• drug resistance
• immune microenvironment
• immunotherapy
• microrna biogenesis

• R01 CA266128 NCI NIH HHS
• R56 DK136596 NIDDK NIH HHS

• Nrf2 dysregulation
• drug resistance
• hepatocellular carcinoma
• immune evasion
• molecular pathogenesis

• NF-E2-Related Factor 2/metabolism
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/metabolism
• Humans
• Liver Neoplasms/immunology
• Liver Neoplasms/metabolism
• Signal Transduction
• Animals
• Tumor Escape
• Oxidative Stress
• Drug Resistance, Neoplasm
• Immune Evasion
• Gene Expression Regulation, Neoplastic

• Angiogenesis
• Cell proliferation
• Hepatocellular carcinoma
• Invasion
• miRNA

• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/drug therapy
• Humans
• MicroRNAs/analysis
• MicroRNAs/antagonists & inhibitors
• Apoptosis
• Cell Proliferation
• Neoplasm Metastasis
• Neovascularization, Physiologic
• Liver Neoplasms/diagnosis
• Liver Neoplasms/drug therapy
• Biomarkers, Tumor/analysis

• HepG2
• hypoxia inducible factor 1 (HIF-1)
• intermittent hypoxia (IH)
• liver cancer
• obstructive sleep apnea syndrome (OSA)
• sustained hypoxia (SH)
• vascular endothelial growth factor (VEGF)

• ET-1
• Epstein-Barr virus
• FOXO1
• gastric carcinoma
• mechanisms

• Humans
• Herpesvirus 4, Human/genetics
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Epstein-Barr Virus Infections/genetics
• MAP Kinase Signaling System
• Endothelin-1/genetics
• Endothelin-1/metabolism
• Carcinoma/complications
• Carcinoma/genetics
• Carcinogenesis
• Forkhead Box Protein O1/genetics
• Forkhead Box Protein O1/metabolism

• Natural Science Foundation of Shandong Province (Natural Science Foundation of Shandong)
• Qingdao Municipal Science and Technology Bureau

• 5-FU
• Endothelin-1
• Gastric cancer
• miR-648

Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC.

Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.

• biomarker
• hepatocellular carcinoma
• microRNA
• pathogenesis
• therapeutic target

• EGFR-TKI resistance
• immunotherapy predictor
• miR-1
• tumor immune microenvironment

Sorafenib, a multityrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC), but the clinical response to sorafenib is seriously limited by drug resistance. Programmed death ligand-1 (PD-L1) is one of the most important inhibitory molecules involved in tumor immune evasion. Recently, it has been reported that PD-L1 could play crucial roles in drug resistance of many kinds of cancers. However, the expression, function, and regulation of PD-L1 in sorafenib-resistant hepatoma cells remain unclear. In this study, we reported that PD-L1 was overexpressed in sorafenib-resistant hepatoma cells, and shRNA-mediated PD-L1 depletion attenuated drug resistance and suppressed the migration, invasion, colony formation, and tumorigenesis in sorafenib-resistant hepatoma cells in vitro and in vivo. Mechanistic investigations indicated that loss of microRNA-1 (miR-1), a tumor-suppressive microRNA, contributed to the PD-L1 upregulation in sorafenib-resistant hepatoma cells, and PD-L1 was a direct regulatory target of miR-1. Further study revealed that an oncogenic transcriptional factor, nuclear factor E2-related factor 2 (NRF-2), was induced in sorafenib-resistant hepatoma cells and inhibited expression of miR-1 in vitro. From molecular mechanism insight back to the functional verification, we eventually demonstrated that miR-1 executed its tumor-suppressive effects on drug resistance and other malignant properties in sorafenib-resistant hepatoma cells partially by PD-L1 inhibition in vitro and in vivo. In conclusion, our data suggested that a NRF-2/miR-1/PD-L1 regulatory axis contributed to the development and maintenance of drug resistance and other tumorigenic properties in sorafenib-resistant hepatoma cells and provided a potential therapeutic target for overcoming sorafenib resistance in HCC.

• Adrenal tumors
• Hepatoblastoma
• Hepatocarcinoma
• Nephroblastoma
• Neuroblastoma
• miRNA

Triple-negative breast cancer (TNBC) is a particular subtype of breast malignant tumor with poorer prognosis than other molecular subtypes. Previous studies have demonstrated that some abnormal expression of non-coding RNAs including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) were closely related to tumor cell proliferation, apoptosis, invasion, migration and drug sensitivity. However, the role of non-coding RNAs in the pathogenesis of TNBC is still unclear. In order to characterize the molecular mechanism of non-coding RNAs in TNBC, we downloaded RNA data and miRNA data from the cancer genome atlas database. We successfully identified 686 message RNAs (mRNAs), 26 miRNAs and 50 lncRNAs as key molecules for high risk of TNBC. Then, we hypothesized that the lncRNA–miRNA–mRNA regulatory axis positively correlates with TNBC and constructed a competitive endogenous RNA (ceRNA) network of TNBC. Our series of analyses has shown that five molecules (TERT, TRIML2, PHBP4, mir-1-3p, mir-133a-3p) were significantly associated with the prognosis of TNBC, and there is a prognostic ceRNA sub-network between those molecules. We mapped the Kaplan–Meier curve of RNA on the sub-network and also suggested that the expression level of the selected RNA is related to the survival rate of breast cancer. Reverse transcription-quantitative polymerase chain reaction showed that the expression level of TRIML2 in TNBC cells was higher than normal. In general, our findings have implications for predicting metastasis, predicting prognosis and discovering new therapeutic targets for TNBC.

• Survival prognosis
• Triple-negative breast cancer
• ceRNA network

MicroRNA-1 (miRNA-1) has been long viewed as a muscle-specific miRNA and plays a critical role in myocardium and cardiomyocytes by controlling myocyte growth and rhythm. We identified that miRNA-1 is expressed in cardiac fibroblasts, which are one of the major non-muscle cell types in myocardium and are responsible for cardiac fibrosis in pathological conditions. In this study, we aimed to investigate the effect and mechanism of action of miRNA-1 on cardiac fibroblast proliferation. Subcutaneous angiotensin II (Ang II) infusion via osmotic minipumps for 4 weeks was used to induce myocardial interstitial fibrosis in male Sprague-Dawley rats. MiRNA-1 expression was significantly down-regulated by 68% in freshly isolated ventricular fibroblasts from Ang II-infused rats than that from control rats. Similar results were obtained in adult rat ventricular fibroblasts that were stimulated in culture by Ang II or TGFβ for 48 h. Functionally, overexpression of miRNA-1 inhibited fibroblast proliferation, whereas knockdown of endogenous miRNA-1 increased fibroblast proliferation. We then identified and validated cyclin D2 and cyclin-dependent kinase 6 (CDK6) as direct targets of miRNA-1 in cardiac fibroblasts using biochemical assays. Moreover, we showed that the inhibitory effects of miRNA-1 on cardiac fibroblast proliferation can be blunted by overexpression of its target, cyclin D2. In conclusion, our findings demonstrate miRNA-1 expression and regulation in adult ventricular fibroblasts, where it acts as a novel negative regulator of adult cardiac fibroblast proliferation that is at least partially mediated by direct targeting of two cell cycle regulators. Our results expand the understanding of the regulatory roles of miRNA-1 in cardiac cells (i.e., from myocytes to a major non-muscle cells in the heart).

• Cdk6
• TGFβ
• angiotensin II
• cardiac fibroblasts
• cell cycle regulator
• cell proliferation
• cyclin D2
• microRNA-1

• AntagomiR
• Kv1.5 channels
• miR-1
• pulmonary hypertension

• Action Potentials
• Animals
• COS Cells
• Cell Hypoxia
• Chlorocebus aethiops
• Down-Regulation
• Hypertension, Pulmonary/etiology
• Hypertension, Pulmonary/metabolism
• Indoles/toxicity
• Kv1.5 Potassium Channel/genetics
• Kv1.5 Potassium Channel/metabolism
• Male
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Myocytes, Smooth Muscle/metabolism
• Myocytes, Smooth Muscle/physiology
• Potassium Channel Blockers/pharmacology
• Pulmonary Artery/drug effects
• Pulmonary Artery/metabolism
• Pulmonary Artery/physiopathology
• Pyrroles/toxicity
• Rats
• Rats, Wistar

• Chronic heart failure
• Endothelial function
• Iptakalim
• Natakalim
• SUR2B/Kir6.1 channel
• miRNA

The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development and progression of HCC. Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) is a cytosolic transcription factor, which regulates redox homeostasis by activating the expression of an array of antioxidant response element-dependent genes. Nrf2 displays conflicting roles in normal, healthy liver and HCC; in the former, Nrf2 offers beneficial effects, whereas in the latter it causes detrimental effects favouring the proliferation and survival of HCC. Sustained Nrf2 activation has been observed in HCC and facilitates its progression and aggressiveness. This review summarizes the role and mechanism(s) of action of Nrf2 dysregulation in HCC and therapeutic options that can be employed to modulate this transcription factor.

• Keap1-Nrf2-ARE pathway
• Nrf2 dysregulation
• hepatocellular carcinoma
• microRNAs
• phytochemicals

For the purpose of demonstrating the clinical value and unraveling the molecular mechanisms of micro RNA (miR)-1-3p in colorectal carcinoma (CRC), the present study collected expression and diagnostic data from Gene Expression Omnibus (GEO), ArrayExpress and existing literature to conduct meta-analyses and diagnostic tests. Furthermore, the potential targets of miR-1-3p were attained from datasets that transfected miR-1-3p into CRC cells, online prediction databases and differentially expressed genes from The Cancer Genome Atlas and literature. Subsequently, bioinformatics analysis was conducted based on the aforementioned selected target genes. As a result, downregulation of miR-1-3p was observed. The combined standardized mean difference was −0.51 with 95% confidence interval (CI) of −0.68 to −0.33 using a fixed effect model, which demonstrated a significant downregulation of miR-1-3p in CRC. The combined sensitivity, specificity, positive likelihood ratio, negative likelihood ratio diagnostic score and odds ratio were 0.74 (95%CI: 0.48, 0.90), 0.75 (95%CI: 0.35, 0.94), 2.94 (95%CI: 1.01, 8.55), 0.34 (95%CI: 0.19, 0.60), 2.15 (95%CI: 1.06, 3.23) and 8.57 (95%CI: 2.89, 25.36). The summarized receiver operating characteristic curve demonstrated that the area under the curve was 0.81. In bioinformatics analyses based on 30 promising targets, the most enriched terms in Gene Ontology were positive regulation of transcription from RNA polymerase II promoter, extracellular region and transcription factor binding. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted the pathway termed cytokine-cytokine receptor interaction. In protein-protein interaction analysis, platelet factor 4 was selected as the hub gene. To conclude, miR-1-3p is downregulated in CRC and likely suppresses CRC via multiple biological approaches, which indicates the diagnostic potential and tumor suppressive efficacy.

• apoptosis
• bioinformatics analysis
• endothelin-1
• hepatocellular carcinoma
• migration

Ovaries, which provide a place for follicular development and oocyte maturation, are important organs in female mammals. Follicular development is complicated physiological progress mediated by various regulatory factors including microRNAs (miRNAs). To demonstrate the role of miRNAs in follicular development, this study analyzed the expression patterns of miRNAs in granulosa cells through investigating three previous datasets generated by Illumina miRNA deep sequencing. Furthermore, via bioinformatic analyses, we dissected the associated functional networks of the observed significant miRNAs, in terms of interacting with signal pathways and transcription factors. During the growth and selection of dominant follicles, 15 dysregulated miRNAs and 139 associated pathways were screened out. In comparison of different styles of follicles, 7 commonly abundant miRNAs and 195 pathways, as well as 10 differentially expressed miRNAs and 117 pathways in dominant follicles in comparison with subordinate follicles, were collected. Furthermore, SMAD2 was identified as a hub factor in regulating follicular development. The regulation of miR-26a/b on smad2 messenger RNA has been further testified by real time PCR. In conclusion, we established functional networks which play critical roles in follicular development including pivotal miRNAs, pathways, and transcription factors, which contributed to the further investigation about miRNAs associated with mammalian follicular development.

The advent of targeted therapeutics in human cancer has begun to find novel druggable targets and, in this context, the endothelin-1 receptor (ET-1R), namely ET_A receptor (ET_AR) and ET_B receptor, among the GPCR family represents a class of highly druggable molecules in cancer. ET-1R are aberrantly expressed in human malignancies, potentially representing prognostic factors. Their activation by ligand stimulation initiate signaling cascades activating different downstream effectors, allowing precise control over multiple signaling pathways. ET-1R regulates cell proliferation, survival, motility, cytoskeletal changes, angiogenesis, metastasis as well as drug resistance. The molecular events underlying these responses are the activation of transcriptional factors and coactivators, and downstream genes, acting as key players in tumor growth and progression. ET-1R represent crucial cancer targets that have been exploited for ET-1R therapeutics. Importantly, efforts to explore new information of ET_AR in cancer have uncovered that their functions are crucially regulated by multifunctional scaffold protein β-arrestins (β-arrs) which orchestrate the multidimensionality of ET_AR signaling into highly regulated and distinct signaling complexes, a property that is highly advantageous for tumor signaling. Moreover, the role of β-arr1 in ET-1 signaling in cancer highlights why the pleiotropic effects of ET-1 and its dynamic signaling are more complex than previously recognized. In order to improve therapeutic strategies that interfere with the widespread effects of ET-1R, it is important to consider antagonists able to turn the receptors “off” selectively controlling β-arr1-dependent signaling, highlighting the possibility that targeting ET_AR/β-arr1 may display a large therapeutic window in cancer.

• Cancer
• Endothelin
• Endothelin receptors
• G-protein coupled receptors
• β-arrestin

Several aberrant microRNAs (miRNAs or miRs) have been implicated in esophageal cancer (EC), which is widely prevalent in China. However, their role in EC tumorigenesis has not yet been fully elucidated. In the present study, we determined that miR-1 was downregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent non-neoplastic tissues using RT-qPCR, and confirmed this using an ESCC cell line. Using a nude mouse xenograft model, we confirmed that the re-expression of miR-1 significantly inhibited ESCC tumor growth. A tetrazolium assay and a trypan blue exclusion assay revealed that miR-1 suppressed ESCC cell proliferation and increased apoptosis, whereas the silencing of miR-1 promoted cell proliferation and decreased apoptosis, suggesting that miR-1 is a novel tumor suppressor. To elucidate the molecular mechanisms of action of miR-1 in ESCC, we investigated putative targets using bioinformatics tools. MET, cyclin D1 and cyclin-dependent kinase 4 (CDK4), which are involved in the hepatocyte growth factor (HGF)/MET signaling pathway, were found to be targets of miR-1. miR-1 expression inversely correlated with MET, cyclin D1 and CDK4 expression in ESCC cells. miR-1 directly targeted MET, cyclin D1 and CDK4, suppressing ESCC cell growth. The newly identified miR-1/MET/cyclin D1/CDK4 axis provides new insight into the molecular mechanisms of ESCC pathogenesis and indicates a novel strategy for the diagnosis and treatment of ESCC.

• Biomarker
• Cancer
• Cellular response
• Resistance
• microRNA-1

• apoptosis
• cell cycle
• epithelial-mesenchymal transition
• hepatocellular carcinoma
• metastasis
• miRNA

• LASP1
• TAGLN2
• esophageal squamous cell carcinoma
• microRNA-1

MicroRNAs (miRs) are small, noncoding RNAs that negatively regulate gene expressions at posttranscriptional level. Each miR can control hundreds of gene targets and play important roles in various biological and pathological processes such as hematopoiesis, organogenesis, cell apoptosis and proliferation. Aberrant miR expression contributes to initiation and cell progression of cancers. Accumulating studies have found that miRs play a significant role in cutaneous squamous cell carcinoma (cSCC). Deregulations of miRs may contribute to cSCC carcinogenesis is through acting as oncogenic or tumour suppressive miRs. In this study, we summarized the recent data available on cSCC‐associated miRs. In particular, we will discuss the contribution of miR to the initiation and progression of cSCCs. Although there are many obstacles to be overcome, clinical use of miRs as biomarkers for diagnosis, prediction of prognosis and target for therapies, will be a promising area in the future with more expression and functional role of miRs revealed.

• cutaneous squamous cell carcinoma
• miR
• microRNAs
• oncogene

• (−)-Epigallocatechin-3-gallate (EGCG)
• Crizotinib
• MicroRNA-1
• Osteosarcoma
• c-MET

• Diagnosis
• Hepatocellular carcinoma
• MicroRNA
• Prognosis
• Serum
• Targeted therapy

• diagnosis
• hepatocellular carcinoma
• microRNA
• prognosis
• therapy

Hepatocellular carcinoma (HCC) is the leading primary liver cancer and its clinical outcome is still poor. MicroRNAs (miRNAs) have demonstrated an interesting potential to regulate gene expression at post-transcriptional level. Current findings suggest that miRNAs deregulation in cancer is caused by genetic and/or epigenetic, transcriptional and post-transcriptional modifications resulting in abnormal expression and hallmarks of malignant transformation: aberrant cell growth, cell death, differentiation, angiogenesis, invasion and metástasis. The important role of miRNAs in the development and progression of HCC has increased the efforts to understand and develop mechanisms of control overt this single-stranded RNAs. Several studies have analyzed tumoral response to the regulation and control of deregulated miRNAs with good results in vitro and in vivo, proving that targeting aberrant expression of miRNAs is a powerful anticancer therapeutic. Identification of up and/or down regulated miRNAs related to HCC has led to the discovery of new potential application for detection of their presence in the affected organism. MiRNAs represent a relevant new target for diagnosis, prognosis and treatment in a wide variety of pathologic entities, including HCC. This manuscript intends to summarize current knowledge regarding miRNAs and their role in HCC development.

• Hepatocellular carcinoma
• MicroRNAs
• Regulation
• Therapeutic targets

• Gastric cancer
• Non-coding RNA
• Target therapy
• Tumor suppressor gene
• miR-1

• diagnostic and prognostic markers
• hepatocellular carcinoma
• miRNA
• therapeutic target

• ezh2
• mir-1
• endothelin-1
• angiogenesis
• nasopharyngeal carcinoma

• 3' Untranslated Regions
• Angiogenesis Inhibitors/genetics
• Angiogenesis Inhibitors/metabolism
• Animals
• Base Sequence
• Carcinoma
• Cell Line, Tumor
• Cell Proliferation/physiology
• Chick Embryo
• Endothelin-1/biosynthesis
• Endothelin-1/genetics
• Endothelin-1/metabolism
• Enhancer of Zeste Homolog 2 Protein
• Gene Knockdown Techniques
• Heterografts
• Human Umbilical Vein Endothelial Cells
• Humans
• Mice
• MicroRNAs/antagonists & inhibitors
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms/blood supply
• Nasopharyngeal Neoplasms/genetics
• Nasopharyngeal Neoplasms/metabolism
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Polycomb Repressive Complex 2/biosynthesis
• Polycomb Repressive Complex 2/genetics
• Polycomb Repressive Complex 2/metabolism
• Transfection

• Apoptosis
• Apoptosis Regulatory Proteins/biosynthesis
• Apoptosis Regulatory Proteins/genetics
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Gene Expression Regulation, Neoplastic/genetics
• Hep G2 Cells
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Neoplasm Proteins/biosynthesis
• Neoplasm Proteins/genetics
• Nuclear Proteins/biosynthesis
• Nuclear Proteins/genetics
• RNA, Neoplasm/biosynthesis
• RNA, Neoplasm/genetics

• IFNs
• MicroRNAs
• Oncogenic viruses

• Endothelial cells
• Glucose
• MicroRNA

Aberrant expression of miR-1 has been implicated in various cancers. However, the mechanisms underlying the role of miR-1 in CRC progression still have not been clarified clearly. Here, we showed the decreased expression of miR-1 in colorectal carcinoma (CRC) tissues and cell lines. Ectopic introduction of miR-1 suppressed cell proliferation and migration, whereas miR-1 inhibitor performed contrary functions in CRC cells. Stable overexpression of miR-1 was sufficient to inhibit tumor growth and homing capacity in vivo. Proteomic analysis revealed that miR-1 modulated the expression of key cellular molecules and involved in the MAPK and PI3K/AKT pathways by inhibiting phosphorylation of ERK and AKT. Meanwhile, miR-1 also reversed epithelial–mesenchymal transition (EMT), which played a pivotal role in the initiation of metastasis. Further studies found that miR-1 can target the 3' untranslated region (3'UTR) of LIM and SH3 protein 1 (LASP1) mRNA and suppress the expression of LASP1, identified as a CRC-associated protein. In contrast to the phenotypes induced by miR-1 restoration, LASP1-induced cell proliferation and migration partly rescued miR-1-mediated biological behaviors. Our results illustrated that miR-1 play a critical role in CRC progression, which suggests its potential role in the molecular therapy of cancer.

• Circadian rhythms
• Endothelin
• Melanophores
• Melanopsins
• Xenopus laevis

• Animals
• Circadian Rhythm/drug effects
• Circadian Rhythm/physiology
• Circadian Rhythm/radiation effects
• Endothelins/pharmacology
• Light
• Melanins/metabolism
• Melanophores/cytology
• Melanophores/drug effects
• Melanophores/metabolism
• Melanophores/radiation effects
• Photoperiod
• Receptors, Endothelin/genetics
• Receptors, Endothelin/metabolism
• Rod Opsins/metabolism
• Xenopus laevis

• chordoma
• invasion
• miRNA-1 (miR-1)
• migration
• slug

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a key transcription factor that regulates the expression of over a hundred cytoprotective and antioxidant genes that provide cellular protection from reactive oxygen species. Chemotherapy resistance in several cancers has been linked to dysregulation of the NRF2 signalling pathway, moreover there is growing evidence that NRF2 may contribute to tumorigenesis. MicroRNA (miRNA) are small non-coding RNA sequences that post-transcriptionally regulate mRNA sequences. In cancer pathogenesis, aberrantly expressed miRNAs can act as either tumor suppressor or oncogenic miRNA. Recent evidence has been described that identifies a number of miRNA that can be regulated by NRF2. This review outlines the importance of NRF2 in regulating miRNA, and the functional role this may have in the tumorigenesis of human malignancies and their chemotherapy resistance.

While the mechanisms of human cancer development are not fully understood, evidence of microRNA (miRNA, miR) dysregulation has been reported in many human diseases, including cancer. miRs are small noncoding RNA molecules that regulate posttranscriptional gene expression by binding to complementary sequences in the specific region of gene mRNAs, resulting in downregulation of gene expression. Not only are certain miRs consistently dysregulated across many cancers, but they also play critical roles in many aspects of cell growth, proliferation, metastasis, apoptosis, and drug resistance. Recent studies from our group and others revealed that miR-1 is frequently downregulated in various types of cancer. Through targeting multiple oncogenes and oncogenic pathways, miR-1 has been demonstrated to be a tumor suppressor gene that represses cancer cell proliferation and metastasis and promotes apoptosis by ectopic expression. In this review, we highlight recent findings on the aberrant expression and functional significance of miR-1 in human cancers and emphasize its significant values for therapeutic potentials.

• Primary liver cancer
• SerpinB3
• Small non coding RNA

• Animals
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/metabolism
• Base Sequence
• Carcinoma, Hepatocellular
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Liver Neoplasms
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA Interference
• RNA Processing, Post-Transcriptional
• Serpins/genetics
• Serpins/metabolism

• Endothelin
• Endothelin receptor antagonists
• Extracellular matrix
• Fibrosis

Hepatocarcinogenesis is a multistep process that starts from fatty liver and transitions to fibrosis and, finally, into cancer. Many etiological factors, including hepatitis B virus X antigen (HBx) and p53 mutations, have been implicated in hepatocarcinogenesis. However, potential synergistic effects between these two factors and the underlying mechanisms by which they promote hepatocarcinogenesis are still unclear. In this report, we show that the synergistic action of HBx and p53 mutation triggers progressive hepatocellular carcinoma (HCC) formation via src activation in zebrafish. Liver-specific expression of HBx in wild-type zebrafish caused steatosis, fibrosis and glycogen accumulation. However, the induction of tumorigenesis by HBx was only observed in p53 mutant fish and occurred in association with the up-regulation and activation of the src tyrosine kinase pathway. Furthermore, the overexpression of src in p53 mutant zebrafish also caused hyperplasia, HCC, and sarcomatoid HCC, which were accompanied by increased levels of the signaling proteins p-erk, p-akt, myc, jnk1 and vegf. Increased expression levels of lipogenic factors and the genes involved in lipid metabolism and glycogen storage were detected during the early stages of hepatocarcinogenesis in the HBx and src transgenic zebrafish. The up-regulation of genes involved in cell cycle regulation, tumor progression and other molecular hallmarks of human liver cancer were found at later stages in both HBx and src transgenic, p53 mutant zebrafish. Together, our study demonstrates that HBx and src overexpression induced hepatocarcinogenesis in p53 mutant zebrafish. This phenomenon mimics human HCC formation and provides potential in vivo platforms for drug screening for therapies for human liver cancer.

• Animals
• Animals, Genetically Modified
• Apoptosis/genetics
• Biomarkers, Tumor/metabolism
• CSK Tyrosine-Protein Kinase
• Carcinogenesis/genetics
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Cycle/genetics
• Enzyme Activation/genetics
• Fibrosis
• Gene Expression
• Glycogen/metabolism
• Humans
• Hyperplasia/genetics
• Lipogenesis/genetics
• Liver/metabolism
• Liver/pathology
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Mutation
• Neoplasm Metastasis
• Organ Specificity
• Proliferating Cell Nuclear Antigen/metabolism
• Recombinant Fusion Proteins/genetics
• Signal Transduction/genetics
• Trans-Activators/genetics
• Tumor Suppressor Protein p53/genetics
• Viral Regulatory and Accessory Proteins
• Zebrafish/genetics
• Zebrafish/metabolism
• src-Family Kinases/genetics

Hepatocellular carcinoma (HCC) represents a major form of primary liver cancer in adults. MicroRNAs (miRs), small non-coding single-stranded RNAs of 19-24 nucleotides in length, negatively regulate the expression of many target genes at the post-transcriptional and/or translational levels and play a critical role in the initiation and progression of HCC. In this review we have summarized the information of aberrantly expressed miRs in HCC, their mechanism of action and relationship to cancer. The recent advances in HCC research reveal that miRs regulate expression of various oncogenes and tumor suppressor genes, thereby contributing to the modulation of diverse biological processes including proliferation, apoptosis, epithelial to mesenchymal transition and metastasis. From a clinical viewpoint, polymorphisms within miR-binding sites are associated with the risk of HCC. Polymorphisms in miR related genes have been shown to correlate with survival or treatment outcome in patients. Furthermore, the review focuses on the potential role of miRs as novel biomarkers and their translational applications for diagnosis and therapy in HCC. With further insights into miR deregulation in HCC, it is expected that novel miR-based therapeutics will arise. Also, we orient the readers to other reviews that may provide better understanding of miR research in HCC.

• MicroRNA
• Cancer
• Hepatocellular carcinoma
• Biomarker
• Polymorphism

• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/therapy
• Epigenesis, Genetic
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/therapy
• MicroRNAs/metabolism