• abnormal mammogram
• benign breast lesions
• breast cancer
• liquid biopsy
• serum miRNA

• Humans
• Female
• MicroRNAs/genetics
• MicroRNAs/blood
• Mammography
• Breast Neoplasms/genetics
• Breast Neoplasms/diagnostic imaging
• Breast Neoplasms/diagnosis
• Middle Aged
• Logistic Models
• Adult
• Aged
• Gene Expression Profiling
• Biomarkers, Tumor/genetics

• KCNH6
• cancer
• ceRNA
• lncRNA-miRNA-mRNA network
• miRNA-147

• 2021Y9191 Joint Funds for the innovation of science and Technology,Fujian province
• 2021Y9195 Joint Funds for the innovation of science and Technology,Fujian province
• 2020J011109 Natural Science Foundation of Fujian Province
• 2019J01196 Natural Science Foundation of Fujian Province
• 2019-CX-5 Medical Innovation Program of Fujian Province
• 2021Y2014 Fujian Clinical Research Center for Radiation and Therapy of Digestive, Respiratory and Genitourinary Malignancies

The aim of this study was to verify the biological function of miR-1273h-5p in gastric cancer (GC) and its underlying mechanisms. The differential expression of microRNAs between GC and tumor-adjacent normal tissues was detected using microarrays, miR-1273h-5p, and chemokine (C-X-C motif) ligand 12 (CXCL12) mRNA, and protein levels were evaluated using polymerase chain reaction and Western blotting methods, cell proliferation, apoptosis, migration, and invasion were determined by CCK-8, flow cytometry, and transwell assay. Compared to tumor-adjacent normal tissue and gastric epithelial mucosa cell line cells, miR-1273h-5p was significantly downregulated in tissues and cells of GC. The overexpression of miR-1273h-5p could inhibit cell proliferation, migration, invasion, and promote cell apoptosis; in contrast, inhibition of miR-1273h-5p expression could reverse this process. Moreover, a significant upregulation of CXCL12 was observed when the miR-1273h-5p was downregulated in GC cells. Additionally, miR-1273h-5p significantly reduces tumor volume and weight. Thus, this study suggests that miR-1273h-5p regulates cell proliferation, migration, invasion, and apoptosis during GC progression by directly binding to CXCL12 mRNA 3′-untranslational regions, which may be a novel diagnostic and therapeutic target in GC.

• apoptosis
• gastric cancer
• invasion
• miR-1273h-5p
• migration
• proliferation

• ginsenoside Rh2
• miR-524-5p
• thyroid cancer

Gastric cancer (GC) is one of the most aggressive malignancies, currently ranking third among cancers leading to death worldwide. Despite the recent advancements in GC research, it is most often diagnosed during the terminal stages and with limited treatment modalities contributing to its poor prognosis and a lower survival rate.

Much research has provided conflicting results between a vitamin D deficient status and the development of GC. Vitamin D is a well-known and essential hormone classically known to regulate calcium and phosphate absorption, enabling adequate mineralization of the skeletal system. However, the function of vitamin D is multidimensional. It possesses unique roles, including acting as antioxidants or immunomodulators while crossing the cell membrane, performing several intracellular functions, participating in gene regulation, and controlling the proliferation and invasion of cancer cells, including those of GC.

In light of this, it is imperative to analyze the causes of GC, review the factors that can be used to enhance the effectiveness of treatments, and discover the tools to determine prognosis, reduce mortality, and prevent GC development. In this review, we have summarized recent investigations on multiple associations between vitamin D and GC, emphasizing genetic associations, vitamin D receptors, and the prevalence of hormone deficiency in those developing this aggressive malignancy.

• cholecalciferol
• ergocalciferol
• gastric cancer
• genetic polymorphism
• vitamin d
• vitamin d deficiency
• vitamin d receptor

• BZW1
• NEAT1
• glioma
• miR-98-5p

• Animals
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Cell Line, Tumor
• Cell Proliferation
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic
• Glioma/genetics
• Glioma/metabolism
• Glioma/pathology
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Signal Transduction
• Tumor Burden
• Mice

• ARF6
• Apoptosis
• Gastric cancer
• MiR-1299
• Proliferation

• CircRNA
• Gastric cancer
• MiRNA
• Pepsinogen C
• ceRNA network

Ovarian cancer is a major gynaecological malignant tumor associated with a high mortality rate. Identifying survival-related variants may improve treatment and survival in patients with ovarian cancer. In this work, we proposed a support vector regression (SVR)-based method called OV-SURV, which is incorporated with an inheritable bi-objective combinatorial genetic algorithm for feature selection to identify a miRNA signature associated with survival in patients with ovarian cancer. There were 209 patients with miRNA expression profiles and survival information of ovarian cancer retrieved from The Cancer Genome Atlas database. OV-SURV achieved a mean correlation coefficient of 0.77±0.01and a mean absolute error of 0.69±0.02 years using 10-fold cross-validation. Analysis of the top ranked miRNAs revealed that the miRNAs, hsa-let-7f, hsa-miR-1237, hsa-miR-98, hsa-miR-933, and hsa-miR-889, were significantly associated with the survival in patients with ovarian cancer. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that four of these miRNAs, hsa-miR-182, hsa-miR-34a, hsa-miR-342, and hsa-miR-1304, were highly enriched in fatty acid biosynthesis, and the five miRNAs, hsa-let-7f, hsa-miR-34a, hsa-miR-342, hsa-miR-1304, and hsa-miR-24, were highly enriched in fatty acid metabolism. The prediction model with the identified miRNA signature consisting of prognostic biomarkers can benefit therapeutic decision making of ovarian cancer.

• machine learning
• miRNA signature
• ovarian cancer
• survival estimation

Normal B-cell development is a tightly regulated complex procedure, the deregulation of which can lead to lymphomagenesis. One common group of blood cancers is the B-cell non-Hodgkin lymphomas (NHLs), which can be categorized according to the proliferation and spread rate of cancer cells into indolent and aggressive ones. The most frequent indolent B-cell NHLs are follicular lymphoma and marginal zone lymphoma. MicroRNAs (miRNAs) are small non-coding RNAs that can greatly influence protein expression. Based on the multiple interactions among miRNAs and their targets, complex networks of gene expression regulation emerge, which normally are essential for proper B-cell development. Multiple miRNAs have been associated with B-cell lymphomas, as the deregulation of these complex networks can lead to such pathological states. The aim of the present review is to summarize the existing information regarding the multifaceted role of miRNAs in indolent B-cell NHLs, affecting the main B-cell subpopulations. We attempt to provide insight into their biological function, the complex miRNA-mRNA interactions, and their biomarker utility in these malignancies. Lastly, we address the limitations that hinder the investigation of the role of miRNAs in these lymphomas and discuss ways that these problems could be overcome in the future.

• Waldenström’s macroglobulinemia
• diagnosis
• follicular lymphoma
• hairy cell leukemia
• marginal zone lymphoma
• miRNAs
• normal B-cell development
• primary cutaneous follicle center lymphoma
• prognosis
• therapeutic target

Aberrantly expressed microRNAs play important roles in gastric tumorigenesis. However, use of miRNAs as a therapeutic option in gastric cancer still remains as a challenging problem.

We performed transient transfection of miR-34a-5p mimic and stable transfection of pre-mir-34a into KatoIII cells. Then, we evaluated the effect of transfected miRNAs on numerous cellular and molecular processes.

Following transient transfection of miR-34a-5p mimic at 25 nM—a commonly used concentration—into KatoIII cells, inhibition of two target genes expression, namely Notch1 and β-catenin, was not observed, but a non-significant marginal increase of these genes was detected. No changes were detected in the percentage of apoptotic cells as well as in CD44 + and EpCAM + cells after 25 nM miR-34a-5p mimic transfection. Interestingly, stable transfection of pre-mir-34a into KatoIII cells (named as KatoIII-pGFPC1-34a cells) caused a significant repression in β-catenin protein and Notch1 mRNA levels (p < 0.05 and p < 0.01, respectively) relative to equivalent control (KatoIII- pGFPC1-empty cells). The percentage of CD44 + cells in the KatoIII-pGFPC1-34a cells (< 40%) was significantly lower than that in control cells (~ 95%) (p < 0.05). An increase of ~ 3.5% in apoptotic cells and a slower proliferation rate were detected in KatoIII-pGFPC1-34a cells.

Our study revealed that the effect of miR mimic in target gene repression can be dependent to its concentration as well as to the cell type. Meanwhile, our findings further support a regulatory function for pre-miRNAs in target repression and will help to develop effective therapeutic strategies in cancer treatment.

The online version contains supplementary material available at 10.1186/s12935-021-01872-5.

• Cancer stem cells
• Gastric cancer
• MicroRNA-34a
• Precursor miRNA
• Transfection

• AMI
• CAD
• MI
• acute myocardial infarction
• cardiovascular diseases
• coronary artery disease
• miR
• miRNA
• microRNA
• myocardial infarction

Background: Breast cancer is the most common malignancy, and approximately 70% of breast cancers are estrogen receptor-α (ERα) positive. The anti-estrogen tamoxifen is a highly effective and commonly used treatment for patients with ER+ breast cancer. However, 30% of breast cancer patients fail adjuvant tamoxifen therapy and most of metastatic breast cancer patients develop tamoxifen resistance. Although increasing evidence suggests that microRNA (miRNA) dysregulation influences tamoxifen sensitivity, the mechanism of the cross-talk between miRNA and ERα signaling remains unclear. miR-575 has been reported to be involved in carcinogenesis and progression, however, the role of miR-575 in breast cancer remains limited. The aim of this study was to understand the mechanism of miR-575 in breast cancer tamoxifen resistance.

Method: RT-qPCR was employed to assess miR-575 expression in breast cancer tissues and cell lines. The association of miR-575 expression with overall survival in patients with breast cancer was evaluated with KM plotter. Additionally, the effects of miR-575 on breast cancer proliferation and tamoxifen sensitivity were investigated both in vitro and in vivo. Bioinformatic analyses and luciferase reporter assays were performed to validate CDKN1B and BRCA1 as direct targets of miR-31-5p. The ERα binding sites in the miR-575 promoter region was validated with ChIP and luciferase assays. ERα interactions with CDKN1B, cyclin D1 or BRCA1 were determined by IP analysis, and protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively.

Results: miR-575 levels were higher in ER+ breast cancer than in ER- breast cancer and patients with high miR-575 expression had a significantly poorer outcome than those with low miR-575 expression. ERα bound the miR-575 promoter to activate its transcription, and tamoxifen treatment downregulated miR-575 expression in ER+ breast cancer. Overexpression of miR-575 decreased tamoxifen sensitivity by targeting CDKN1B and BRCA1. CDKN1B and BRCA1 were both able to antagonize ERα activity by inhibiting ERα nuclear translocation and interaction with cyclin D1. Furthermore, miR-575 expression was found to be upregulated in ER+ breast cancer cell with acquired tamoxifen resistance, whereas depletion of miR-575 partially re-sensitized these cells to tamoxifen by regulation of CDKN1B.

Conclusions: Our data reveal the ERα-miR-575-CDKN1B feedback loop in ER+ breast cancer, suggesting that miR-575 can be used as a prognostic biomarker in patients with ER+ breast cancer, as well as a predictor or a promising target for tamoxifen sensitivity.

• miR-575 regulates ER+ breast cancer tamoxifen sensitivity

Gastric cancer (GC) is one of the most prevalent cancers and a major cause of cancer related mortality worldwide. Incidence of GC is affected by various factors, including genetic and environmental factors. Despite extensive research has been done for molecular characterization of GC, it remains largely unknown. Therefore, further studies specially conducted among various ethnicities in different geographic locations, are required to know the precise molecular mechanisms leading to tumorigenesis and progression of GC. The expression patterns of seven candidate genes, including β-catenin, Notch1, GATA6, CDX2, miR-34a, miR-181a, and miR-93 were determined in 24 paired GC tissues and corresponding non-cancerous tissues by quantitative Real-Time PCR. The association between the expression of these genes and clinicopathologic factors were also investigated. Our results demonstrated that overall mRNA levels of GATA6 were significantly decreased in the tumor samples in comparison with the non-cancerous tissues (median fold change (FC) = 0.3143; P = 0.0003). Overall miR-93 levels were significantly increased in the tumor samples relative to the non-cancerous gastric tissues (FC = 2.441; P = 0.0002). β-catenin mRNA expression showed a strong positive correlation with miR-34a (r = 0.5784; P = 0.0031), and miR-181a (r = 0.5652; P = 0.004) expression. miR-34a and miR-181a expression showed a significant positive correlation (r = 0.4862; P = 0.016). Moreover, lower expression of Notch1 was related to distant metastasis in GC patients with a borderline statistical significance (p = 0.0549). These data may advance our understanding of the molecular biology that drives GC as well as provide potential targets for defining novel therapeutic strategies for GC treatment.

• Extracellular vesicles
• GRHL2
• Gastric cancer
• M2 macrophages
• MLL3
• microRNA-130b-3p

Immune escape is an immunological mechanism underlying tumorigenesis, and T cells play an important role in this process. In this study, immune-related genes were evaluated in tumor-infiltrating CD4⁺ and CD8⁺ T cells in colon cancer.

ESTIMATE was used to calculate stromal and immune scores for tumor datasets downloaded from The Cancer Genome Atlas–Colon Cancer (COAD). Differentially expressed genes (DEGs) between samples with high and low stromal and immune scores were screened, followed by a functional enrichment analysis of the overlapping DEGs. The DEGs related to CD4⁺ and the CD8⁺ T cells were then screened. Predicted miRNA–mRNA and lncRNA–miRNA pairs were used to construct a competing endogenous RNA (ceRNA) network. Furthermore, chemical–gene interactions were predicted for genes in the ceRNA network. Kaplan–Meier survival curves were also plotted.

In total, 83 stromal-related DEGs (5 up-regulated and 78 down-regulated) and 1270 immune-related DEGs (807 up-regulated and 293 down-regulated genes) were detected. The 79 overlapping DEGs were enriched for 39 biological process terms. Furthermore, 79 CD4⁺ T cell-related genes and 8 CD8⁺ T cell-related genes, such as ELK3, were screened. Additionally, ADAD1 and DLG3, related to CD4⁺ T cells, were significantly associated with the prognosis of patients with colon cancer. The chr22-38_28785274–29,006,793.1–miR-106a-5p-DDHD1 and chr22-38_28785274–29,006,793.1–miR-4319-GRHL1 axes obtained from CD4⁺ and CD8⁺ T cell-related ceRNAs were identified as candidates for further studies.

ELK3 is a candidate immune-related gene in colon cancer. The chr22-38_28785274–29,006,793.1–miR-106a-5p-DDHD1 and chr22-38_28785274–29,006,793.1–miR-4319-GRHL1 axes may be related to CD4⁺ and CD8⁺ T cell infiltration in colon cancer.

• CD4+ T cells
• CD8+ T cells
• Colon cancer
• Competing endogenous RNAs
• Immunity

Lung cancer is one of the most common cancers that threaten human life and health. Recently, microRNAs (miRNAs) have been shown to play a unique role in many malignancies. Although the dysregulation of miR-147 has been detected in non-small cell lung cancer (NSCLC), the biological function of miR-147 is still unknown in NSCLC. The expression of miR-147 was observed by real-time quantitative polymerase chain reaction (RT-qPCR). Methyl thiazolyl tetrazolium (MTT) and Transwell assays were used to investigate the function of miR-147 in NSCLC. Target genes of miR-147 were verified using dual luciferase reporter assay. Western blot analysis was used to explore the PI3K/AKT pathway. The expression of miR-147 was decreased in NSCLC tissues, which was associated with poor prognosis in NSCLC patients. Furthermore, overexpression of miR-147 inhibited the viability and metastasis of NSCLC cells. In addition, miR-147 inhibited epithelial-mesenchymal transition (EMT) and inactivated the PI3K/AKT pathway in NSCLC. Furthermore, miR-147 directly targets brain-derived neurotrophic factor (BDNF) and negatively regulates BDNF expression in NSCLC. Upregulation of BDNF attenuated the inhibitory effect of miR-147 in NSCLC. In conclusion, miR-147 inhibits cell proliferation, migration and invasion in NSCLC through suppressing BDNF expression.

• BDNF
• PI3K/AKT
• miR-147
• non-small cell lung cancer

• gallbladder cancer
• miR-575
• p27 Kip1

MicroRNAs (miRNAs) are a class of endogenous non-coding single-stranded small-molecule RNAs that regulate gene expression by repressing target messenger RNA (mRNA) translation or degrading mRNA. miR-34a is one of the most important miRNAs participating in various physiological and pathological processes. miR-34a is abnormally expressed in a variety of tumors. The roles of miR-34a in gastrointestinal cancer (GIC) draw lots of attention. Numerous studies have demonstrated that dysregulated miR-34a is closely related to the proliferation, differentiation, migration, and invasion of tumor cells, as well as the diagnosis, prognosis, treatment, and chemo-resistance of tumors. Thus, we systematically reviewed the abnormal expression and regulatory roles of miR-34a in GICs including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and gallbladder cancer (GBC). It may provide a profile of versatile roles of miR-34a in GICs.

• gastrointestinal cancer
• miR-34a
• migration
• prognosis
• proliferation

Evaluating the expression levels of miR-378a-5p both in a large melanoma patient cohort from The Cancer Genome Atlas database and in melanoma patients from our Institute, we found that miR-378a-5p is upregulated in metastatic melanoma specimens. miR-378a-5p expression was also increased in melanoma cells resistant to target therapy, and decreased in response to drug treatment. We also demonstrated that overexpression of miR-378a-5p enhances in vitro cell invasion and migration, and facilitates the ability of melanoma cells to form de novo vasculogenic structures. While performing downstream targeting studies, we confirmed the ability of miR-378a-5p to modulate the expression of known target genes, such as SUFU, FUS-1, and KLF9. Luciferase-3′UTR experiments also identified STAMBP and HOXD10 as new miR-378a-5p target genes. MMP2 and uPAR, two HOXD10 target genes, were positively regulated by miR-378a-5p. Genetic and pharmacologic approaches inhibiting uPAR expression and activity evidenced that the in vitro tumor-promoting functions of miR-378a-5p, were in part mediated by uPAR. Of note miR-378a-5p was also able to increase VEGF, as well as in vitro and in vivo angiogenesis. Finally, genetic and pharmacologic modulation of Bcl-2 evidenced Bcl-2 ability to regulate miR-378a-5p expression. In conclusion, to the best of our knowledge, this is the first study demonstrating that miR-378a-5p acts as an oncogenic microRNA in melanoma.

• Helicobacter pylori
• antigen presentation
• gastric cancer
• macrophages
• miRNA

• Aged
• Cell Line, Tumor
• Cells, Cultured
• Female
• Gene Expression Profiling/methods
• HLA Antigens/immunology
• Helicobacter Infections/immunology
• Helicobacter pylori/immunology
• Humans
• Macrophages/immunology
• Male
• MicroRNAs/immunology
• Middle Aged
• Nuclear Proteins/immunology
• Stomach Neoplasms/immunology
• Trans-Activators/immunology
• Up-Regulation/immunology

• cognitive decline
• genome-wide association study
• hippocampal atrophy rate

• Aged
• Atrophy/genetics
• Cognitive Dysfunction/genetics
• Female
• Genetic Predisposition to Disease/genetics
• Genome-Wide Association Study
• Hippocampus/pathology
• Humans
• Male
• Membrane Transport Proteins/genetics
• Mitochondrial Precursor Protein Import Complex Proteins
• Polymorphism, Single Nucleotide

• U01 AG024904 NIA NIH HHS

• asymptomatic hyperuricemia
• genome-wide association study
• gout
• individually-tailored preemptive medicine
• uric acid

• ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
• Adult
• Aldehyde Dehydrogenase, Mitochondrial/genetics
• Asymptomatic Diseases
• Contactins/genetics
• Genetic Loci/genetics
• Genome-Wide Association Study
• Genotyping Techniques
• Glucose Transport Proteins, Facilitative/genetics
• Gout/blood
• Gout/genetics
• Humans
• Hyperuricemia/genetics
• Male
• MicroRNAs/genetics
• Middle Aged
• Neoplasm Proteins/genetics
• Risk Factors
• Uric Acid/blood
• Zinc Fingers/genetics

• Kawano Masanori Memorial Foundation for Promotion of Pediatrics
• Gout Research Foundation of Japan
• Ministry of Education, Culture, Sports, Science and Technology of Japan

MicroRNAs (miRNAs) have been considered to participate in many tumorigenesis, including gastric cancer (GC). Abnormal expression of miR-601 has been reported in GC, but its role is not clear. The goal of this study is to explore the expression patterns, clinical value and functional role of miR-601 in GC.

Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to evaluate the expression level of miR-601. The association between miR-601 expression and overall survival was estimated by the Kaplan-Meier survival method. The significance of different variables with respect to survival was analyzed by using the Cox regression assay. Cell experiments were applied to investigate the functional role of miR-601 in GC.

We found that miR-601 was significantly up-regulated in GC tissues and cells compared with the controls (all P < 0.01). The levels of miR-601 expression were significantly associated with TNM stage, lymph node metastasis, lymphatic invasion, and distant metastasis (all P < 0.05). Kaplan-Meier survival analysis showed that patients in the high miR-601 expression group had poor overall survival (log-rank P = 0.001). Moreover, we confirmed that miR-601, TNM stage, and distant metastasis were independent prognostic factors for GC patients. Overexpression of miR-601 in AGS and SGC-7901 cells by miR-601 mimic transfection significantly promoted the cell proliferation, migration, and invasion (P < 0.05).

The expression level of miR-601 is dramatically up-regulated in GC. The overexpression of miR-601 promotes the tumor progression of GC, and may be a novel prognostic factor for poor survival in GC patients.

• Gastric cancer
• MicroRNA-601
• Prognosis
• Progression

• Akt signaling pathway
• JAZF1
• angiogenesis
• apoptosis
• cardiac microvascular endothelial cell
• myocardial ischemia-reperfusion injury
• proliferation

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by suppressing the target mRNA and inhibiting translation in order to regulate multiple biological processes. miRNAs play important roles as oncogenes or tumor suppressors in the development of various types of human cancer. The regulation of mammalian target of rapamycin (mTOR) by miRNAs has been studied in several types of cancer, including colorectal cancer (CRC). However, to the best of our knowledge, only limited information regarding the function of miRNAs in human CRC is available. In the present study, the expression of 22 miRNAs in CRC cell lines were investigated in regard to key genes in the mTOR pathway. Initially, it was revealed that mTOR, regulatory-associated protein of mTOR complex I and rapamycin-intensive companion of mTOR were overexpressed in CRC cell lines when compared with a normal colorectal cell line. Subsequently, putative miRNA-mRNA associations were identified via multiple miRNA target prediction programs. The expression levels for the candidate miRNAs were validated using quantitative real-time polymerase chain reaction. Expression analysis revealed that, among 20 miRNAs, five miRNAs (miR-496, miR-1185, miR-654, miR-3183 and miR-495) exhibited significant downregulation in association with the mTOR signaling pathway. Taken together, the results from the present study suggest that several miRNAs that are associated with CRC, with possible roles in mTOR signaling, may have potential therapeutic or diagnostic benefits in CRC treatment.

• colorectal cancer
• mammalian target of rapamycin
• microRNA
• rapamycin-insensitive companion of mammalian target of rapamycin
• regulatory-associated protein of mammalian target of rapamycin complex 1

Gastric MALT lymphoma (GML) is directly caused by Helicobacter pylori infection but occurs only in a small number of infected subjects. Mechanisms underlying the initiation and progression of GML remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs that are now considered as major players in inflammation and carcinogenesis, acting as oncogenes or tumor suppressors. Previous laboratory studies have shown in a GML mouse model that overexpression of a distinct set of five miRNAs (miR-21a, miR-135b, miR-142a, miR-150, miR-155) could play a critical role in the pathogenesis of GML. Our goal was to compare the miRNA expression profile obtained in the GML mouse model to that in human GML (11 cases of GML compared to 17 cases of gastritis control population). RTqPCR on the five dysregulated miRNAs in the GML mouse model and PCR array followed by RTqPCR confirmation showed that four miRNAs were up-regulated (miR-150, miR-155, miR-196a, miR-138) and two miRNAs down-regulated (miR-153, miR-7) in the stomachs of GML patients vs. gastritis control population. The analysis of their validated targets allowed us to postulate that these miRNAs (except miR-138) could act synergistically in a common signaling cascade promoting lymphomagenesis and could be involved in the pathogenesis of GML.

• Helicobacter
• MALT lymphoma
• miRNA
• proliferation

Gastric carcinogenesis can be induced by chronic inflammation triggered by Helicobacter pylori (H. pylori) infection. Tumor necrosis factor (TNF)-α and its receptors (TNFR1 and TNFR2) regulate important cellular processes, such as apoptosis and cell survival, and the disruption of which can lead to cancer. This signaling pathway is also modulated by microRNAs (miRNAs), altering gene expression.

To evaluate the mRNA and miRNAs expression involved in the TNF-α signaling pathway in gastric cancer (GC) tissues and its relationship.

Quantitative polymerase chain reaction (qPCR) by TaqMan^® assay was used to quantify the RNA transcript levels of TNF-α signaling pathway (TNF, TNFR1, TNFR2, TRADD, TRAF2, CFLIP, NFKB1, NFKB2, CASP8, CASP3) and miRNAs that targets genes from this pathway (miR-19a, miR-34a, miR-103a, miR-130a, miR-181c) in 30 GC fresh tissue samples. Molecular diagnosis of H. pylori was performed by nested PCR for gene HSP60. A miRNA:mRNA interaction network was construct using Cytoscape v3.1.1 from the in silico analysis performed using public databases.

Up-regulation of cellular survival genes as TNF, TNFR2, TRADD, TRAF2, CFLIP, and NFKB2, besides CASP8 and miR-34a was observed in GC tissues, whereas mediators of apoptosis such as TNFR1 and CASP3 were down-regulated. When the samples were stratified by histological type, the expression of miR-103a and miR-130a was significantly increased in the diffuse-type of GC compared to the intestinal-type. However, no influence of H. pylori infection was observed on the expression levels of mRNA and miRNAs analyzed. Moreover, the miRNA:mRNA interaction network showed several interrelations between the miRNAs and their target genes, highlighting miR-19a and miR-103a, which has as predicted or validated target a large number of genes in the TNF-α pathway, including TNF, TNFR1, TNFR2, CFLIP, TRADD, CASP3 and CASP8.

Our findings show that cell survival genes mediated by TNF/TNFR2 binding is up-regulated in GC favoring its pro-tumoral effect, while pro-apoptotic genes as CASP3 and TNFR1 are down-regulated, indicating disbalance between apoptosis and cell proliferation processes in this neoplasm. This process can also be influenced by an intricate regulatory network of miRNA:mRNA.

• Gastric cancer
• Tumor necrosis factor-α signaling
• TNFR1
• TNFR2
• Cellular survival
• MicroRNAs

• Biomarkers
• Clinical applications
• Diagnosis and prognosis
• Gastric cancer
• Noninvasive biomarkers
• microRNAs

Previous studies demonstrated microRNA-185 (miR-185) as a tumor suppressive microRNA (miRNA) in various types of cancer. The current study aimed to verify this finding in hepatocellular carcinoma (HCC) and explored the downstream channel of miR-185-5p. We detected miR-185-5p and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) mRNA and protein levels by reverse transcription-quantitative PCR (RT-qPCR) and western blotting in HCC tissues and cell lines. Luciferase reporter assay proved the direct relationship between miR-185-5p and ROCK2. Cell migration and invasion were assessed via Transwell assay. miR-185-5p level was reduced in HCC tissues and cell lines. miR-185-5p overexpression impeded migration and invasion of HCC cells. Moreover, miR-185-5p directly targeted ROCK2 which was repressed by miR-185-5p in HCC. In addition, ROCK2 contributed to cell metastasis of HCC. In summary, miR-185-5p inhibited cell metastasis of HCC by suppressing ROCK2. The novel miR-185/ROCK2 axis shows potential in improving the therapies of HCC and enhancing HCC survival.

• Rho-associated coiled-coil containing protein kinase 2
• hepatocellular carcinoma
• invasion
• miR-185-5p
• migration

A cancer cell line originating from human epithelial colorectal adenocarcinoma (Caco-2 cells) serves as a high capacity model for a preclinical screening of drugs. Recent need for incorporating barrier tissue into multi-organ chips calls for inclusion of Caco-2 cells into microperfused environment.

This article describes a series of systems biology insights obtained from comparing Caco-2 models cells grown as conventional 2D layer and in a microfluidic chip. When basic electrical parameters of Caco-2 monolayers were evaluated using impedance spectrometry and MTT assays, no differences were noted. On the other hand, the microarray profiling of mRNAs and miRNAs revealed that grows on a microfluidic chip leads to the change in the production of specific miRNA, which regulate a set of genes for cell adhesion molecules (CAMs), and provide for more complete differentiation of Caco-2 monolayer. Moreover, the sets of miRNAs secreted at the apical surface of Caco-2 monolayers grown in conventional 2D culture and in microfluidic device differ.

When integrated into a multi-tissue platform, Caco-2 cells may aid in generating insights into complex pathophysiological processes, not possible to dissect in conventional cultures.

• 2D layer
• Caco-2 cell lines
• Microfluidic chip
• On-the-chip models

Rapid changes in the expression of many messenger RNA (mRNA) species follow exposure of cells to ionizing radiation. One of the hypothetical mechanisms of this response may include microRNA (miRNA) regulation, since the amounts of miRNAs in cells also vary upon irradiation. To address this possibility, we designed experiments using cancer-derived cell lines transfected with luciferase reporter gene containing sequences targeted by different miRNA species in its 3′- untranslated region. We focus on the early time-course response (1 h past irradiation) to eliminate secondary mRNA expression waves.

Experiments revealed that the irradiation-induced changes in the mRNA expression depend on the miRNAs which interact with mRNA. To identify the strongest interactions, we propose a mathematical model which predicts the mRNA fold expression changes, caused by perturbation of microRNA-mRNA interactions. Model was applied to experimental data including various cell lines, irradiation doses and observation times, both ours and literature-based. Comparison of modelled and experimental mRNA expression levels given miRNA level changes allows estimating how many and which miRNAs play a significant role in transcriptome response to stress conditions in different cell types. As an example, in the human melanoma cell line the comparison suggests that, globally, a major part of the irradiation-induced changes of mRNA expression can be explained by perturbed miRNA-mRNA interactions. A subset of about 30 out of a few hundred miRNAs expressed in these cells appears to account for the changes. These miRNAs play crucial roles in regulatory mechanisms observed after irradiation. In addition, these miRNAs have a higher average content of GC and a higher number of targeted transcripts, and many have been reported to play a role in the development of cancer.

Our proposed mathematical modeling approach may be used to identify miRNAs which participate in responses of cells to ionizing radiation, and other stress factors such as extremes of temperature, exposure to toxins, and drugs.

The online version of this article (10.1186/s12864-019-5464-0) contains supplementary material, which is available to authorized users.

• ionizing radiation
• miRNA
• miRNA-mRNA interactions
• stressing factor

Endometrial cancer (EC) is one of the most common malignancies of the female reproductive system, and metastasis is a major cause of mortality. In this study, we aimed to explore the role of CP-31398 in the migration, invasion and apoptosis of EC cells by its regulation of the expression of the murine double minute 2 (MDM2) gene. For this purpose, EC tissues and adjacent normal tissues were collected, and the positive expression rate of MDM2 in these tissues was assessed. Subsequently, the cellular 50% inhibitory concentration (IC50) of CP-31398 was measured. The EC RL95-2 and KLE cell lines had a higher MDM2 expression and were thus selected for use in subsequent experiments. The EC cells were then treated with CP-31398 (2 µg/ml), and were transfected with siRNA against MDM2 or an MDM2 overexpression plasmid in order to examine the effects of CP-31398 and MDM2 on EC cell activities. The expression of p53, p21, Bad, Bax, B-cell lymphoma-2 (Bcl-2), cytochrome c (Cyt-c), caspase-3, Cox-2, matrix metalloproteinase (MMP)-2 and MMP-9 was measured to further confirm the effects of CP-31398 on cell migration, invasion and apoptosis. Our results indicated that MDM2 was highly expressed in EC tissues. Notably, EC cell viability decreased with the increasing concentrations of CP-31398. The EC cells treated with CP-31398 or siRNA against MDM2 exhibited an increased apoptosis and a suppressed migration and invasion, corresponding to an increased expression of p53, p21, Bad, Bax, Cyt-c and caspase-3, as well as to a decreased expression of Bcl-2, Cox-2, MMP-2 and MMP-9. Moreover, treatment with CP-31398 and siRNA against MDM2 further enhanced these effects. Taken together, the findings of this study indicate that the CP-31398-mediated downregulation of MDM2 may suppress EC progression via its inhibitory role in EC cell migration, invasion and resistance to apoptosis. Therefore, treatment with CP-31398 may prove to be possible therapeutic strategy for EC.

• Rab5
• angiogenesis
• endothelial cell
• essential hypertension and atherosclerosis
• miR-575

The role of TDRG1 in tumorigenesis and the progression of seminoma, as well as its role in regulating chemosensitivity of seminoma to cisplatin through the PI3K/Akt/mTOR signaling pathway, has been previously defined. However, the detailed mechanism underlying TDRG1 expression and concomitant chemoresistance conditions are unknown. Furthermore, it has been reported that non‐protein‐coding RNAs play an important role in a variety of vital processes including cellular chemosensitivity. However, the role of non‐protein‐coding RNAs in regulating the chemosensitivity of seminoma remains unknown. In this study, using microarray analysis, we found that long non‐coding RNA H19 was upregulated while miRNA‐106b‐5p was downregulated in an established cisplatin‐resistant TCam‐2 cell line. Moreover, H19 acts as a miRNA‐106b‐5p sponge and thus impairs the function of miRNA‐106b‐5p on its target gene, TDRG1. Based on these findings, we propose that H19 promotes the expression of TDRG1 by sequestering miRNA‐106b‐5p and uses this mechanism to facilitate cell survival in cisplatin‐based chemotherapeutic conditions. These findings elucidate the mechanisms, at least partially, applied to deregulate TDRG1 and cisplatin sensitivity, and may provide new therapeutic possibilities for chemoresistant seminoma.

• chemotherapy
• drug resistance
• long non-coding RNA
• microRNA
• seminoma

• Animals
• Antineoplastic Agents/pharmacology
• Cell Line, Tumor
• Cisplatin/pharmacology
• Drug Resistance, Neoplasm/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs
• Proteins/genetics
• RNA, Long Noncoding
• Seminoma/drug therapy
• Seminoma/genetics
• Testicular Neoplasms/drug therapy
• Testicular Neoplasms/genetics

Breast cancer is the most common tumor among women. miR-638 has been demonstrated to play an important role in various cancers.

In this study, we aimed to investigate the function and prognostic value of miR-638 in breast cancer.

Quantitative real-time polymerase chain reaction analysis was used to evaluate the expression of miR-638 in breast cancer tissues and cell lines. The correlation of miR-638 with clinicopathological features was analyzed using the chi-squared test. Kaplan–Meier survival analysis and Cox regression assay were performed to investigate the prognostic value of miR-638 in breast cancer patients. The effects of miR-638 on the biological behavior of breast cancer cells were evaluated using functional assays.

The expression of miR-638 was downregulated in breast cancer tissues and cell lines (all P<0.05). Decreased expression of miR-638 was significantly correlated with lymph node metastasis (P=0.015) and TNM stage (P=0.021). Patients with low miR-638 expression had shorter overall survival compared with those with high levels (Log-rank P=0.025). The miR-638 could be considered as an independent prognostic factor for the patients (HR =0.321, 95% CI =0.117–0.882, P=0.027). Downregulation of miR-638 was capable of promoting cell proliferation, migration, and invasion in MDA-MB-231 and MCF-7 cells.

All the results indicate that miR-638 is a tumor suppressor in breast cancer and is involved in the progression of breast cancer. Thus, it may serve as a prognostic biomarker for breast cancer.

• breast cancer
• cell proliferation
• invasion
• miR-638
• migration
• prognosis

Intestinal-type gastric carcinoma exhibits a multistep carcinogenic sequence from adenoma to carcinoma with a gradual increase in genomic alterations. But the roles of microRNAs (miRNA) in this multistage cascade are not fully explored. To identify differentially expressed miRNA (DEM) during early gastric carcinogenesis, we performed miRNA microarray profiling with 24 gastric cancers and precursor lesions (7 early gastric cancer [EGC], 3 adenomas with high-grade dysplasia, 4 adenomas with low-grade dysplasia, and 10 adjacent normal tissues). Alterations in the expression of 132 miRNA were detected; these were categorized into three groups based on their expression patterns. Of these, 42 miRNAs were aberrantly expressed in EGC. Five miRNA (miR-26a, miR-375, miR-574-3p, miR-145, and miR-15b) showed decreased expression since adenoma. Expression of two miRNA, miR-200C and miR-29a, was down-regulated in EGCs compared to normal mucosa or adenomas. Six miRNA (miR-601, miR-107, miR-18a, miR-370, miR-300, and miR-96) showed increased expression in gastric cancer compared to normal or adenoma samples. Five representative miRNAs were further validated with RT-qPCR in independent 77 samples. Taken together, these results suggest that the dysregulated miRNA show alterations at the early stages of gastric tumorigenesis and may be used as a candidate biomarker.

• HCC
• MIR31HG
• Metastasis
• Proliferation
• ST7L
• miR-575

• Adult
• Aged
• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation/genetics
• Female
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Male
• Mice
• MicroRNAs/genetics
• Middle Aged
• Neoplasm Metastasis
• RNA, Long Noncoding/genetics
• RNA-Binding Proteins/genetics
• Tumor Suppressor Proteins
• Xenograft Model Antitumor Assays

• CTNNB1
• Invasion
• MicroRNA-340
• Notch signaling pathway
• Osteosarcoma
• Proliferation

Long non-coding (lnc) RNAs plays an important role in chronic myeloid leukemia (CML). In this study, we aimed to uncover the mechanism of the lncRNA maternally expressed 3 (MEG3) and its target microRNA-147 (miR-147) in CML.

Sixty CML patients and 10 healthy donors were included in the study. The methylation of MEG3 and miR-147 promoter was determined by methylation-specific PCR. The relationship of MEG3 and miR-147 was explored by luciferase assay. The interactions of proteins were studied by RNA pull-down assay, RNA immunoprecipitation and co-immunoprecipitation.

Patients in accelerated phase CML (CML-AP) and blast phase CML (CML-BP) showed lower expressions of MEG3 and miR-147 and higher expressions of DNMT1, DNMT3B, MBD2, MECP2 and HDAC1 compared to the controls. These patients also showed a higher degree of methylation of MEG3 and miR-147 while there was a reduction after chidamide treatment. Furthermore, the overexpression of MEG3 and miR-147 inhibited cell proliferation both in vivo and in vitro, promoted apoptosis and decreased the expressions of DNMT1, DNMT3A, DNMT3B, MBD2, HDAC1 and MECP2. We also found MEG3 interacted with DNMT1, JAK2, STAT3, HDAC1, and TYK2, and JAK2 was bound to STAT3, STAT5 and MYC. More interestingly, JAK2 was bound to TYK2 by the bridge of MEG3.

LncRNA MEG3 and its target miR-147 may serve as a novel therapeutic target for CML blast crisis, and chidamide might have a potential clinical application in treating CML blast crisis.

• Chidamide
• Chronic myeloid leukemia blast crisis
• lncRNA MEG3
• miR147 and epigenetic

MicroRNAs biomarkers have shown value for diagnosis and prognosis of various cancers. Combination with established tumor markers has rarely been done.

Breast cancer patients had significantly higher serum RNA loads (AUC 0.665), lower miR-34a (AUC 0.772), higher CEA and CA 15-3 levels (AUCs 0.717 and 0.721) than healthy controls. miR-34a correlated with tumor stage and hormone receptor status. There was no significant difference between groups for all other miRNAs. Combination of miR-34a with CEA or CA 15-3 led to improved AUCs of 0.844 and 0.800, respectively. Sensitivity of miR-34a and CA 15-3 reached 56.1% at 95% specificity. When compared with benign breast diseases, combination of miR-34a (AUC 0.719) and CEA (0.623) or CA 15-3 (0.619) resulted in improved performances (0.794 and 0.741). Sensitivity of miR-34a and CA 15-3 reached 53.7% at 95% specificity.

While miR-34a provides valuable information for diagnosis and staging, combination with tumor markers CA15-3 or CEA improves the sensitivity for breast cancer detection.

The diagnostic relevance of the miR-21, miR-34a, miR-92a, miR-155, miR-222 and miR-let-7c was tested in sera of 103 individuals (55 breast cancer, 20 benign breast diseases, 28 healthy controls). MiRNAs were detected by quantitative rt-PCR after extraction and reverse transcription. Cel-miR-39 and miR-16 were used for normalization. Established tumor markers CEA, CA 15-3, CA 19-9 and CA 125 were measured by automatized immunoassays. Diagnostic performance was tested by areas under the curve (AUC) of receiver operating characteristic (ROC) curves and sensitivities at 90% and 95% specificity.

• CA 15-3
• CEA
• breast cancer
• miR-34a
• miRNA

Vimentin plays important roles in the epithelial-to-mesenchymal transition (EMT). In this study, we found that vimentin was highly expressed in human gastric cancer (GC) tissues and cell lines and significantly promoted cell growth, migration and invasion. Ubiquitin-specific protease 14 (USP14) interacted with the vimentin protein, which led to its de-ubiquitination. miR-320a was found to bind to the 3′UTR of both vimentin and USP14 transcripts and downregulate the expression of both proteins. The downregulation of miR-320a upregulates vimentin expression by directly binding to the 3′UTR of vimentin to derepress expression and indirectly by augmenting USP14 to increase vimentin stability in GC cells. Taken together, these results provide new insight into malignancy in gastric cancers.

• USP14
• gastric cancer
• miR-320a
• vimentin