• METTL3
• SMAD4
• m6A RNA methylation
• miR-146a-5p
• oral cancer

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Humans
• Methyltransferases/metabolism
• Methyltransferases/genetics
• Mouth Neoplasms/genetics
• Mouth Neoplasms/pathology
• Mouth Neoplasms/metabolism
• Smad4 Protein/metabolism
• Smad4 Protein/genetics
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Carcinoma, Squamous Cell/metabolism
• Gene Expression Regulation, Neoplastic
• Cell Line, Tumor
• Signal Transduction
• Adenosine/analogs & derivatives
• Adenosine/metabolism
• Cell Proliferation

• Staphylococcus aureus
• inflammation
• miR-146a
• osteogenesis
• osteomyelitis

Helicobacter pylori (H. pylori) infection promotes gastric carcinogenesis by increasing oxidative stress, inflammation, and dysregulation of cell survival and proliferation of gastric epithelial cells. Astaxanthin (ASTX), a bioactive carotenoid, exhibits antioxidant and anticancer effects by modulating aberrant signaling pathways that lead to dysregulation of cell death and proliferation. To elucidate the molecular mechanism of H. pylori-induced gastric carcinogenesis and to examine the inhibitory effect of ASTX on H. pylori-induced gastric epithelial cell gene expression changes, we performed comparative RNA-sequencing (RNA-Seq) analysis for H. pylori-infected gastric epithelial cells treated with or without ASTX. RNA-Seq results reveal that differentially expressed genes (DEGs) in H. pylori-infected cells were mainly associated with the Wnt/β-catenin signaling pathway, which is related to cell proliferation. ASTX significantly reversed H. pylori-induced transcriptional alterations of the key mediators involved in β-catenin signaling, notably, porcupine (gene symbol, PORCN), spermine oxidase (SMOX), bone morphogenetic protein (BMP) and activin membrane-bound inhibitor (BAMBI), SMAD family member 4 (SMAD4), transforming growth factor-β1 (TGFB1), Fos-like 1 (FOSLI), and c-myc (MYC). We suggest that ASTX may be a potential therapeutic agent that can suppress H. pylori-induced proliferation-associated gene expression changes, in part, by counter-regulating the Wnt/β-catenin signaling pathway.

• Helicobacter pylori
• astaxanthin
• cell proliferation
• gastric cancer
• gastric epithelial cells
• β-catenin

• Gastric cancer
• Gastric carcinogenesis
• Gastric preneoplastic conditions
• microRNAs

• Adult
• Aged
• Biopsy
• Carcinogenesis/genetics
• Cross-Sectional Studies
• Female
• Gastric Mucosa/pathology
• Gene Expression
• Gene Expression Profiling
• Humans
• Male
• MicroRNAs/blood
• MicroRNAs/classification
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Precision Medicine/methods
• Precision Medicine/standards
• Stomach/pathology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/physiopathology

• angiogenesis
• chemoresistance
• epithelial-mesenchymal transition (EMT)
• gastric cancer
• microRNA
• signaling pathway
• tumor microenvironment

• Animals
• Apoptosis/physiology
• Cell Cycle/physiology
• Cell Line, Tumor
• Cell Proliferation/physiology
• Disease Progression
• Drug Resistance, Neoplasm/physiology
• Epithelial-Mesenchymal Transition/physiology
• Gene Expression Regulation/physiology
• Humans
• MicroRNAs/metabolism
• Signal Transduction/physiology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/physiopathology
• Tumor Microenvironment/physiology

• R01 CA192395 NCI NIH HHS

• epstein-barr virus
• tgf/smad
• core 2β-1,6-acetylglucosaminyltransferase
• gastric carcinoma
• latent membrane protein 2a
• mtorc1 pathway

Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions, particularly critical pathways for cell death, by affecting various intracellular mediators. MicroRNAs (miRNAs) are a major example of these mediators because they are involved in many (if not most) cellular mechanisms. Virus-regulated miRNAs have been implicated in three cell death pathways, namely, apoptosis, autophagy, and anoikis. Several molecules (e.g., BECN1 and B cell lymphoma 2 [BCL2] family members) are involved in both apoptosis and autophagy, while activation of anoikis leads to cell death similar to apoptosis. These mechanistic similarities suggest that common regulators, including some miRNAs (e.g., miR-21 and miR-192), are involved in different cell death pathways. Because the balance between cell proliferation and cell death is pivotal to the homeostasis of the human body, miRNAs that regulate cell death pathways have drawn much attention from researchers. miR-21 is regulated by several viruses and can affect both apoptosis and anoikis via modulating various targets, such as PDCD4, PTEN, interleukin (IL)-12, Maspin, and Fas-L. miR-34 can be downregulated by viral infection and has different effects on apoptosis, depending on the type of virus and/or host cell. The present review summarizes the existing knowledge on virus-regulated miRNAs involved in the modulation of cell death pathways. Understanding the mechanisms for virus-mediated regulation of cell death pathways could provide valuable information to improve the diagnosis and treatment of many viral diseases.

• anoikis
• apoptosis
• autophagy
• cell death
• microRNAs
• viruses

Background: Gastric carcinoma (GC) is one of the most common malignant tumors and seriously threatens human life and health.

Methods: In the present study, 243 differentially expressed proteins in GC were identified using laser capture microdissection (LCM) combined with isotopically labeled quantitative proteomics technology. The expression of serine protease 1 (PRSS1) protein was analyzed by immunohistochemistry and Western blot. MTT and colony formation assays were employed to determine the effect of PRSS1 expression on the growth and proliferation of GC cells. Then, we observed the expression of miR-146a-5p in GC by qRT-PCR. A dual luciferase assay was performed to determine whether PRSS1 is a target gene of miR-146a-5p. We also explored the influence of miR-146a-5p expression on PRSS1 expression and on the growth and proliferation of GC cells. Finally, Western blotting was used to analyze the effect of PRSS1 expression on the activation of the ERK signaling pathway.

Results: We confirmed that PRSS1 expression was significantly increased and was positively correlated with the differentiation, tumor size and lymph node metastasis of GC. Subsequently, we found that overexpression of PRSS1 promoted the growth and proliferation of cells, whereas silencing PRSS1 expression inhibited the growth and proliferation of MGC803 cells by inhibiting activation of the ERK signaling pathway via reductions in PAR-2 activation. MiR-146a-5p targets PRSS1 and suppresses the growth and proliferation of MGC803 cells.

Conclusions: miR-146a-5p targets PRSS1 and suppresses the growth and proliferation of MGC803 cells. Silencing PRSS1 expression inhibits the ERK signaling pathway by reducing PAR-2 activation, resulting in suppressed growth and proliferation of MGC803 GC cells.

• ERK
• PAR-2
• PRSS1
• gastric carcinoma
• miR-146a-5p
• proteomics

Non-small cell lung cancer (NSCLC) is the most deadly cancer in the world due to its often delayed diagnosis. Identification of biomarkers with high sensitivity, specificity, and accessibility for early detection, such as circulating microRNAs, is therefore of utmost importance. In the present study, we identified a significantly higher expression of miR-146a-5p in the serum and tissue samples of NSCLC patients than that of the healthy controls. In parallel, miR-146a-5p was also highly expressed in three human NSCLC adenocarcinoma-cell lines (A549, H1299, and H1975) compared to the human bronchial epithelium cell line (HBE). By dual-luciferase reporter assay and manipulation of the expressions of miR-146a-5p and its target gene, tumor necrosis factor receptor-associated factor 6 (TRAF6), we showed that the functional effects of miR-146a-5p on NSCLC cell survival and migration were mediated by direct binding to and suppression of TRAF6. Overexpression of TRAF6 sufficiently reversed miR-146a-5p-induced cancer cell proliferation, migration, and apoptosis resistance. Our data implied that miR-146a-5p/TRAF6/NF-κB-p65 axis could be a promising diagnostic marker and a therapeutic target for NSCLC.

• TRAF6
• apoptosis
• miR-146a-5p
• migration
• non-small cell lung cancer

• CCL2
• HuR
• Inflammation
• RNA-Seq
• gene expression
• lung adenocarcinoma
• microRNA
• post-transcriptional regulation

Endometrial cancer is the most common gynecologic malignancy in developed countries. Estrogen-dependent tumors (type I, endometrioid) account for 80% of cases and non-estrogen-dependent (type II, non-endometrioid) account for the rest. Endometrial cancer type I is generally thought to develop via precursor lesions along with the increasing accumulation of molecular genetic alterations. Endometrial hyperplasia with atypia/Endometrial Intraepithelial Neoplasia is the least common type of hyperplasia but it is the type most likely to progress to type I cancer, whereas endometrial hyperplasia without atypia rarely progresses to carcinoma. MicroRNAs are a class of small, non-coding, single-stranded RNAs that negatively regulate gene expression mainly binding to 3′-untranslated region of target mRNAs. In the current study, we identified a microRNAs signature (miR-205, miR-146a, miR-1260b) able to discriminate between atypical and typical endometrial hyperplasia in two independent cohorts of patients. The identification of molecular markers that can distinguish between these two distinct pathological conditions is considered to be highly useful for the clinical management of patients because hyperplasia with an atypical change is associated with a higher risk of developing cancer. We show that the combination of miR-205, −146a, and −1260b has the best predictive power in discriminating these two conditions (>90%). With the aim to find a biological role for these three microRNAs, we focused our attention on a common putative target involved in endometrial carcinogenesis: the oncosuppressor gene SMAD4. We showed that miRs-146a,−205, and−1260b directly target SMAD4 and their enforced expression induced proliferation and migration of Endometrioid Cancer derived cell lines, Hec1a cells. These data suggest that microRNAs-mediated impairment of the TGF-β pathway, due to inhibition of its effector molecule SMAD4, is a relevant molecular alteration in endometrial carcinoma development. Our findings show a potential diagnostic role of this microRNAs signature for the accurate diagnosis of Endometrial hyperplasia with atypia/Endometrial Intraepithelial Neoplasia and improve the understanding of their pivotal role in SMAD4 regulation.

• SMAD4
• TGF-β pathway
• biomarkers
• endometrial cancer
• endometrial hyperplasia
• microRNAs

• ZEB1-AS1
• invasion
• melanoma
• microRNA-1224-5p
• proliferation

The multifunctional transforming growth factors-beta (TGF-βs) have been extensively studied regarding their role in the pathogenesis of neovascular age-related macular degeneration (nAMD), a major cause of severe visual loss in the elderly in developed countries. Despite this, their effect remains somewhat controversial. Indeed, both pro- and antiangiogenic activities have been suggested for TGF-β signaling in the development and progression of nAMD, and opposite therapies have been proposed targeting the inhibition or activation of the TGF-β pathway. The present article summarizes the current literature linking TGF-β and nAMD, and reviews experimental data supporting both pro- and antiangiogenic hypotheses, taking into account the limitations of the experimental approaches.

• TGF-β
• angiogenesis
• choroidal neovascularization (CNV)
• neovascular age-related macular degeneration (nAMD)

MiRNA polymorphisms had potential to be biomarkers for hepatocellular cancer (HCC) susceptibility. Recently, miRNA single nucleotide polymorphisms (SNPs) were reported to be associated with HCC risk, but the results were inconsistent. We performed a systematic review with a meta-analysis for the association of miRNA SNPs with HCC risk. Thirty-seven studies were included with a total of 11821 HCC patients and 15359 controls in this meta-analysis. We found hsa-mir-146a rs2910164 was associated with a decreased HCC risk in the recessive model (P=0.017, OR = 0.90, 95% confidence interval (CI) = 0.83–0.98). While hsa-mir-34b/c rs4938723 was related with an increased HCC risk in the co-dominant model (P=0.016, odds ratio (OR) = 1.19, 95%CI = 1.03–1.37). When analyzing the Hepatitis B virus (HBV)-related HCC risk, hsa-mir-196a-2 rs11614913 was associated with a decreased HBV-related HCC risk in the co-dominant and allelic models. And hsa-mir-149 rs2292832 was found to be associated with a decreased HBV-related HCC risk in the dominant and recessive models. In conclusion, hsa-mir-146a rs2910164 and hsa-mir-34b/c rs4938723 could be biomarkers for the HCC risk while hsa-mir-196a-2 rs11614913 and hsa-mir-149 rs2292832 had potential to be biomarkers for HBV-related HCC risk.

• hepatocellular cancer
• meta-analysis
• miRNA
• single nucleotide polymorphism
• system review

Previous studies have explored the functions of microRNA (miR)-146a in different types of cancer through mediating different targets. However, the roles of miR-146a in malignant melanoma (MM) cell migration and invasion remain largely elusive. In the present study, the potential molecular function of miR-146a in MM was investigated. Reverse transcription-quantitative polymerase chain reaction was utilized to detect miR-146a expression in MM tissues and cell lines. A Transwell assay was performed to confirm the ability of migration and invasion. A luciferase assay and biological analysis were used to predict and determine the targets of miR-146a. The expression of miR-146a was upregulated in melanoma tissues and cell lines. Clinicopathological analysis indicated that the miR-146a level was negatively correlated with the progression of melanoma. Abnormal expression of miR-146a promoted cell migration and invasion in MM cells. Additionally, it was also observed that Mothers against decapentaplegic homolog 4 (SMAD4) was a novel target of miR-146a in MM. SMAD4 was negatively associated with miR-146a in MM and abnormal expression of SMAD4 attenuated miR-146a-mediated promotion of cell migration and invasion. In conclusion, miR-146a functioned as an oncogene by directly targeting SMAD4 and it may be a novel diagnostic and therapeutic marker of MM.

• invasion
• melanoma
• miR-146a
• migration
• mothers against decapentaplegic homolog 4

Kaposi's sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS). Both KSHV and HIV infections are endemic in Uganda, where KS is among the most common cancers in HIV-infected individuals. Recent studies examined the use of small RNAs as biomarkers of disease, including microRNAs (miRNAs), with viral and tumor-derived miRNAs being detected in exosomes from individuals with KSHV-associated malignancies. In the current study, the host and viral extracellular mature miRNA expression profiles were analyzed in blood of KS-negative individuals in Uganda, comparing those with or without KSHV detectable from the oropharynx. We observed increased levels of cellular oncogenic miRNAs and decreased levels of tumor-suppressor miRNAs in plasma of infected individuals exhibiting oral KSHV shedding. These changes in host oncomiRs were exacerbated in people co-infected with HIV, and partially reversed after 2 years of anti-retroviral therapy. We also detected KSHV miRNAs in plasma of KSHV infected individuals and determined that their expression levels correlated with KSHV plasma viremia. Deep sequencing revealed an expected profile of small cellular RNAs in plasma, with miRNAs constituting the major RNA biotype. In contrast, the composition of small RNAs in exosomes was highly atypical with high levels of YRNA and low levels of miRNAs. Mass spectrometry analysis of the exosomes revealed eleven different peptides derived from the malaria parasite, Plasmodium falciparum, and small RNA sequencing confirmed widespread plasmodium co-infections in the Ugandan cohorts. Proteome analysis indicated an exosomal protein profile consistent with erythrocyte and keratinocyte origins for the plasma exosomes. A strong correlation was observed between the abundance of Plasmodium proteins and cellular markers of malaria. As Plasmodium falciparum is an endemic pathogen in Uganda, our study shows that co-infection with other pathogens, such as KSHV, can severely impact the small RNA repertoire, complicating the use of exosome miRNAs as biomarkers of disease.

Inflammation is a potent inducer of tumorigenesis. Increased DNA damage or loss of genome integrity is thought to be one of the mechanisms linking inflammation and cancer development. It has been suggested that NF-κB-induced microRNA-146 (miR146a) may be a mediator of the inflammatory response. Based on our initial observation that miR146a overexpression strongly increases DNA damage, we investigated its potential role as a modulator of DNA repair. Here, we demonstrate that FANCM, a component in the Fanconi Anemia pathway, is a novel target of miR146a. miR146a suppressed FANCM expression by directly binding to the 3′ untranslated region of the gene. miR146a-induced downregulation of FANCM was associated with inhibition of FANCD2 monoubiquitination, reduced DNA homologous recombination repair and checkpoint response, failed recovery from replication stress, and increased cellular sensitivity to cisplatin. These phenotypes were recapitulated when miR146a expression was induced by overexpressing the NF-κB subunit p65/RelA or Helicobacter pylori infection in a human gastric cell line; the phenotypes were effectively reversed with an anti-miR146a antagomir. These results suggest that undesired inflammation events caused by a pathogen or over-induction of miR146a can impair genome integrity via suppression of FANCM.

• DNA interstrand cross-links (ICLs) repair
• FANCM
• NF-κB
• miR146a
• Fanconi anemia pathway

• Gastric cancer
• Organoid
• Smad4
• Wnt
• miR-324-3p

• DNA methylation
• apoptosis
• cancer
• epigenetics
• microRNA
• tumor suppressor genes
• ubiquitin-like with PHD and RING finger domains 1

• ZNRF3
• growth
• miR-146a-5p
• osteosarcoma
• recurrence

Exosomes have been implicated in the cell-cell transfer of oncogenic proteins and genetic material. We speculated this may be one mechanism by which an intrinsically platinum-resistant population of epithelial ovarian cancer (EOC) cells imparts its influence on surrounding tumor cells. To explore this possibility we utilized a platinum-sensitive cell line, A2780 and exosomes derived from its resistant subclones, and an unselected, platinum-resistant EOC line, OVCAR10. A2780 cells demonstrate a ~2-fold increase in viability upon treatment with carboplatin when pre-exposed to exosomes from platinum-resistant cells as compared to controls. This coincided with increased epithelial to mesenchymal transition (EMT). DNA sequencing of EOC cell lines revealed previously unreported somatic mutations in the Mothers Against Decapentaplegic Homolog 4 (SMAD4) within platinum-resistant cells. A2780 cells engineered to exogenously express these SMAD4 mutations demonstrate up-regulation of EMT markers following carboplatin treatment, are more resistant to carboplatin, and release exosomes which impart a ~1.7-fold increase in resistance in naive A2780 recipient cells as compared to controls. These studies provide the first evidence that acquired SMAD4 mutations enhance the chemo-resistance profile of EOC and present a novel mechanism in which exchange of tumor-derived exosomes perpetuates an EMT phenotype, leading to the development of subpopulations of platinum-refractory cells.

• EMT
• SMAD4
• exosomes
• ovarian cancer
• platinum-resistance

• Bacteria
• gram negative
• host immunity
• microRNAs

• Adaptive Immunity
• Animals
• Cell Differentiation
• Gram-Negative Bacteria/immunology
• Gram-Negative Bacterial Infections/immunology
• Host-Parasite Interactions
• Humans
• Immunity, Innate
• Immunomodulation
• MicroRNAs/genetics

• R01 HD061580 NICHD NIH HHS
• R03 AI117714 NIAID NIH HHS

• Gastric cancer
• Single-nucleotide polymorphisms
• Target genes
• miRNA

• Adult
• Aged
• Antigens, CD/genetics
• Case-Control Studies
• Cyclin D1/genetics
• Female
• Genotype
• Germany
• Humans
• Interleukin-10/genetics
• Interleukin-12 Subunit p40/genetics
• Latvia
• Leukocytes, Mononuclear
• Lithuania
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Receptor, Insulin/genetics
• Regression Analysis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism

• Biomarkers, Tumor/blood
• Biomarkers, Tumor/urine
• Carcinogenesis
• Cell Proliferation
• Humans
• MicroRNAs/blood
• MicroRNAs/urine
• Retinoblastoma-Binding Protein 1/genetics
• Stomach Neoplasms/blood
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Up-Regulation

• Ministry of Science and Technology, Taiwan
• National Yang-Ming University Hospital (TW)

• Chondrocyte
• MicroRNA-146a
• NF-κB signaling pathway
• Osteoarthritis
• Proliferation
• TRAF6

• BARF1
• Epstein-Barr virus
• NFκB
• SMAD4
• miR-146a

• Cell Line, Tumor
• Cell Proliferation
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Herpesvirus 4, Human/genetics
• Herpesvirus 4, Human/metabolism
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• NF-kappa B/genetics
• NF-kappa B/metabolism
• RNA Interference
• Signal Transduction
• Smad4 Protein/genetics
• Smad4 Protein/metabolism
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Stomach Neoplasms/virology
• Time Factors
• Transfection
• Viral Proteins/genetics
• Viral Proteins/metabolism

Alterations in epigenetic control of gene expression play an important role in many diseases, including gastric cancer. Many studies have identified a large number of upregulated oncogenic miRNAs and downregulated tumour-suppressor miRNAs in this type of cancer. In this review, we provide an overview of the role of miRNAs, pointing to their potential to be useful as diagnostic and/or prognostic biomarkers in gastric cancer. Moreover, we discuss the influence of polymorphisms and epigenetic modifications on miRNA activity.

• Gastric cancer
• Epigenetic
• Diagnostic biomarkers
• miRNAs
• Prognostic biomarkers

• Biomarkers, Tumor/metabolism
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/metabolism
• MicroRNAs/therapeutic use
• Polymorphism, Genetic
• Polymorphism, Single Nucleotide
• Prognosis
• RNA, Messenger/metabolism
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism

AIM: To evaluate the role of microRNA (miR)-146a, -155 and -122 in the duodenal mucosa of pediatric patients with Crohn’s disease (CD) and the effect of transforming growth factor-β (TGF-β) on these miRs in duodenal epithelial and fibroblast cells.

METHODS: Formalin-fixed, paraffin-embedded biopsies derived from the macroscopically inflamed (CD inflamed: n = 10) and intact (CD intact: n = 10) duodenal mucosa of pediatric CD patients and control children (C: n = 10) were examined. Expression of miR-146a, -155 and -122 was determined by real-time polymerase-chain reaction (PCR). The expression of the above miRs was investigated in recombinant human TGF-β (1 nmol/L, 24 h) or vehicle treated small intestinal epithelial cells (CCL-241) and primary duodenal fibroblast cells derived from healthy children as well.

RESULTS: Expression of miR-146a was significantly higher in the inflamed duodenal mucosa compared to the intact duodenal mucosa of children with CD (CD inflamed: 3.21 ± 0.50 vs CD intact: 0.62 ± 0.26, P≤ 0.01) and to the control group (CD inflamed: 3.21 ± 0.50 vs C: 1.00 ± 0.33, P≤ 0.05). The expression of miR-155 was significantly increased in the inflamed region of the duodenum compared to the control group (CD inflamed: 4.87 ± 1.02 vs Control: 1.00 ± 0.40, P≤ 0.001). The expression of miR-122 was unchanged in the inflamed or intact mucosa of CD patients compared to controls. TGF-β treatment significantly decreased the expression of miR-155 in small intestinal epithelial cells (TGF-β: 0.7 ± 0.083 vs Control: 1 ± 0.09, P≤ 0.05) and also the expression of miR-146a (TGF-β: 0.67 ± 0.04 vs Control: 1 ± 0.15, P≤ 0.01) and miR-155 (TGF-β: 0.72 ± 0.09 vs Control: 1 ± 0.06, P≤ 0.05) in primary duodenal fibroblasts compared to corresponding vehicle treated controls. TGF-β treatment did not influence the expression of miR-122.

CONCLUSION: The elevated expression of miR-146a and -155 in the inflamed duodenal mucosa of CD patients suggests the role of these miRs in the pathomechanism of inflammatory bowel disease. Anti-inflammatory TGF-β plays an important role in the regulation of the expression of these miRs.

• Inflammatory bowel disease
• Crohn’s disease
• Pediatric
• MicroRNAs
• Transforming growth factor-β

• Adolescent
• Child
• Crohn Disease/genetics
• Crohn Disease/metabolism
• Duodenum/cytology
• Duodenum/drug effects
• Duodenum/metabolism
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Female
• Fibroblasts/drug effects
• Fibroblasts/metabolism
• Humans
• In Vitro Techniques
• Intestinal Mucosa/cytology
• Intestinal Mucosa/drug effects
• Intestinal Mucosa/metabolism
• Male
• MicroRNAs/drug effects
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Transforming Growth Factor beta/pharmacology

• biomarker
• diagnosis
• gastric cancer
• microRNAs
• prognosis

• Animals
• Apoptosis
• Biomarkers, Tumor
• Cell Cycle/genetics
• Cell Proliferation
• Early Detection of Cancer
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• Neoplasm Metastasis
• Prognosis
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/mortality
• Stomach Neoplasms/therapy

• apoptosis
• gastric cancer
• kinesin family member C1
• miR-135a
• proliferation

Biological research increasingly relies on network models to study complex phenomena. Signal Transduction Pathways are molecular circuits that model how cells receive, process, and respond to information from the environment providing snapshots of the overall cell dynamics. Most of the attempts to reconstruct signal transduction pathways are limited to single regulator networks including only genes/proteins. However, networks involving a single type of regulator and neglecting transcriptional and post-transcriptional regulations mediated by transcription factors and microRNAs, respectively, may not fully reveal the complex regulatory mechanisms of a cell. We observed a lack of computational instruments supporting explorative analysis on this type of three-component signal transduction pathways.

We have developed CyTRANSFINDER, a new Cytoscape plugin able to infer three-component signal transduction pathways based on user defined regulatory patterns and including miRNAs, TFs and genes. Since CyTRANSFINDER has been designed to support exploratory analysis, it does not rely on expression data. To show the potential of the plugin we have applied it in a study of two miRNAs that are particularly relevant in human melanoma progression, miR-146a and miR-214.

CyTRANSFINDER supports the reconstruction of small signal transduction pathways among groups of genes. Results obtained from its use in a real case study have been analyzed and validated through both literature data and preliminary wet-lab experiments, showing the potential of this tool when performing exploratory analysis.

The online version of this article (doi:10.1186/s12859-016-0964-2) contains supplementary material, which is available to authorized users.

• Cytoscape
• Data fusion
• Network analysis
• Network modules
• Pathway analysis
• Signal transduction pathways
• microRNA

• Blood
• Head and neck squamous cell carcinoma
• Metastasis
• microRNA

• Adult
• Aged
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/metabolism
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Line, Tumor
• Cell Proliferation
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms/metabolism
• Head and Neck Neoplasms/pathology
• Humans
• Male
• MicroRNAs/blood
• MicroRNAs/metabolism
• Middle Aged
• Predictive Value of Tests
• Prognosis
• Real-Time Polymerase Chain Reaction
• Squamous Cell Carcinoma of Head and Neck

• escc
• mir-146a
• prognosis
• diagnosis
• tissue
• serum
• ffpe

• Aged
• Biomarkers, Tumor/genetics
• Carcinoma, Squamous Cell/diagnosis
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Case-Control Studies
• Disease-Free Survival
• Esophageal Neoplasms/diagnosis
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/pathology
• Esophageal Squamous Cell Carcinoma
• Female
• Gene Expression Profiling
• Humans
• Male
• MicroRNAs/genetics
• Middle Aged
• Multivariate Analysis
• Neoplasm Grading
• Neoplasm Staging
• Prognosis
• Proportional Hazards Models
• ROC Curve
• Reproducibility of Results
• Reverse Transcriptase Polymerase Chain Reaction
• Sensitivity and Specificity

Dysregulation of microRNAs (miRNAs) has been implicated in almost every known survival mechanisms utilized by cancer cells. One of such mechanisms, anoikis resistance, plays a pivotal role in enabling metastasis by allowing cancer cells to circumvent cell death induced by lack of attachment. Understanding how miRNAs regulate the various anoikis pathways has become the research question of increasing number of studies published in the past years. Through these studies, a growing list of miRNAs has been identified to be important players in promoting either anoikis or resistance to anoikis. In this review, we will be focusing on these miRNAs and how the findings from those studies can contribute to novel therapeutic strategies against cancer progression. We will be examining miRNAs that have been found to promote anoikis sensitivity in numerous cancer types followed by miRNAs that inhibit anoikis. In addition, we will also be taking a look at major signaling pathways involved in the action of the each of these miRNAs to gain a better understanding on how miRNAs regulate anoikis.

• DNA methylation
• Gastric cancer
• Helicobacter pylori
• Immune response
• Inflammation
• MicroRNA
• Preneoplastic conditions
• Stomach neoplasms

• HCC
• STAT3
• anti-tumor immune suppression
• miR-146a
• miRNA

• SMAD4
• miR-301a-3p
• pancreatic ductal adenocarcinoma
• prognosis
• xenograft tumor

• Aged
• Animals
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/metabolism
• Cell Movement
• Cell Proliferation
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Immunohistochemistry
• In Situ Hybridization
• Lymphatic Metastasis
• Male
• Mice
• Mice, Nude
• MicroRNAs/metabolism
• Middle Aged
• Multivariate Analysis
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreaticoduodenectomy
• Prognosis
• Real-Time Polymerase Chain Reaction
• Smad4 Protein/metabolism
• Tissue Array Analysis

• HTLV-I infections
• T-lymphotrophic virus 1
• adult T-cell
• cell line
• cell transformation
• gene expression regulation
• human
• leukemia-lymphoma
• microRNAs
• virus replication

• Algorithms
• Bayes Theorem
• Binding Sites
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/physiology
• Cell Line, Tumor
• Cell Proliferation
• Computational Biology
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Ligands
• Models, Theoretical
• Nuclear Proteins
• Probability
• Protein Structure, Tertiary
• Stomach Neoplasms/physiopathology

• Glioblastoma
• MiRNA-146a
• Regulation
• TGF-β Signaling

Gastric cancer is the fourth most common cancer in the world and the second leading cause of cancer-related death. More than 80% of diagnoses occur at the middle to late stage of the disease, highlighting an urgent need for novel biomarkers detectable at earlier stages. Recently, aberrantly expressed microRNAs (miRNAs) have received a great deal of attention as potential sensitive and accurate biomarkers for cancer diagnosis and prognosis. This review summarizes the current knowledge about potential miRNA biomarkers for gastric cancer that have been reported in the publicly available literature between 2008 and 2013. Available evidence indicates that aberrantly expressed miRNAs in gastric cancer correlate with tumorigenesis, tumor proliferation, distant metastasis and invasion. Furthermore, tissue and cancer types can be classified using miRNA expression profiles and next-generation sequencing. As miRNAs in plasma/serum are well protected from RNases, they remain stable under harsh conditions. Thus, potential functions of these circulating miRNAs can be deduced and may implicate their diagnostic value in cancer detection. Circulating miRNAs, as well as tissue miRNAs, may allow for the detection of gastric cancer at an early stage, prediction of prognosis, and monitoring of recurrence and/or lymph node metastasis. Taken together, the data suggest that the participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic and prognostic tests for gastric cancer.

• MicroRNAs
• Gastric cancer
• Biomarker
• Clinical application

• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Gene Expression Regulation, Neoplastic
• Genetic Testing
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Predictive Value of Tests
• Prognosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy

Gastric cancer is one of the most common malignant diseases worldwide. Emerging evidence has shown that microRNAs (miRNAs) are associated with tumor development and progression. Our previous studies have revealed that H. pylori infection was able to induce the altered expression of miR-30b in gastric epithelial cells. However, little is known about the potential role of miR-30b in gastric cancer.

We analyzed the expression of miR-30b in gastric cancer cell lines and human gastric cancer tissues. We examined the effect of miR-30b mimics on the apoptosis of gastric cancer cells in vitro by flow cytometry (FCM) and caspase-3/7 activity assays. Nude mouse xenograft model was used to determine whether miR-30b is involved in tumorigenesis of gastric cancer. The target of miR-30b was identified by bioinformatics analysis, luciferase assay and Western blot. Finally, we performed the correlation analysis between miR-30b and its target expression in gastric cancer.

miR-30b was significantly down-regulated in gastric cancer cells and human gastric cancer tissues. Enforced expression of miR-30b promoted the apoptosis of gastric cancer cells in vitro, and miR-30b could significantly inhibit tumorigenicity of gastric cancer by increasing the apoptosis proportion of cancer cells in vivo. Moreover, plasminogen activator inhibitor-1 (PAI-1) was identified as the potential target of miR-30b, and miR-30b level was inversely correlated with PAI-1 expression in gastric cancer. In addition, silencing of PAI-1 was able to phenocopy the effect of miR-30b overexpression on apoptosis regulation of cancer cells, and overexpression of PAI-1 could suppressed the effect of promoting cell apoptosis by miR-30b, indicating PAI-1 is potentially involved in miR-30b-induced apoptosis on cancer cells.

miR-30b may function as a novel tumor suppressor gene in gastric cancer by targeting PAI-1 and regulating the apoptosis of cancer cells. miR-30b could serve as a potential biomarker and therapeutic target against gastric cancer.

• Animals
• Apoptosis/genetics
• Biomarkers, Tumor/genetics
• Blotting, Western
• Carcinogenesis/genetics
• Cell Line, Tumor
• Cell Proliferation/genetics
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/genetics
• Middle Aged
• Plasminogen Activator Inhibitor 1/genetics
• Plasminogen Activator Inhibitor 1/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Transplantation, Heterologous
• Tumor Burden/genetics