• Colorectal cancer
• MicroRNAs
• Nanoparticles
• Natural products
• Non-coding RNAs
• Targeted therapy

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Biological Products/therapeutic use
• Biological Products/pharmacology
• Animals
• Phytochemicals/therapeutic use
• Phytochemicals/pharmacology
• Gene Expression Regulation, Neoplastic/drug effects
• Signal Transduction/drug effects

• Crohn's disease
• Diagnosis
• Fibrosis
• Inflammation
• Therapy
• miRNA

• Crohn Disease/genetics
• Crohn Disease/therapy
• Crohn Disease/pathology
• MicroRNAs/genetics
• Humans
• Animals
• Inflammation/genetics
• Fibrosis/genetics

• Colon cancer stem cells
• EMT
• IL-6/STAT3
• Metastasis
• miR-513b-5p

• A2022375/A2022067 Guandong Medical Research Fund
• 8200100073/8210101308 Guangdong Provincial People's Hospital Research Fund
• Guangdong Provincial People’s Hospital Research Fund

• Biomarkers
• Colorectal cancer
• Epigenetics
• Small molecules
• Targeted pathways

• Humans
• Phosphatidylinositol 3-Kinases/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Early Detection of Cancer
• Signal Transduction/genetics
• Biomarkers, Tumor/genetics
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/therapy

• circRNA
• colorectal cancer
• esophageal cancer
• gastric cancer
• liver cancer
• lncRNA
• miRNA
• pancreatic cancer

• Humans
• MicroRNAs/genetics
• RNA, Long Noncoding/genetics
• Gastrointestinal Neoplasms/genetics
• Signal Transduction
• STAT3 Transcription Factor/genetics
• STAT3 Transcription Factor/metabolism

• IL-17-producing Treg
• Th17
• Treg
• breast cancer
• cytokine
• immune checkpoint inhibitor
• microRNA
• regulatory T cell
• secretome
• tumor microenvironment

• COVID-19
• MicroRNA
• SARS-CoV-2
• biomarker
• feature analysis
• rules

• XDA26040304 Strategic Priority Research Program of Chinese Academy of Sciences
• XDB38050200 Strategic Priority Research Program of Chinese Academy of Sciences
• 202002 Fund of the Key Laboratory of Tissue Microenvironment and Tumor of Chinese Academy of Sciences

• CRISPR
• Cancer treatment
• Gene editing
• Solid tumors

• CRISPR-Cas Systems
• Gene Editing/methods
• Genetic Therapy
• Humans
• Neoplasms/diagnosis
• Neoplasms/genetics
• Neoplasms/therapy
• Technology

• ALS
• FUS
• WNT
• iPSC
• miR-139
• microRNA
• motor neurons
• sporadic

• Amyotrophic Lateral Sclerosis/genetics
• Amyotrophic Lateral Sclerosis/metabolism
• DNA-Binding Proteins/metabolism
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Motor Neurons/metabolism
• Mutation
• Neurodegenerative Diseases/metabolism
• RNA-Binding Protein FUS/genetics
• RNA-Binding Protein FUS/metabolism
• Up-Regulation/genetics
• beta Catenin/genetics
• beta Catenin/metabolism

• Wellcome Trust
• MR/T033029/1 Medical Research Council
• WT204909MA Wellcome Trust

• Colorectal carcinoma
• Inflammatory bowel disease
• Targeted therapy
• Ulcerative colitis
• miRNAs

Mounting data show that MIR139 is commonly silenced in solid cancer and hematological malignancies. MIR139 acts as a critical tumor suppressor by tuning the cellular response to different types of stress, including DNA damage, and by repressing oncogenic signaling pathways. Recently, novel insights into the mechanism of MIR139 silencing in tumor cells have been described. These include epigenetic silencing, inhibition of POL-II transcriptional activity on gene regulatory elements, enhanced expression of competing RNAs and post-transcriptional regulation by the microprocessor complex. Some of these MIR139-silencing mechanisms have been demonstrated in different types of cancer, suggesting that these are more general oncogenic events. Reactivation of MIR139 expression in tumor cells causes inhibition of tumor cell expansion and induction of cell death by the repression of oncogenic mRNA targets. In this review, we discuss the different aspects of MIR139 as a tumor suppressor gene and give an overview on different transcriptional mechanisms regulating MIR139 in oncogenic stress and across different types of cancer. The novel insights into the expression regulation and the tumor-suppressing activities of MIR139 may pave the way to new treatment options for cancer.

• MIR139
• cancer
• microRNAs
• transcriptional regulation
• tumor suppressor

• Carcinogenesis/genetics
• Cell Proliferation/genetics
• Genes, Tumor Suppressor
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasms/genetics
• Neoplasms/pathology

Circular RNAs (circRNAs), a novel type of noncoding RNAs, have been demonstrated to behave as microRNA (miRNA) sponges to exert their effects during pathological processes of diseases. However, the roles of circRNAs have not been explored in necrotizing enterocolitis (NEC). This study sought to identify differentially expressed circRNAs and predict their potential biological functions in NEC. circRNA expression profiles in terminal ileum from newborn rats with NEC and normal controls were explored using next-generation sequencing. In the NEC group, 53 circRNAs were significantly differentially expressed, including 9 upregulated and 44 downregulated. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted, and circRNA-miRNA interaction networks were generated to predict the potential roles of circRNAs in NEC progression. Further investigation revealed that most circRNAs include miRNA binding sites and that some are implicated in NEC development. In conclusion, this study's findings demonstrate that differentially expressed circRNAs are involved in NEC development via their interactions with miRNAs, making them prospective targets for NEC diagnosis and treatment.

Cancer is a complex disease extremely dependent on its microenvironment and is highly regulated by a variety of stimuli inside and outside the cell. Evidence suggests that active camel whey fraction (TR35) confer anti-tumor effects in non-small cell lung cancer (NSCLC). However, its exact mechanisms remain elusive. Here, we investigated the mechanisms underlying suppression of NSCLC cell growth and proliferation by TR35. Treatment of A549 and H1299 cells with TR35 suppressed their growth and enhanced apoptosis, as revealed by CCK-8, colony formation and flow cytometric analyses. We find that TR35 suppresses tumor growth in a xenograft nude mouse model without losses in body weight. RNA-seq and KEGG pathway analyses showed that the DEGs were enriched in mitogen-activated protein kinase (MAPK) and Jak-STAT signaling pathways. After test the key factors’ activity associated with these pathways by Immunohistochemical (IHC) staining and western blotting, the activation of JNK phosphorylation and inhibition of p38 and STAT3 phosphorylation was observed both in TR35 treated lung cancer cell and tumor tissue. Taken together, these results showed that TR35 play a significant role in the NSCLC progression in the tumor microenvironment via MAPK and Jak-STAT signaling, highlighting TR35 as a potential therapeutic agent against lung cancer.

Sepsis-induced acute lung injury (ALI) is an inflammatory process that involves inflammatory cytokine production and cell apoptosis. In the present study, the regulatory role of microRNA (miR)-139-5p in sepsis-induced ALI was investigated using a murine model of cecal ligation puncture (CLP) and an in vitro model using lipopolysaccharide (LPS)-induced normal human bronchial epithelial cells (NHBEs). Sepsis-induced pathological changes in the lungs of ALI mice were detected using hematoxylin and eosin staining. Lung water content was determined, and the expression of proinflammatory cytokines in the bronchoalveolar lavage fluid and serum of sepsis-induced ALI mice were quantified using ELISA. The levels of oxidative stress in lung tissues were determined using commercial kits. The degree of apoptosis was determined using a TUNEL assay. The expression levels of miR-139-5p and Rho-kinase 1 (ROCK1) were determined using reverse transcription-quantitative PCR and western blot analyses. A dual-luciferase reporter assay was used to confirm the direct targeting of ROCK1 by miR-139-5p. NHBEs were co-transfected with vectors expressing ROCK1 (or empty vector) and miR-139-5p mimics or control mimics prior to LPS treatment. The transcriptional activity of caspase-3, the ratio of apoptotic cells, the expression levels of mucin 5AC, mucin 1, TNF-α, IL-1β, IL-6, NLR family pyrin domain containing 3, apoptosis-associated speck-like protein containing a CARD and caspase-1 were evaluated. Compared with the normal group, mice that underwent CLP exhibited abnormal lung morphology, enhanced production of TNF-α, IL-1β and IL-6, increased reactive oxygen species (ROS), malondialdehyde and lactate dehydrogenase levels, an increased proportion of apoptotic cells and increased ROCK1 expression. Superoxide dismutase, glutathione peroxidase and miR-139-5p levels were decreased following CLP. In the NHBEs, stimulation with LPS caused a marked increase in inflammatory cytokine levels and apoptosis compared with the untreated cells. Overexpression of miR-139-5p attenuated cell apoptosis and inflammation. Overexpression of ROCK1 in NHBEs restored the ROS levels and proinflammatory cytokine production inhibited by miR-139-5p. In conclusion, miR-139-5p alleviated sepsis-induced ALI via suppression of its downstream target, ROCK1, suggesting that miR-139-5p may hold promise in the treatment of sepsis-induced ALI.

• Rho-kinase 1
• acute lung injury
• apoptosis
• inflammation
• microRNA
• sepsis

• LPS
• goats
• microRNA
• rice grain
• spleen

• Nanog
• ceRNA
• lncRNA
• miR-139-5p
• microRNA
• pluripotency

• 3' Untranslated Regions/genetics
• Animals
• Cell Differentiation/genetics
• Embryo, Mammalian/cytology
• Embryo, Mammalian/embryology
• Embryo, Mammalian/metabolism
• Embryonic Stem Cells/cytology
• Embryonic Stem Cells/metabolism
• Gene Expression Regulation, Developmental
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs/genetics
• Nanog Homeobox Protein/genetics
• Nanog Homeobox Protein/metabolism
• Octamer Transcription Factor-3/genetics
• Octamer Transcription Factor-3/metabolism
• Promoter Regions, Genetic/genetics
• Protein Binding
• RNA, Long Noncoding/genetics
• RNA-Seq/methods
• Reverse Transcriptase Polymerase Chain Reaction/methods
• SOXB1 Transcription Factors/genetics
• SOXB1 Transcription Factors/metabolism
• Mice

The TNM staging remains the gold standard for determining the prognosis of patients with colorectal cancer (CRC), which is inadequate at identifying the subset of high-risk stage II and III patients that have a high potential of developing tumor recurrence and may experience death. Emerging evidence indicates that not only microRNAs (miRNAs) play important functional role in CRC development but may serve as important disease biomarkers. In this study we aimed to develop a miRNA-based classifier as a prognostic signature for improving the clinical outcome of patients with stage II/III CRC.

We performed a systematic and comprehensive discovery step to identify differentially expressed miRNAs in CRC. We subsequently determined the prognostic relevance of these miRNAs in stage II/III patients using qRT-PCR and developed a miRNA-based classifier for predicting disease-free survival (DFS) in a clinical cohort (n=186).

Based upon miRNA expression profiling studies, we identified a panel of 10 miRNAs which are consistently differentially expressed in CRC vs. normal tissues. By using cox proportional hazard models, we then developed 6-miRNA-classifier (miR-183, -20a, -21, -195, -139 and -20a) to predict prognosis in clinical cohort, that had significantly superior predictive performance compared to other clinicopathological factors, and could successfully identify high-risk stage II and III CRC patients with poor prognosis [hazard ratio (HR) =2.16; P=0.0048]. In a multivariate analysis, this miRNA-based classifier emerged as an independent prognostic signature for poor DFS.

Our miRNA-based classifier is a reliable predictive tool for determining prognosis in patents with stage II/III CRC, and might be able to identify high-risk patients that are candidates for more targeted personalized clinical management and surveillance.

• MicroRNA (miRNA)
• biomarker
• colorectal cancer (CRC)
• prognosis

Hunting for natural compounds that can modulate the structure of the intestinal flora is a new hotspot for colitis‐associated cancer (CAC) prevention or treatment. Alisol B 23-acetate (AB23A) is a natural tetracyclic triterpenoid found in Alismatis rhizoma which is well known for dietary herb. Alismatis rhizoma is often used clinically to treat gastrointestinal diseases in China. In this study, we investigated the potential prevention of AB23A in male mouse models of azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CAC. AB23A intervention alleviated the body weight loss, disease activity index, colon tumor load, tissue injury, and inflammatory cytokine changes in CAC mice. AB23A intervention leads to remarkable reductions in the activation of TLR, NF-κB and MAPK. AB23A significantly decreased the phosphorylation of p38, ERK, and JNK and up-regulated mucin-2 and the expression of tight junction proteins. The gut microbiota of AB23A-interfered mice was characterized with high microbial diversity, the reduced expansion of pathogenic bacteria, such as Klebsiella, Citrobacter, and Akkermansia, and the increased growth of bacteria including Bacteroides, Lactobacillus, and Alloprevotella. These data reveal that AB23A has the potential to be used to treat CAC in the future.

• Alisol B 23-acetate
• TLR/NF-κB/MAPK
• colitis-associated cancer
• gut microbiota
• intestinal barrier

• biomarkers
• colitis-associated colorectal cancer
• colorectal cancer
• inflammatory bowel disease
• microRNA

• Carcinogenesis/genetics
• Colitis/complications
• Colitis/genetics
• Colitis/pathology
• Colorectal Neoplasms/complications
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• MicroRNAs/genetics

• Bcl-2
• Development
• HDAC4
• Hypoxic-ischemic brain damage
• Neural behavior
• microRNA-139-5p

• Animals
• Apoptosis/physiology
• Brain/metabolism
• Disease Models, Animal
• Histone Deacetylases/genetics
• Histone Deacetylases/metabolism
• Hypoxia-Ischemia, Brain/genetics
• Hypoxia-Ischemia, Brain/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neurons/metabolism
• Oxidative Stress/physiology
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Rats
• Rats, Sprague-Dawley
• Up-Regulation

Intracranial aneurysms (IAs) may cause lethal subarachnoid hemorrhage upon rupture, but the molecular mechanisms are poorly understood. The aims of this study were to analyze the transcriptional profiles to explore the functions and regulatory networks of differentially expressed genes (DEGs) in IA rupture by bioinformatics methods and to identify the underlying mechanisms. In this study, 1,471 DEGs were obtained, of which 619 were upregulated and 852 were downregulated. Gene enrichment analysis showed that the DEGs were mainly enriched in the inflammatory response, immune response, neutrophil chemotaxis, and macrophage differentiation. Related pathways include the regulation of actin cytoskeleton, leukocyte transendothelial migration, nuclear factor κB signaling pathway, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, and chemokine signaling pathway. The enrichment analysis of 20 hub genes, subnetworks, and significant enrichment modules of weighted gene coexpression network analysis showed that the inflammatory response and immune response had a causal relationship with the rupture of unruptured IAs (UIAs). Next, the CIBERSORT method was used to analyze immune cell infiltration into ruptured IAs (RIAs) and UIAs. Macrophage infiltration into RIAs increased significantly compared with that into UIAs. The result of principal component analysis revealed that there was a difference between RIAs and UIAs in immune cell infiltration. A 4-gene immune-related risk model for IA rupture (IRMIR), containing CXCR4, CXCL3, CX3CL1, and CXCL16, was established using the glmnet package in R software. The receiver operating characteristic value revealed that the model represented an excellent clinical situation for potential application. Enzyme-linked immunosorbent assay was performed and showed that the concentrations of CXCR4 and CXCL3 in serum from RIA patients were significantly higher than those in serum from UIA patients. Finally, a competing endogenous RNA network was constructed to provide a potential explanation for the mechanism of immune cell infiltration into IAs. Our findings highlighted the importance of immune cell infiltration into RIAs, providing a direction for further research.

• ceRNA network
• functional enrichment analysis
• immune cell infiltration
• immune-related risk model
• intracranial aneurysms

• ASMCs
• JAK3/STAT5 pathway
• LncRNA NEAT1
• inflammation
• miR-139

• Eif4g2
• JTXK
• Jiang Tang Xiao Ke
• Staphylococcus aureus
• Wound
• miR-139-5p

• mir-139-5p
• sepsis
• acute lung injury

• Acute Lung Injury/genetics
• Animals
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs/genetics
• Myeloid Differentiation Factor 88/genetics
• Myeloid Differentiation Factor 88/metabolism
• NF-kappa B/metabolism
• Sepsis/genetics
• Signal Transduction
• Toll-Like Receptor 4/genetics
• Toll-Like Receptor 4/metabolism

• MicroRNA-139-5p
• apoptosis
• atherosclerosis
• enhancer of zeste homolog 2
• methylation
• signal transducer and activator of transcription 1

• RNA deep sequencing
• bioactive compound
• circular RNA
• colorectal cancer
• functional prediction
• regulatory network

• F16-094-1-00 Key Laboratory Foundation from Shenyang S&T Projects
• 31828005 National Natural Science Foundation of China
• 81501346 National Natural Science Foundation of China
• 81601370 National Natural Science Foundation of China
• 81603149 National Natural Science Foundation of China
• 81673475 National Natural Science Foundation of China
• 81872905 National Natural Science Foundation of China
• U1608281 National Natural Science Foundation of China and Liaoning joint fund key program
• 17 to 123-9-00 Shenyang S&T Projects
• Z18-4 to 020 Shenyang S&T Projects
• LS201617 Key Laboratory Foundation from Liaoning Province

• CRISPR
• Cancer
• Therapy

• CircRNA
• Pseudorabies virus infection
• RNA-seq

• Animals
• Binding Sites
• Herpesvirus 1, Suid/genetics
• MicroRNAs
• RNA, Circular
• RNA, Messenger

• cancer
• cytokines
• inflammation
• miRNA
• tumor microenvironment

• Cancer
• Signaling pathway
• miR-139-5p
• miRNA

Colitis-associated cancer (CAC) is known as inflammatory bowel disease (IBD)-developed colorectal cancer, the pathogenesis of which involves the occurrence of apoptosis. Western drugs clinically applied to CAC are often single-targeted and exert many adverse reactions after long-term administration, so it is urgent to develop new drugs for the treatment of CAC. Herbal medicines commonly have multiple components with multiple targets, and most of them are low-toxicity. Some herbal medicines have been reported to ameliorate CAC through inducing apoptosis, but there is still a lack of systematic review. In this work, we reviewed articles published in Sci Finder, Web of Science, PubMed, Google Scholar, CNKI, and other databases in recent years by setting the keywords as apoptosis in combination with colitis-associated cancer. We summarized the herbal medicine extracts or their compounds that can prevent CAC by modulating apoptosis and analyzed the mechanism of action. The results show the following. (1) Herbal medicines regulate both the mitochondrial apoptosis pathway and death receptor apoptosis pathway. (2) Herbal medicines modulate the above two apoptotic pathways by affecting signal transductions of IL-6/STAT3, MAPK/NF-κ B, Oxidative stress, Non-canonical TGF-β1, WNT/β-catenin, and Cell cycle, thereby ameliorating CAC. We conclude that following. (1) Studies on the role of herbal medicine in regulating apoptosis through the Ras/Raf/ERK, WNT/β-catenin, and Cell cycle pathways have not yet been carried out in sufficient depth. (2) The active constituents of reported anti-CAC herbal medicine mainly include polyphenols, terpenoids, and saccharide. Also, we identified other herbal medicines with the constituents mentioned above as their main components, aiming to provide a reference for the clinical use of herbal medicine in the treatment of CAC. (3) New dosage forms can be utilized to elevate the targeting and reduce the toxicity of herbal medicine.

• apoptosis
• colitis-associated cancer
• herbal medicine
• inflammatory bowel disease
• signaling pathways

• cancer
• differentiation
• inflammatory bowel disease
• intestinal stem cells
• miRNA
• mucosal inflammation.

• Cancer
• Inflammation
• MicroRNAs
• Obesity

• Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences

• RAS/MAPK signaling
• colorectal cancer
• microRNA

• Animals
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Gene Expression Regulation, Neoplastic/genetics
• Gene Expression Regulation, Neoplastic/physiology
• Humans
• MAP Kinase Signaling System/genetics
• MAP Kinase Signaling System/physiology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Signal Transduction/genetics
• Signal Transduction/physiology
• ras Proteins/genetics
• ras Proteins/metabolism

• bioinformatics analysis
• clinicopathological features
• hepatocellular carcinoma
• microRNA-139-5p
• progressive

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. This study aims to understand the underlying mechanism of lncRNA, actin filament-associated protein 1 antisense RNA 1(AFAP1-AS1) in mediating chemotherapeutic resistance in NSCLC. The levels of AFAP1-AS1 in NSCLC tissues and cells were determined using RT-PCR. The protein levels of RRM2, EGFR, and p-AKT were analyzed using Western blotting. Binding between AFAP1-AS1 and miR-139-5p was confirmed using dual luciferase reporter and RNA immunoprecipitation (RIP) assays, and binding between miR-139-5p and RRM2 was confirmed by a dual luciferase reporter assay. NSCLC cell proliferation, apoptosis, and colony formation were examined using MTT, flow cytometry, and colony formation assays, respectively. It was found that AFAP1-AS1 expression was upregulated in NSCLC tissues and cells. In addition, AFAP1-AS1 bound to and downregulated the expression of miR-139-5p, which was reduced in NSCLC tissues. Knockdown of AFAP1-AS1 and overexpression of miR-139-5p inhibited NSCLC cell proliferation, colony formation and chemotherapy resistance and increased cell apoptosis. Additionally, AFAP1-AS1 upregulates RRM2 expression via sponging miR-139-5p. Furthermore, AFAP1-AS1 enhanced NSCLC cell proliferation and chemotherapy resistance through upregulation of RRM2 by inhibiting miR-139-5p expression. Moreover, RRM2 promoted cellular chemotherapy resistance by activating EGFR/AKT. Finally, knockdown of AFAP1-AS1 significantly suppressed tumor growth and chemoresistance in nude mice. In conclusion, AFAP1-AS1 promoted chemotherapy resistance by supressing miR-139-5p expression and promoting RRM2/EGFR/AKT signaling pathway in NSCLC cells.

• AFAP1-AS1
• EGFR/AKT
• RRM2
• miR-139-5p
• non-small cell lung cancer

The inflammatory microenvironment, which mediates the initiation and malignant development of tumors, has been reported to be associated with microRNA (miRNA) dysregulation. In the present study, the expression of miR-139-5p was analyzed in colorectal cancer (CRC) cell lines SW480, HT29, HCT-8, LoVo and HCT116, aiming to investigate the function and mechanism of miR-139-5p in the regulation of the malignant phenotypes of CRC. miR-139-5p expression was found to be considerably downregulated in CRC cell lines compared with the human normal colon mucosal epithelial cell line NCM460. Subsequently, it was demonstrated that overexpression of miR-139-5p in colon cancer cell lines significantly suppressed the cell proliferation in vitro and in vivo. In addition, overexpression of miR-139-5p further inhibited the invasion ability of colon cancer cells in vitro, concomitantly with downregulation of key invasion-associated proteins, including matrix metalloproteinase 9 (MMP9) and MMP7. Furthermore, it was demonstrated that overexpression of miR-139-5p decreased the expression levels of inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α), by suppressing nuclear factor (NF)-κB activity. Therefore, these findings collectively indicated that miR-139-5p regulated chronic inflammation by suppressing NF-κB activity in order to inhibit cell proliferation and invasion in CRC, thereby indicating a novel molecular mechanism in CRC therapy.

• chronic inflammation
• colorectal cancer
• invasion
• microRNA-139-5p
• proliferation

The emergence of resistance to chemotherapy or target therapy, tumor metastasis, and systemic toxicity caused by available anticancer drugs hamper the successful colorectal cancer (CRC) treatment. The rise in epidermal growth factor receptor (EGFR; human epidermal growth factor receptor 1; HER1) expression and enhanced phosphorylation of HER2 and HER3 are associated with tumor resistance, metastasis and invasion, thus resulting in poor outcome of anti-CRC therapy. The use of afatinib, a pan-HER inhibitor, is a potential therapeutic approach for resistant CRC. Additionally, miR-139 has been reported to be negatively correlated with chemoresistance, metastasis, and epithelial–mesenchymal transition (EMT) of CRC. Hence, we develop a nanoparticle formulation consisting of a polymer core to carry afatinib or miR-139, which is surrounded by lipids modified with a targeting ligand and a pH-sensitive penetrating peptide to improve the anticancer effect of cargos against CRC cells.

Our findings show that this formulation displays a spherical shape with core/shell structure, homogeneous particle size distribution and negative zeta potential. The prepared formulations demonstrate a pH-sensitive release profile and an enhanced uptake of cargos into human colorectal adenocarcinoma Caco-2 cells in response to the acidic pH. This nanoparticle formulation incorporating afatinib and miR-139 exhibits low toxicity to normal cells but shows a better inhibitory effect on Caco-2 cells than other formulations. Moreover, the encapsulation of afatinib and miR-139 in peptide-modified nanoparticles remarkably induces apoptosis and inhibits migration and resistance of Caco-2 cells via suppression of pan-HER tyrosine kinase/multidrug resistance/metastasis pathways.

This study proposes a multifunctional nanoparticle formulation for targeted modulation of apoptosis/EGFR/HER/EMT/resistance/progression pathways to increase the sensitivity of colon cancer cells to afatinib.

The online version of this article (10.1186/s12951-019-0519-6) contains supplementary material, which is available to authorized users.

• Afatinib
• Cell-penetrating peptides
• Colorectal cancer
• Epidermal growth factor receptor (EGFR)
• Nanoparticles
• Targeting delivery

microRNA (miR/miRNA)-27a-3p has been reported to be abnormally expressed in various types of cancer, including colorectal cancer (CRC). B-cell translocation gene 1 (BTG1) has also been implicated with CRC. However, the association between miR-27a-3p and BTG1 in CRC, to the best of our knowledge, has not been investigated. In order to assess whether miR-27a-3p is associated with CRC, reverse transcription-quantitative PCR was performed on 20 paired CRC and paracancerous tissues for miRNA analysis. For the screening and validation of miR-27a-3p expression in colon cancer, several colon cancer cell lines (HCT-116, HCT8, SW480, HT29, LOVO and Caco2) and the normal colorectal epithelial cell line NCM460 were examined. The highest expression levels of miR-27a-3p were detected in the HCT-116, which was selected for further experimentation. The HCT-116 cells were divided into control, miR-27a-3p mimic and inhibitor groups, and cell proliferation was tested using an MTT assay. Additionally, miR-27a-3p inhibitor/mimic or BTG1 plasmid were transfected into the HCT-116 cells, and flow cytometry was performed to analyze cell cycle distributions. TUNEL analysis was performed to detect apoptosis. Protein levels of factors in the downstream signaling pathway mediated by miR-27a-3p [ERK/mitogen-activated extracellular signal-regulated kinase (MEK)] were detected. miR-27a-3p was revealed to be overexpressed in human CRC tissues and colon cancer cell lines. Knockdown of miR-27a-3p suppressed proliferation of HCT-116 cells and apoptosis was increased. It further markedly upregulated expression levels of BTG1 and inhibited activation of proteins of the ERK/MEK signaling pathway. In addition, overexpression of BTG1 in HCT-116 cells triggered G₁/S phase cell cycle arrest and increased apoptosis via the ERK/MEK signaling pathway. In conclusion, the present study demonstrated that the effects of miR-27a-3p on colon cancer cell proliferation and apoptosis were similar to those of the tumor suppressor gene BTG1. The miR-27a-3p/BTG1 axis may have potential implications for diagnostic and therapeutic approaches in CRC.

• B-cell translocation gene 1
• colorectal cancer
• microRNA

Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer (CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.

• Colorectal cancer
• Inflammation
• DNA methylation
• Histone modification
• LncRNA
• MicroRNAs
• Epigenetics

• Cell Transformation, Neoplastic/genetics
• Colon/immunology
• Colon/pathology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/pathology
• Disease Progression
• Epigenesis, Genetic/immunology
• Gene Expression Regulation, Neoplastic/immunology
• Humans
• Inflammation/genetics
• Inflammation/immunology
• Inflammation/pathology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/pathology
• Rectum/immunology
• Rectum/pathology
• Tumor Microenvironment/genetics
• Tumor Microenvironment/immunology

Emerging evidence suggests that endothelial-to-mesenchymal transition (EndMT) in endothelial dysfunction due to persistent inflammation is a key component and emerging concept in the pathogenesis of vascular diseases. Ginsenoside Rg3 (Rg3), an active compound from red ginseng, has been known to be important for vascular homeostasis. However, the effect of Rg3 on inflammation-induced EndMT has never been reported. Here, we hypothesize that Rg3 might reverse the inflammation-induced EndMT and serve as a novel therapeutic strategy for vascular diseases.

EndMT was examined under an inflammatory condition mediated by the NOD1 agonist, γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP), treatment in human umbilical vein endothelial cells. The expression of EndMT markers was determined by Western blot analysis, real-time polymerase chain reaction, and immunocytochemistry. The underlying mechanisms of Rg3-mediated EndMT regulation were investigated by modulating the microRNA expression.

The NOD1 agonist, iE-DAP, led to a fibroblast-like morphology change with a decrease in the expression of endothelial markers and an increase in the expression of the mesenchymal marker, namely EndMT. On the other hand, Rg3 markedly attenuated the iE-DAP–induced EndMT and preserved the endothelial phenotype. Mechanically, miR-139 was downregulated in cells with iE-DAP–induced EndMT and partly reversed in response to Rg3 via the regulation of NF-κB signaling, suggesting that the Rg3–miR-139-5p-NF-κB axis is a key mediator in iE-DAP-induced EndMT.

These results suggest, for the first time, that Rg3 can be used to inhibit inflammation-induced EndMT and may be a novel therapeutic option against EndMT-associated vascular diseases.

• endothelial-to-mesenchymal transition
• ginsenoside Rg3
• iE-DAP
• inflammation
• microRNA

• Colorectal cancer
• Invasion
• Metastasis
• Prognosis
• Stomatin-like protein-2
• Wnt/β-catenin signal pathway