/genetics
• Nucleophosmin
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/metabolism
• RNA, Long Noncoding/genetics
• Xenograft Model Antitumor Assays/methods
• Mice

• C5759/A20971 Cancer Research UK
• C5759/A20465 Cancer Research UK

• Enzyme-based signal amplification in mass spectrometry
• ToF-SIMS
• miRNA sensing
• molecular signal enhancer
• single base mismatch discrimination

• P41 EB002027 NIBIB NIH HHS

• CKS1B
• cell cycling
• drug resistance
• human cancers
• therapeutic target

The diffuse-type of gastric cancer is associated with epithelial to mesenchymal transition. Loss of E-cadherin expression is the hallmark of this process and is largely due to the upregulation of the transcription factors ZEB1/2, Snail, Slug, and Twist1/2. However, miRNA and lncRNAs can also participate through these transcription factors which directly target E-cadherin. The competing endogenous RNA (ceRNA) network hypothesis state that lncRNA can sponge the miRNA pool that targets these transcripts. Based on the lack of said networks in the epithelial to mesenchymal transition, we performed a prediction analysis that resulted in novel ceRNA networks which will expand our knowledge of the molecular basis of the diffuse-type of gastric cancer.

The diffuse-type of gastric cancer (DGC), molecularly associated with epithelial to mesenchymal transition (EMT), is increasing in incidence. Loss of E-cadherin expression is the hallmark of the EMT process and is largely due to the upregulation of the EMT-inducing transcription factors ZEB1/2, Snail, Slug, and Twist1/2. However, ncRNA, such as miRNA and lncRNAs, can also participate in the EMT process through the direct targeting of E-cadherin and other EMT-inducing transcription factors. Additionally, lncRNA can sponge the miRNA pool that targets these transcripts through competing endogenous RNA (ceRNA) networks. In this review, we focus on the role of ncRNA in the direct deregulation of E-cadherin, as well as EMT-inducing transcription factors. Based on the relevance of the ceRNA network hypothesis, and the lack of said networks in EMT, we performed a prediction analysis for all miRNAs and lncRNAs that target E-cadherin, as well as EMT-inducing transcription factors. This analysis resulted in novel predicted ceRNA networks for E-cadherin and EMT-inducing transcription factors (EMT-TFs), as well as the expansion of the molecular basis of the DGC.

• E-cadherin
• EMT-inducing transcription factors
• competing endogenous RNA
• diffuse-type gastric cancer
• epithelial to mesenchymal transition
• long non-coding RNA
• microRNA

Epigenetic change is one of the mechanisms that regulates the expression of microRNAs (miRNAs) and is known to play a role in Helicobacter pylori-associated gastric carcinogenesis. We aimed to evaluate the epigenetic changes of miR-200a/b in H. pylori-associated gastric carcinogenesis and restoration after eradication.

The expression and methylation levels of miR-200a/b were evaluated in gastric cancer (GC) cell lines, human gastric mucosa of H. pylori-negative and -positive controls, and H. pylori-positive GC patients. Next, the changes in the expression and methylation levels of miR-200a/b were compared between H. pylori-eradication and H. pylori-persistence groups at 6 months. Real-time reverse transcription-polymerase chain reaction was conducted to investigate the miRNA expression levels, and MethyLight was performed to assess the methylation levels.

In the GC cell lines, the level of miR-200a/b methylation decreased and the level of expression increased after demethylation. In the human gastric mucosa, the miR-200a/b methylation levels increased in the following group order: H. pylori-negative control group, H. pylori-positive control group, and H. pylori-positive GC group. Conversely, the miR-200a/b expression levels decreased in the same order. In the H. pylori-persistence group, no significant changes were observed in the methylation and expression levels of miR-200a/b after 6 months, whereas the level of methylation decreased and the level of expression of miR-200a/b increased significantly 6 months in the H. pylori-eradication group.

Epigenetic alterations of miR-200a/b may be implicated in H. pylori-induced gastric carcinogenesis. This field defect for cancerization is suggested to be improved by H. pylori eradication.

• Epigenetic alteration
• Helicobacter pylori
• Methylation
• MicroRNAs
• Stomach neoplasm

Gastric carcinoma is a very diverse disease. The progression of gastric carcinoma is influenced by complicated gene networks. This study aims to investigate the actual and potential prognostic biomarkers related to survival in gastric carcinoma patients to further our understanding of tumor biology.

A weighted gene co-expression network analysis was performed with a transcriptome dataset to identify networks and hub genes relevant to gastric carcinoma prognosis. Data was obtained from 300 primary gastric carcinomas (GSE62254). A validation dataset (GSE34942 and GSE15459) and TCGA dataset confirmed the results. Gene ontology, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA) were performed to identify the clusters responsible for the biological processes and pathways of this disease.

A brown transcriptional module enriched in the organizational process of the extracellular matrix was significantly correlated with overall survival (HR = 1.586, p = 0.005, 95% CI [1.149–2.189]) and disease-free survival (HR = 1.544, p = 0.008, 95% CI [1.119–2.131]). These observations were confirmed in the validation dataset (HR = 1.664, p = 0.006, 95% CI [1.155–2.398] in overall survival). Ten hub genes were identified and confirmed in the validation dataset from this brown module; five key biomarkers (COL8A1, FRMD6, TIMP2, CNRIP1 and GPR124 (ADGRA2)) were identified for further research in microsatellite instability (MSI) and epithelial-tomesenchymal transition (MSS/EMT) gastric carcinoma molecular subtypes. A high expression of these genes indicated a poor prognosis.

A transcriptional co-expression network-based approach was used to identify prognostic biomarkers in gastric carcinoma. This method may have potential for use in personalized therapies, however, large-scale randomized controlled clinical trials and replication experiments are needed before these key biomarkers can be applied clinically.

• Gastric carcinoma
• Gene expression profiling
• Prognostic biomarker
• System biology
• WGCNA

• Biomarkers, Tumor/blood
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/standards
• Humans
• MicroRNAs/blood
• MicroRNAs/metabolism
• MicroRNAs/standards
• Predictive Value of Tests
• Stomach Neoplasms/blood
• Stomach Neoplasms/metabolism

Gastric cancer (GC) is one of the most common malignant tumors of the digestive tract, and its morbidity and mortality still rank the second among all cancers. The proportion of patients with advanced GC is higher, and their therapeutic effect is extremely poor. In recent years, numerous studies have shown that the content of miR-200c in GC patients is significantly increased, and the level of miR-200c is closely related to epithelial-mesenchymal transition and lymph node metastasis. Therefore, in-depth disclosure of the role of miR-200c in the diagnosis of GC will not only contribute to the early diagnosis of GC, but also help develop new effective treatment strategies and judge the prognosis of patients with GC. This article reviews the role of miR-200c in the early diagnosis of GC and discusses its application prospects.

• miR-200c
• Gastric cancer
• Diagnosis

Currently, cancer-related competing endogenous RNA (ceRNA) networks are attracting significant interest. As long noncoding RNA ZEB1-AS1 has been reported to function as an oncogene due to sponging microRNAs (miRNAs) in several cancers, we hypothesized that it could interact with specific miRNAs to form regulatory networks and facilitate the growth of gastric cancer (GC).

MiRNAs interacting with ZEB1-AS1 were screened for and selected by bioinformatics analysis. Overexpression or repression of ZEB1-AS1 was performed to determine whether it could regulate selected miRNAs. Quantitative real-time polymerase chain reactions (qPCR) validated the expression profiles of ZEB1-AS1 and miR-149-3p in GC cell lines and tissue. Statistical analysis determined the clinical significance of ZEB1-AS1 in relation to miR-149-3p. Cell counting, wound healing and transwell assays were performed to assess cell proliferation, migration and invasion. A luciferase reporter assay was utilized to confirm the putative miR-149-3p-binding sites in ZEB1-AS1.

Briefly, bioinformatics analysis inferred that ZEB1-AS1 interacts with miR-204, miR-610, and miR-149. Gain- or loss-of function assays suggested that ZEB1-AS1 negatively regulates miR-149-3p, miR-204-5p and miR-610 in GC cells. Validated by qPCR, ZEB1-AS1 was up-regulated and miR-149-3p down-regulated in GC cells and tissue. Data analyses indicated that ZEB1-AS1 and miR-149-3p are associated with the independent diagnosis and prognosis of GC. Functional assays support the theory that miR-149-3p hinders GC proliferation, migration and invasion, whereas its overexpression abrogates the corresponding effects induced by ZEB1-AS1. Lastly, dissection of the molecular mechanisms involved indicated that ZEB1-AS1 can regulate GC partly via a ZEB1-AS1/miR-149-3p axis.

ZEB1-AS1 can interact with specific miRNAs, forming a miRNA-mediated ceRNA network and promoting GC progress, partly through a ZEB1-AS1/miR-149-3p axis.

The online version of this article (10.1186/s12935-019-0742-0) contains supplementary material, which is available to authorized users.

• Biomarker
• GC progression
• Gastric cancer
• ZEB1-AS1
• ceRNA regulatory network
• miR-149-3p

Objective: The aim of this study was to conduct a meta-analysis of 49 relevant studies to evaluate the prognostic value of miRNA-200c in various human malignant neoplasms.

Methods: All relevant studies were identified by searching PubMed, Embase and Web of Science until August 15^st, 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of miRNA-200c for overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS)/disease-free survival (DFS) were calculated to investigate such associations.

Results: Overall, 49 eligible studies were included in this meta-analysis. Our results showed that high expression of miRNA-200c was significantly correlated with a poor OS in cancer (pooled HR = 1.32, 95% CI: 1.06-1.65), but was not significantly correlated with PFS/RFS/DFS in cancer (pooled HR=1.05, 95% CI: 0.84-1.23). In our subgroup analysis, high miRNA-200c expression predicted a significantly worse OS (pooled HR = 1.50, 95% CI: 1.12-2.01) only in Caucasians. Moreover, high miRNA-200c expression even showed significantly poor OS (pooled HR = 1.88, 95% CI: 1.39-2.54) in blood samples. In addition, a significantly unfavorable OS (pooled HR = 2.69, 95% CI: 1.49-4.85) and (pooled HR = 2.66, 95% CI: 1.07-6.59) associated with up-regulated miRNA-200c expression were observed in breast cancer and endometrial cancer, respectively. Besides, high miRNA-200c expression also showed significantly poor PFS/RFS/DFS (pooled HR=1.66, 95% CI: 1.03-2.67) in breast cancer.

Conclusions: Our findings indicated that high miRNA-200c expression was a promising biomarker for patient survival and disease progression in malignant tumors, especially in breast cancer and endometrial cancer. Considering the insufficient evidence, further large-scale researches and clinical studies were needed to verify these results.

• malignant neoplasms
• miRNA-200c
• overall survival
• prognosis
• progression-free survival

• CD163
• gastric carcinoma
• miR-4262
• prognosis
• proliferation and invasion

Renal cell carcinoma (RCC) is the most common renal carcinoma in the human kidney. To date, to the best of our knowledge, there are no biomarkers for the early monitoring and diagnosis of RCC patients. The present study aimed to develop deeper insight into the molecular mechanisms of microRNAs (miRNAs/miRs) in the regulation of RCC development and to reveal candidate miRNA biomarkers in human RCC. A meta-analysis was used to integrate the published and independent RCC miRNA expression profiling investigations that compared the miRNA expression profiles in RCC samples with control samples. The meta-signature miRNA target genes were then predicted in TargetScan. The predicted targets were further analyzed using Gene Ontology and pathway enrichment analysis with the Database for Annotation, Visualization and Integrated Discovery online tool, and then the transcription factors of meta-signature miRNA target genes were identified in Tfacts. A total of 7 publicly available and independent RCC miRNA expression profiling datasets were collected, and 2 upregulated (hsa-miR-155-5p and hsa-miR-210-5p) and 6 downregulated (hsa-miR-138-5p, hsa-miR-141-5p, hsa-miR-200c-5p, hsa-miR-362-5p, hsa-miR-363-5p and hsa-miR-429) meta-signature miRNAs in renal carcinoma were identified. The targeted gene enrichment analysis indicated that the meta-signature miRNAs may influence several pathways that participate in cancerogenesis, including the ‘rap1 signaling pathway’, ‘renal cell carcinoma’ and ‘microRNAs in cancer’. Overall, the present meta-analysis identified 2 upregulated and 6 downregulated meta-signature miRNAs from 7 renal carcinoma datasets, the dysregulated miRNAs that may contribute to kidney carcinoma development. This research may reveal candidate miRNA biomarkers in human RCC.

• meta-analysis
• microRNAs
• pathway
• renal cell carcinoma
• transcription factor

Gastric cancer (GC) is a common malignancy and frequent cause of cancer-related death. Long non-coding RNAs (lncRNAs) have emerged as important regulators and tissue-specific biomarkers of multiple cancers, including GC. Recent evidence has indicated that the novel lncRNA LINC01133 plays an important role in cancer progression and metastasis. However, its function and molecular mechanism in GC remain largely unknown.

LINC01133 expression was detected in 200 GC and matched non-cancerous tissues by quantitative reverse transcription PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of LINC01133 both in vitro and in vivo. Insights into the underlying mechanisms of competitive endogenous RNAs (ceRNAs) were determined by bioinformatics analysis, dual-luciferase reporter assays, quantitative PCR arrays, TOPFlash/FOPFlash reporter assay, luciferase assay, and rescue experiments.

LINC01133 was downregulated in GC tissues and cell lines, and its low expression positively correlated with GC progression and metastasis. Functionally, LINC01133 depletion promoted cell proliferation, migration, and the epithelial–mesenchymal transition (EMT) in GC cells, whereas LINC01133 overexpression resulted in the opposite effects both in vitro and in vivo. Bioinformatics analysis and luciferase assays revealed that miR-106a-3p was a direct target of LINC01133, which functioned as a ceRNA in regulating GC metastasis. Mechanistic analysis demonstrated that miR-106a-3p specifically targeted the adenomatous polyposis coli (APC) gene, and LINC01133/miR-106a-3p suppressed the EMT and metastasis by inactivating the Wnt/β-catenin pathway in an APC-dependent manner.

Our findings suggest that reduced expression of LINC01133 is associated with aggressive tumor phenotypes and poor patient outcomes in GC. LINC01133 inhibits GC progression and metastasis by acting as a ceRNA for miR-106a-3p to regulate APC expression and the Wnt/β-catenin pathway, suggesting that LINC01133 may serve as a potential prognostic biomarker and anti-metastatic therapeutic target for GC.

The online version of this article (10.1186/s12943-018-0874-1) contains supplementary material, which is available to authorized users.

• APC
• Gastric cancer
• LINC01133
• Progression
• Wnt/β-catenin pathway
• ceRNA
• miR-106a-3p

• biomarker
• carcinoma
• miR‐200 family
• prognosis

• National Natural Science Foundation of China (Beijing, China)

Purpose: Based on the previous 3 well-defined subtypes of gastric adenocarcinoma (invasive, proliferative and metabolic), we aimed to find potential biomarkers and biological features of each subtype.

Methods: The genome-wide co-expression network of each subtype of gastric cancer was firstly constructed. Then, the functional modules in each genome-wide co-expression network were divided. Next, the key genes were screened from each functional module. Finally, the enrichment analysis was performed on the key genes to mine the biological features of each subtype. Comparative analysis between each pair of subtypes was performed to find the common and unique features among different subtypes.

Results: A total of 207 key genes were identified in invasive, 215 key genes in proliferative, and 204 key genes in metabolic subtypes. Most key genes in each subtype were unique and new findings compared with that of the existing related researches. The GO and KEGG enrichment analyses for the key genes of each subtype revealed important biological features of each subtype.

Conclusions: For a subtype, most identified key genes and important biological features were unique, which means that the key genes can be used as the potential biomarker of a subtype, and each subtype of gastric cancer might have different occurrence and development mechanisms. Thus, different diagnosis and therapy methods should be applied to the invasive, proliferative and metabolic subtypes of gastric cancer.

• Genome-wide co-expression network
• Key genes
• Molecular subtype
• Potential biomarker
• Single disease samples

• miRNA signature
• overall survival
• prognostic biomarkers
• stomach adenocarcinoma

• IL-22
• PPP3R1
• miR-548a-3p
• psoriasis

• Calcineurin/drug effects
• Cell Line
• Cell Proliferation
• Humans
• Interleukins/pharmacology
• Keratinocytes/cytology
• MicroRNAs/genetics
• MicroRNAs/physiology
• Polymerase Chain Reaction
• Psoriasis/drug therapy
• Transcriptional Activation
• Up-Regulation
• Interleukin-22

• 81573046 National Naturtal Science Fundation of China

• PPM1F
• gastric cancer
• invasion
• miR-590-3p
• proliferation

The TMPRSS2-ERG fusion occurs in approximately 50% of prostate cancer (PCa), resulting in expression of the oncogenic ERG in the prostate. Because ERG is a transcriptional activator, we hypothesized that ERG-regulated genes contribute to PCa development. Since microRNA (miRNA) has crucial functions in cancer, we searched for miRNAs regulated by ERG in PCas. We mined published datasets based on the MSKCC Prostate Oncogene Project, in which a comprehensive analysis defined the miRNA transcriptomes in 113 PCas. We retrieved the miRNA expression datasets, and identified miRNAs differentially expressed between ERG-positive and ERG-negative samples. Out of 369 miRNAs, miR-200a, −200b, −429 and −205 are the only miRNAs significantly increased in ERG-positive tumors. Strikingly, miR-200a, −200b and −429 are transcribed as a single polycistronic transcript, suggesting they are regulated at the transcriptional level. With ChIP-qPCR and in vitro binding assay, we identified two functional ETS motifs in the miR-200b/a/429 gene promoter. Knockdown of ERG in PCa cells reduced expression of these three miRNAs. In agreement with the well-established tumor suppressor function, overexpression of the miR-200b/a/429 gene inhibited PCa cell growth and invasion. In summary, our study reveals that miR-200b/a/429 is an ERG target gene, which implicates an important role in TMPRSS2/ERG-dependent PCa development. Although induction of the tumor suppressive miR-200b subfamily by oncogenic ERG appears to be counterintuitive, it is consistent with the observation that the vast majority of primary prostate cancers are slow-growing and indolent.

• ERG
• miR-200
• miR-205
• prostate cancer

B-cell specific moloney leukemia virus insertion site 1 (Bmi-1) gene plays important roles in gastric cancer, but the epigenetic regulatory mechanism by microRNA (miRNA) and the functional significance of Bmi-1 inhibition in gastric cancer remains elusive. In this study, we systematically investigated the functional roles of miRNA mediated Bmi-1 suppression in gastric cancer. Our results show that the expression of miR-15a is significantly reduced in gastric cancer and the protein expression levels of Bmi-1 are inversely correlated with miR-15a (P = 0.034) in gastric cancer patient samples. Functional studies revealed that ectopic expression of miR-15a decreased Bmi-1 in gastric cancer cell lines with reduced proliferation and tumor invasion. High levels of Bmi-1 in gastric cancer patients are significantly associated with better overall survival (P = 0.024) based on the Kaplan-Meier survival analysis.

• Bmi-1
• gastric cancer
• miR-15a
• survival

Gastric cancer (GC) is the second most frequent cause of cancer-related deaths worldwide. MicroRNAs are single-stranded RNA molecules of 21–23 nucleotides that regulate target gene expression through specific base-pairing interactions between miRNA and untranslated regions of targeted mRNAs. In this study, we generated a multistep approach for the integrated analysis of miRNA and mRNA expression. First, both miRNA and mRNA expression profiling datasets in gastric cancer from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) identified 79 and 1042 differentially expressed miRNAs and mRNAs, respectively, in gastric cancer. Second, inverse correlations between miRNA and mRNA expression levels identified 3206 miRNA–mRNA pairs combined with 79 dysregulated miRNAs and their 774 target mRNAs predicted by three prediction tools, miRanda, PITA, and RNAhybrid. Additionally, miR-204, which was found to be down-regulated in gastric cancer, was ectopically over-expressed in the AGS gastric cancer cell line and all down-regulated targets were identified by RNA sequencing (RNA-seq) analysis. Over-expression of miR-204 reduced the gastric cancer cell proliferation and suppressed the expression of three targets which were validated by qRT-PCR and luciferase assays. For the first time, we identified that CKS1B, CXCL1, and GPRC5A are putative targets of miR-204 and elucidated that miR-204 acted as potential tumor suppressor and, therefore, are useful as a promising therapeutic target for gastric cancer.

• expression profiling
• gastric cancer
• integrated analysis
• microRNA (miRNA)

Scirrhous type gastric cancer is characterized by diffuse infiltration of poorly differentiated adenocarcinoma cells and poor prognosis. Although association of poorly differentiated histology with reduction in E-cadherin expression, as well as association of microRNA (miR)-200c with E-cadherin through regulation of ZEB1/2, has been reported, participation of miR-200c in gastric carcinogenesis is not fully understood. We used 6 cell lines originating from gastric cancers, and investigated levels of miR-200c along with its target mRNAs ZEB1/2 and E-cadherin by qRT-PCR. ZEB1 and E-cadherin protein expression was also assessed via western blotting. Furthermore, we investigated the expression levels of miR-200c by in situ hybridization, along with the expression of ZEB1 and E-cadherin by immunohistochemistry, in 97 gastric adenocarcinoma tissues. Inverse correlation between miR-200c and ZEB1 levels were obtained by qRT-PCR in cell lines (P<0.05). Cell lines with low miR-200c and high ZEB1 exhibited low E-cadherin expression in both qRT-PCR and western blotting, and exhibited spindle-shaped morphology, in contrast to round cell morphology in those cell lines with high miR-200c levels. Inverse correlations were also obtained between miR-200c and ZEB1 as well as between ZEB1 and E-cadherin levels in tissue samples (P<0.001). Cancer tissues with low miR-200c, high ZEB1, and low E-cadherin expression were associated with poorly differentiated histology, in contrast to tubular form in cancers with high miR-200c expression levels (P<0.001). Our data revealed that downregulation of miR-200c primarily regulated cell morphology by downregulation of E-cadherin through upregulation of ZEB1, leading to poorly differentiated histology in gastric cancer.

• CDK6
• Cyclin D1
• E2F1
• Gastric cancer
• miR-218