• Biomarker
• Diagnosis
• Hepatitis B virus
• Hepatocellular carcinoma
• MicroRNA
• Prognosis

• Humans
• MicroRNAs/genetics
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/genetics
• Hepatitis B virus/genetics
• Liver Neoplasms/diagnosis
• Liver Neoplasms/genetics
• Prognosis
• Biomarkers
• Hepatitis B/complications
• Hepatitis B/diagnosis

• Cancer metabolic control
• Cancer therapeutics
• DDX5
• DDX5 degrader FL118
• DNA repair
• Immune suppression
• Microbiota negative influence
• Oncotarget
• Virus infection promotion
• p68

• Humans
• Male
• Cell Transformation, Neoplastic
• DEAD-box RNA Helicases/genetics
• DNA Repair
• Microbiota
• Prostatic Neoplasms
• Signal Transduction
• Immunosuppression Therapy

• P30 CA016056 NCI NIH HHS
• R01 CA237027 NCI NIH HHS
• R44 CA176937 NCI NIH HHS
• 20-65-FENG Pancreatic Cancer Action Network

• H19 lncRNA
• SHAPE assay
• carcinogenesis
• interactome
• miRNA
• pre-miR-675
• tumours

The transformation of a normal cell into a cancerous one is caused by the deregulation of different metabolic pathways, involving a complex network of protein–protein interactions. The cellular enzymes DDX3X and DDX5 play important roles in the maintenance of normal cell metabolism, but their deregulation can accelerate tumor transformation. Both DDX3X and DDX5 interact with hundreds of different cellular proteins, and depending on the specific pathways in which they are involved, both proteins can either act as suppressors of cancer or as oncogenes. In this review, we summarize the current knowledge about the roles of DDX3X and DDX5 in different tumors. In addition, we present a list of interacting proteins and discuss the possible contribution of some of these protein–protein interactions in determining the roles of DDX3X and DDX5 in the process of cancer proliferation, also suggesting novel hypotheses for future studies.

RNA helicases of the DEAD-box family are involved in several metabolic pathways, from transcription and translation to cell proliferation, innate immunity and stress response. Given their multiple roles, it is not surprising that their deregulation or mutation is linked to different pathological conditions, including cancer. However, while in some cases the loss of function of a given DEAD-box helicase promotes tumor transformation, indicating an oncosuppressive role, in other contexts the overexpression of the same enzyme favors cancer progression, thus acting as a typical oncogene. The roles of two well-characterized members of this family, DDX3X and DDX5, as both oncogenes and oncosuppressors have been documented in several cancer types. Understanding the interplay of the different cellular contexts, as defined by the molecular interaction networks of DDX3X and DDX5 in different tumors, with the cancer-specific roles played by these proteins could help to explain their apparently conflicting roles as cancer drivers or suppressors.

• DDX3X
• DDX5
• DEAD-box RNA helicases
• cancer
• oncogene
• oncosuppressor

• Bioinformatics
• Breast cancer
• Cell cycle
• Prognosis
• Wnt signaling
• miR-802

• Epidrugs
• Epigenetics
• HCC
• Histone modifications
• Methylation
• Non-coding RNAs

• Carcinogenesis/genetics
• Carcinoma, Hepatocellular/pathology
• Epigenesis, Genetic
• Humans
• Liver Neoplasms/pathology
• Prognosis

• Associazione Italiana per la Ricerca sul Cancro

• Dicer
• EZH2
• HOXB-AS3
• Liver cancer
• Sorafenib Resistance

• carcinoma
• immunohistochemistry
• pancreas
• pancreatic neoplasms
• pathology
• surgical

• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Carcinoma, Pancreatic Ductal/mortality
• Carcinoma, Pancreatic Ductal/physiopathology
• DEAD-box RNA Helicases/analysis
• DEAD-box RNA Helicases/metabolism
• Humans
• Neoplasm Staging
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/physiopathology
• Prognosis
• Survival Rate

• DDX5
• DEAD-box RNA helicase
• DNA damage
• DNA repair
• cancer biomarker
• cancer target
• cancer therapeutics
• p68
• transcription cofactor

• R21 CA180764 NCI NIH HHS
• P30 CA016056 NCI NIH HHS
• R01 CA133241 NCI NIH HHS
• R01 CA109481 NCI NIH HHS
• R03 CA182552 NCI NIH HHS
• R44 CA176937 NCI NIH HHS
• R43 CA221389 NCI NIH HHS

Human T-lymphotropic virus 1 (HTLV-1) infection may lead to the development of Adult T-cell leukemia/lymphoma (ATLL). To further elucidate the pathophysiology of this aggressive CD4+ T-cell malignancy, we have performed an integrated systems biology approach to analyze previous transcriptome datasets focusing on differentially expressed miRNAs (DEMs) in peripheral blood of ATLL patients.

Datasets GSE28626, GSE31629, GSE11577 were used to identify ATLL-specific DEM signatures. The target genes of each identified miRNA were obtained to construct a protein-protein interactions network using STRING database. The target gene hubs were subjected to further analysis to demonstrate significantly enriched gene ontology terms and signaling pathways. Quantitative reverse transcription Polymerase Chain Reaction (RTqPCR) was performed on major genes in certain pathways identified by network analysis to highlight gene expression alterations.

High-throughput in silico analysis revealed 9 DEMs hsa-let-7a, hsa-let-7g, hsa-mir-181b, hsa-mir-26b, hsa-mir-30c, hsa-mir-186, hsa-mir-10a, hsa-mir-30b, and hsa-let-7f between ATLL patients and healthy donors. Further analysis revealed the first 5 of DEMs were directly associated with previously identified pathways in the pathogenesis of HTLV-1. Network analysis demonstrated the involvement of target gene hubs in several signaling cascades, mainly in the MAPK pathway. RT-qPCR on human ATLL samples showed significant upregulation of EVI1, MKP1, PTPRR, and JNK gene vs healthy donors in MAPK/JNK pathway.

The results highlighted the functional impact of a subset dysregulated microRNAs in ATLL on cellular gene expression and signal transduction pathways. Further studies are needed to identify novel biomarkers to obtain a comprehensive mapping of deregulated biological pathways in ATLL.

• Adult T-cell leukemia/lymphoma
• Gene expression analysis
• HTLV-1
• JNK pathway
• Systems biology

• Carcinogenesis
• Cellular processes
• DEAD-box proteins
• Oncogenes
• RNA metabolism
• Tumor suppressor genes

The dysregulation of RNA interference (RNAi) has often been observed in cancers, where the main focus of research has been on the small RNA molecules directing RNAi. In this review, we focus on the activity of Argonaute proteins, central components of RNAi, in tumorigenesis, and also highlight their potential applications in grading tumors and anti-cancer therapies.

Argonaute proteins (AGOs) play crucial roles in RNA-induced silencing complex (RISC) formation and activity. AGOs loaded with small RNA molecules (miRNA or siRNA) either catalyze endoribonucleolytic cleavage of target RNAs or recruit factors responsible for translational silencing and target destabilization. miRNAs are well characterized and broadly studied in tumorigenesis; nevertheless, the functions of the AGOs in cancers have lagged behind. Here, we discuss the current state of knowledge on the role of AGOs in tumorigenesis, highlighting canonical and non-canonical functions of AGOs in cancer cells, as well as the biomarker potential of AGO expression in different of tumor types. Furthermore, we point to the possible application of the AGOs in development of novel therapeutic approaches.

• Argonaute
• biomarker
• cancer
• miRNA
• therapeutics
• tumorigenesis

DEAD/H box helicases are implicated in lung cancer but have not been systematically investigated for their clinical significance and function. In this study, we aimed to evaluate the potential of DEAD/H box helicases as prognostic biomarkers and therapeutic targets in lung cancer by integrated bioinformatic analysis of multivariate large-scale databases. Survival and differential expression analysis of these helicases enabled us to identify four biomarkers with the most significant alterations. These were found to be the negative prognostic factors DDX11, DDX55 and DDX56, and positive prognostic factor DDX5. Pathway enrichment analysis indicates that MYC signalling is negatively associated with expression levels of the DDX5 gene while positively associated with that of DDX11, DDX55 and DDX56. High expression levels of the DDX5 gene is associated with low mutation levels of TP53 and MUC16, the two most frequently mutated genes in lung cancer. In contrast, high expression levels of DDX11, DDX55 and DDX56 genes are associated with high levels of TP53 and MUC16 mutation. The tumour-infiltrated CD8 + T and B cells positively correlate with levels of DDX5 gene expression, while negatively correlate with that of the other three DEAD box helicases, respectively. Moreover, the DDX5-associated miRNA profile is distinguished from the miRNA profiles of DDX11, DDX55 and DDX56, although each DDX has a different miRNA signature. The identification of these four DDX helicases as biomarkers will be valuable for prognostic prediction and targeted therapeutic development in lung cancer.

• Bioinformatics
• Biomarker
• Clinical significance
• DEAD/H box
• Helicase
• Lung cancer

• Growth factors
• HCC
• Hedgehog
• Hippo
• JAK/STAT
• Notch
• Signaling pathways
• TGF-β
• Wnt/β-catenin

• EMT
• HNF4A
• PIWI proteins
• PIWIL3
• PIWIL4
• chemoresistance
• motility
• pancreatic cancer
• survival

• PI16/01468 Instituto de Salud Carlos III - FEDER (Spanish Ministry of Economy, Industry, and Competitiveness)

Hepatocellular carcinoma (HCC) is the most frequent subtype of primary liver cancer and one of the leading causes of cancer-related death worldwide. However, the molecular mechanisms underlying HCC pathogenesis have not been fully understood. Emerging evidences have recently suggested the crucial role of long noncoding RNAs (lncRNAs) in the tumorigenesis and progression of HCC. Various HCC-related lncRNAs have been shown to possess aberrant expression and participate in cancerous phenotypes (e.g. persistent proliferation, evading apoptosis, accelerated vessel formation and gain of invasive capability) through their binding with DNA, RNA or proteins, or encoding small peptides. Thus, a deeper understanding of lncRNA dysregulation would provide new insights into HCC pathogenesis and novel tools for the early diagnosis and treatment of HCC. In this review, we summarize the dysregulation of lncRNAs expression in HCC and their tumor suppressive or oncogenic roles during HCC tumorigenesis. Moreover, we discuss the diagnostic and therapeutic potentials of lncRNAs in HCC.

• Biomarker
• Hepatocellular carcinoma
• Long noncoding RNA
• Targeted therapy

Hepatocellular carcinoma (HCC) is a serious cancer which ranked the fourth in cancer-related death worldwide. Hence, more accurate diagnostic models are urgently needed to aid the early HCC diagnosis under clinical scenarios and thus improve HCC treatment and survival. Several conventional methods have been used for discriminating HCC from cirrhosis tissues in patients without HCC (CwoHCC). However, the recognition successful rates are still far from satisfactory. In this study, we applied a computational approach that based on machine learning method to a set of microarray data generated from 1091 HCC samples and 242 CwoHCC samples. The within-sample relative expression orderings (REOs) method was used to extract numerical descriptors from gene expression profiles datasets. After removing the unrelated features by using maximum redundancy minimum relevance (mRMR) with incremental feature selection, we achieved “11-gene-pair” which could produce outstanding results. We further investigated the discriminate capability of the “11-gene-pair” for HCC recognition on several independent datasets. The wonderful results were obtained, demonstrating that the selected gene pairs can be signature for HCC. The proposed computational model can discriminate HCC and adjacent non-cancerous tissues from CwoHCC even for minimum biopsy specimens and inaccurately sampled specimens, which can be practical and effective for aiding the early HCC diagnosis at individual level.

• REOs
• cirrhosis
• early diagnosis
• hepatocellular carcinoma
• mRMR
• support vector machine

MiR-10b, miR-335, and miR-21 are classes of microRNAs (miRNAs) that are overexpressed in breast cancer. Thus, in our study we aimed to test the hypothesis that miRNAs may have direct interactions with proteins and the possibility to inhibit/activate the functional site of proteins and enzymes. For this purpose, we choose three miRNAs involved in breast cancer to study interactions between some proteins and genes, including BRCA1 and PTEN, by processing the docking and matching tools using the Hex8 and HADDOCK server. Mathematically, the hidden Markov models were created by using MATLAB script according to the algorithm in order to study and validate the interactions and bonds between proteins and miRNAs. The main results demonstrate the ability of miR-10b, miR-335, and miR-21 to create direct interactions with 3D protein structures. Furthermore, these results may lead to another pathway of research, i.e. the direct interaction between proteins and their sub-units, to highlight the data obtained previously and demonstrate that proteins may directly interact with ncRNA instead of mRNA. Moreover, our study suggests developing research on different pathways of association proteins-miRNAs as a part of epigenetic extra-nuclear regulation. Taken together, our study provides the first evidence of direct interactions between miRNAs and proteins.

• breast cancer
• gene interactions
• miR-10b
• miR-21
• miR-335

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.

• HCC
• animal models
• microRNA

Hepatocellular carcinoma (HCC) is a lethal human malignancy and a leading cause of cancer‐related death worldwide. Patients with HCC are often diagnosed at an advanced stage, and the prognosis is usually poor. The multikinase inhibitor sorafenib is the first‐line treatment for patients with advanced HCC. However, cases of primary or acquired resistance to sorafenib have gradually increased, leading to a predicament in HCC therapy. Thus, it is critical to investigate the mechanism underlying sorafenib resistance. Transactivation response element RNA‐binding protein 2 (TARBP2) is a multifaceted miRNA biogenesis factor that regulates cancer stem cell (CSC) properties. The tumorigenicity and drug resistance of cancer cells are often enhanced due to the acquisition of CSC features. However, the role of TARBP2 in sorafenib resistance in HCC remains unknown. Our results demonstrate that TARBP2 is significantly downregulated in sorafenib‐resistant HCC cells. The TARBP2 protein was destabilized through autophagic–lysosomal proteolysis, thereby stabilizing the expression of the CSC marker protein Nanog, which facilitates sorafenib resistance in HCC cells. In summary, here we reveal a novel miRNA‐independent role of TARBP2 in regulating sorafenib resistance in HCC cells.

• Nanog
• TARBP2
• cancer stem cells
• hepatocellular carcinoma
• miRNA
• sorafenib resistance

• DDX5
• RNA helicase
• breast cancer
• p68

• biopsy
• cirrhosis
• early diagnosis
• hepatocellular carcinoma
• signature

• Hepatitis B virus infection
• Hepatitis B virus pathogenesis
• MicroRNAs
• Molecular mechanisms

• Cancer
• Cell proliferation
• Hepatocarcinoma
• RNA interference
• microRNA

Human microRNA-125a-5p (miR-125a) is expressed in most tissues where it downregulates the expression of membrane receptors or intracellular transductors of mitogenic signals, thus limiting cell proliferation. Expression of this miRNA generally increases with cell differentiation whereas it is downregulated in several types of tumors, such as breast, lung, ovarian, gastric, colon, and cervical cancers, neuroblastoma, medulloblastoma, glioblastoma, and retinoblastoma. In this study, we focused on hepatocellular carcinoma and used real-time quantitative PCR to measure miR-125a expression in 55 tumor biopsies and in matched adjacent non-tumor liver tissues. This analysis showed a downregulation of miR-125a in 80 % of patients, with a mean decrease of 4.7-fold. Comparison of miRNA downregulation with clinicopathological parameters of patients didn't yield significant correlations except for serum bilirubin. We then evaluated the expression of known targets of miR-125a and found that sirtuin-7, matrix metalloproteinase-11, and c-Raf were up-regulated in tumor tissue by 2.2-, 3-, and 1.7-fold, respectively. Overall, these data support a tumor suppressor role for miR-125a and encourage further studies aimed at the comprehension of the molecular mechanisms governing its expression, eventually leading to treatments to restore its expression in tumor cells.

• cell proliferation
• gene regulation
• hepatocellular carcinoma
• microRNA
• tumor

It has been well established that microRNAs (miRNAs) play important roles in biological processes. To comprehensively measure the altered miRNA expression, we presented the miRNA expression profile of gastric cancer using microarray. We identified 33 miRNAs that were significantly differentially regulated in gastric specimens compared to adjacent normal tissues, among which miR-9-3p expression are significantly down-regulated in gastric cancers. Next, a cohort of 100 gastric cancer tissues and matched normal tissues were enrolled. Kaplan–Meier and multivariate Cox survival analyses were applied to evaluate the prognostic value of miR-9-3p expression, and the result showed that patients with lower miR-9-3p expression level have significantly poorer overall survival. The expression level of miR-9-3p has been proved to be an independent prognostic factor for 5-year overall survival. Furthermore, the result indicated that over-expression of miR-9-3p can inhibit gastric cancer cell invasion. Taken together, our results suggested that miR-9-3p plays important role in tumor invasion, and these findings implicated the potential effects of miR-9-3p on prognosis of gastric cancer.

• cell invasion
• gastric cancer
• miR-9-3p
• microarray
• prognosis

Computational analysis and bioinformatics have significantly advanced the ability of researchers to process and analyze biological data. Molecular data from human and model organisms may facilitate drug target validation and identification of biomarkers with increased predictive accuracy. The aim of the present study was to investigate the function of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) using online databases, and to predict their regulatory mechanism. HCC-associated lncRNAs, their downstream transcription factors and microRNAs (miRNAs/miRs), as well as the HCC-associated target genes, were identified using online databases. HCC-associated lncRNAs, including HOX antisense intergenic RNA (HOTAIR) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were selected based on established databases of lncRNAs. The interaction between the HCC-associated lncRNAs and miRNAs (hsa-miR-1, hsa-miR-20a-5p) was predicted using starBase2.0. Signal transducer and activator of transcription 1, hepatocyte nuclear factor 4α (HNF4A), octamer-binding transcription factor 4, Nanog homeobox (NANOG), caudal type homeobox 2 (CDX2), DEAD-box helicase 5, brahma-related gene 1, MYC-associated factor X and MYC proto-oncogene, bHLH transcription factor have been identified as the transcription factors for HOTAIR and MALAT1 using ChIPBase. Additionally, CDX2, HNF4A, NANOG, ETS transcription factor, Jun proto-oncogene and forkhead box protein A1 were identified as the transcription factors for hsa-miR-1 and hsa-miR-20a-5p. CDX2, HNF4A and NANOG were the transcriptional factors in common between the lncRNAs and miRNAs. Cyclin D1, E2F transcription factor 1, epithelial growth factor receptor, MYC, MET proto-oncogene, receptor tyrosine kinase and vascular endothelial growth factor A were identified as target genes for the HCC progression, two of which were also the target genes of hsa-miR-1 and hsa-miR-20a-5p using the miRwalk and OncoDN. HCC databases. Additionally, these target genes may be involved in biological functions, including the regulation of cell growth, cell cycle progression and mitosis, and in disease progression, as demonstrated using DAVID clustering analysis. The present study aimed to predict a regulatory network of lncRNAs in HCC progression using bioinformatics analysis.

• bioinformatics
• hepatocellular carcinoma
• long non-coding RNA
• regulation network

Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. Despite the availability of a HBV vaccine, current treatments for HCC are inadequate. Globally, 257 million people are chronic HBV carriers, and children born from HBV-infected mothers become chronic carriers, destined to develop liver cancer. Thus, new therapeutic approaches are needed to target essential pathways involved in HCC pathogenesis. Accumulating evidence supports existence of hepatic cancer stem cells (hCSCs), which contribute to chemotherapy resistance and cancer recurrence after treatment or surgery. Understanding how hCSCs form will enable development of therapeutic strategies to prevent their formation. Recent studies have identified an epigenetic mechanism involving the downregulation of the chromatin modifying Polycomb Repressive Complex 2 (PRC2) during HBV infection, which results in re-expression of hCSC marker genes in infected hepatocytes and HBV-associated liver tumors. However, the genesis of hCSCs requires, in addition to the expression of hCSC markers cellular changes, rewiring of metabolism, cell survival, escape from programmed cell death, and immune evasion. How these changes occur in chronically HBV-infected hepatocytes is not yet understood. In this review, we will present the basics about HBV infection and hepatocarcinogenesis. Next, we will discuss studies describing the mutational landscape of liver cancers and how epigenetic mechanisms likely orchestrate cellular reprograming of hepatocytes to enable formation of hCSCs.

• Epigenetics
• Epithelial Cell Adhesion Molecule (EpCAM)
• Hepatitis B Virus (HBV)
• Hepatocellular Carcinoma (HCC)
• Hox transcript antisense RNA (HOTAIR)
• Polycomb Repressive Complex 2 (PRC2)
• hepatic Cancer Stem Cells (hCSCs)
• p68/DDX5 RNA helicase
• pluripotency genes

• P30 CA023168 NCI NIH HHS
• R01 DK044533 NIDDK NIH HHS

The role of Dicer in the prognosis of cancer patients remains controversial. This systematic review is attempted to assess the influence of Dicer as a prognostic predictor for survival in diverse types of cancers.

Studies were selected as candidates if they published an independent evaluation of Dicer expression level together with the correlation with prognosis in cancers. Random-effect model was applied in this meta-analysis. Heterogeneity between studies was assessed by Q-statistic with P < 0.10 to be statistically significant. Publication bias was investigated using funnel plot and test with Begg's and Egger's test. P < 0.05 was regarded as statistically significant.

24 of 44 articles revealed low Dicer status as a predictor of poor prognosis. The aggregate result of overall survival (OS) indicated that low Dicer expression level resulted in poor clinical outcomes, and subgroup of IHC and RT-PCR method both revealed the same result. Overall analysis of progression-free survival (PFS) showed the same result as OS, and both the two subgroups divided by laboratory method revealed positive results. Subgroup analysis by tumor types showed low dicer levels were associated with poor prognosis in ovarian cancer (HR = 1.93, 95% CI: 1.19-3.15), otorhinolaryngological tumors (HR = 2.39, 95% CI: 1.70-3.36), hematological malignancies (HR = 2.45, 95% CI: 1.69-3.56) and neuroblastoma (HR = 4.03, 95% CI: 1.91-8.50).

Low Dicer status was associated with poor prognosis in ovarian cancer, otorhinolaryngological tumors and ematological malignancies. More homogeneous studies with high quality are needed to further confirm our conclusion and make Dicer a useful parameter in clinical application.

• Dicer
• cancer
• hazard ratio
• meta-analysis
• prognosis

Global dysregulation of microRNAs (miRNAs), a class of non-coding RNAs that regulate genes expression, is a common feature of human tumors. Profiling of cellular miRNAs on Adult T cell Leukemia (ATL) cells by Yamagishi et al. showed a strong decrease in expression for 96.7% of cellular miRNAs in ATL cells. However, the mechanisms that regulate the expression of miRNAs in ATL cells are still largely unknown. In this study, we compared the expression of 12 miRs previously described for being overexpress by Tax and the expression of several key components of the miRNAs biogenesis pathways in different HBZ expressing cell lines as well as in primary CD4 (+) cells from acute ATL patients. We showed that the expression of miRNAs and Dicer1 were downregulated in cells lines expressing HBZ as well as in fresh CD4 (+) cells from acute ATL patients. Using qRT-PCR, western blotting analysis and Chromatin Immunoprecipitation, we showed that dicer transcription was regulated by c-Jun and JunD, two AP-1 transcription factors. We also demonstrated that HBZ affects the expression of Dicer by removing JunD from the proximal promoter. Furthermore, we showed that at therapeutic concentration of 1mM, Valproate (VPA) an HDAC inhibitors often used in cancer treatment, rescue Dicer expression and miRNAs maturation. These results might offer a rationale for clinical studies of new combined therapy in an effort to improve the outcome of patients with acute ATL.

• AP-1
• Dicer
• HBZ
• JunD
• miRNAs

Alu sequences are the most abundant short interspersed repeated elements in the human genome. Here we show that in a cell culture model of colorectal cancer (CRC) progression, we observe accumulation of Alu RNA that is associated with reduced DICER1 levels. Alu RNA induces epithelial-to-mesenchymal transition (EMT) by acting as a molecular sponge of miR-566. Moreover, Alu RNA accumulates as consequence of DICER1 deficit in colorectal, ovarian, renal and breast cancer cell lines. Interestingly, Alu RNA knockdown prevents DICER1 depletion-induced EMT despite global microRNA (miRNA) downregulation. Alu RNA expression is also induced by transforming growth factor-β1, a major driver of EMT. Corroborating this data, we found that non-coding Alu RNA significantly correlates with tumor progression in human CRC patients. Together, these findings reveal an unexpected DICER1-dependent, miRNA-independent role of Alu RNA in cancer progression that could bring mobile element transcripts in the fields of cancer therapeutic and prognosis.

MicroRNA-125a-5p (miR-125a) is a vertebrate homolog of lin-4, the first discovered microRNA, and plays a fundamental role in embryo development by downregulating Lin-28 protein. MiR-125a is also expressed in differentiated cells where it generally acts as an antiproliferative factor by targeting membrane receptors or intracellular transductors of mitogenic signals. MiR-125a expression is downregulated in several tumors, including hepatocellular carcinoma (HCC) where it targets sirtuin-7, matrix metalloproteinase-11, VEGF-A, Zbtb7a, and c-Raf. In this study, we have isolated the transcription promoter of human miR-125a and characterized its activity in HCC cells. It is a TATA-less Pol II promoter provided with an initiator element and a downstream promoter element, located 3939 bp upstream the genomic sequence of the miRNA. The activity of the promoter is increased by the transcription factor NF-kB, a master regulator of inflammatory response, and miR-125a itself was found to strengthen this activation through inhibition of TNFAIP3, a negative regulator of NF-kB. This finding contributes to explain the increased levels of miR-125a observed in the liver of patients with chronic hepatitis B.

• DICER
• hepatocellular carcinoma (HCC)
• microRNA
• prognostic biomarker
• single nucleotide polymorphism (SNP)

• Biomarkers/blood
• Carcinoma, Hepatocellular/genetics
• Gene Expression Regulation
• Humans
• Liver/metabolism
• Liver/pathology
• Liver Diseases/genetics
• Liver Neoplasms/genetics
• MicroRNAs/blood
• MicroRNAs/genetics
• Models, Genetic
• Non-alcoholic Fatty Liver Disease/genetics

Tobacco and alcohol are the leading environmental risk factors in the development of human diseases, such as cancer, cardiovascular disease, and liver injury. Despite the copious amount of research on this topic, by 2030, 8.3 million deaths are projected to occur worldwide due to tobacco use. The expression of noncoding RNAs, primarily microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), is modulated by tobacco and alcohol consumption. Drinking alcohol and smoking cigarettes can modulate the expression of miRNAs and lncRNAs through various signaling pathways, such as apoptosis, angiogenesis, and inflammatory pathways—primarily interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), which seems to play a major role in the development of diseases associated with these risk factors. Since they may be predictive and prognostic biomarkers, they can be used both as predictors of the response to therapy and as a targeted therapy. Further, circulating miRNAs might be valuable noninvasive tools that can be used to examine diseases that are related to the use of tobacco and alcohol. This review discusses the function of noncoding RNAs in cancer and other human tobacco- and alcohol-associated diseases.

• alcohol
• cancer
• cardiovascular diseases
• chronic obstructive pulmonary disease
• long noncoding RNAs
• microRNAs
• noncoding RNAs
• tobacco

Single-nucleotide polymorphisms (SNPs) in microRNA machinery genes might affect microRNA processing and subsequently impact tumorigenesis. The aim of this study was to investigate the associations between SNPs in microRNA machinery genes and hepatocellular carcinoma (HCC) in a Korean population. Genotyping of six SNPs in microRNA machinery genes was performed using blood samples from 147 patients with HCC and 209 healthy control subjects. None of the six SNPs in microRNA machinery genes were significantly associated with HCC development. However, among the models for six polymorphic loci—DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), RAN (rs14035) and XPO5 (rs11077)—one allele combination (A-A-T-C-C-C) showed synergistic effects in terms of an increased risk of HCC development (odds ratio = 8.881, 95% confidence interval [CI] = 1.889–41.750; P = 0.002). Multivariate Cox proportional hazard regression analysis showed a significant survival benefit for the DICER rs3742330 GG compared with the AA type (hazard ratio [HR], 0.314; 95% CI, 0.135–0.730; P = 0.007) and for the RAN rs14035 CT compared with the CC genotype (HR, 0.587; 95% CI, 0.349–0.987; P = 0.044). Although we found no direct association between DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), RAN (rs14035) or XPO5 (rs11077) polymorphisms and HCC risk, we demonstrated that DICER (rs3742330) and RAN (rs14035) were associated with the survival of HCC patients. Future studies with larger samples are needed to determine associations of SNPs in microRNA machinery genes with HCC risk and prognosis.

Dicer is a RNaseIII endonuclease of the microRNA processing pathway, which is implicated in carcinogenesis of various types of human cancer. The present study assessed the expression level of Dicer in hepatocellular carcinoma (HCC) tissue to evaluate its association with HCC tumorigenesis. A low expression of Dicer was significantly associated with a shorter postoperative survival time of patients with HCC, which was assessed using the log-rank test with Kaplan-Meier survival analysis. Multivariate analysis identified that Dicer expression was an independent predictor for HCC outcome (relative risk, 0.660; 95% confidence interval, 0.506–0.861; P=0.002). A functional assay demonstrated that Dicer overexpression inhibited the proliferation and promoted the apoptosis of HCC cells. In addition, a Transwell assay revealed that Dicer markedly inhibited the migration and invasion of HCC cells. The present findings indicate that Dicer expression modified the outcomes of HCC patients by inhibiting proliferation, promoting apoptosis and inhibiting metastasis of HCC cells.

• Dicer
• apoptosis
• hepatocellular carcinoma
• metastasis
• microRNA
• proliferation

DGCR8 (DiGeorge syndrome critical region gene 8) is essential for primary microRNA (pri-miRNA) processing in the cell nucleus. It specifically combines with Drosha, a nuclear RNase III enzyme, to form the Microprocessor complex (MC) that cleaves pri-miRNA to precursor miRNA (pre-miRNA), which is further processed to mature miRNA by Dicer, a cytoplasmic RNase III enzyme. Increasing evidences suggest that pri-/pre-miRNAs have direct functions in regulation of gene expression, however the underlying mechanism how it is fine-tuned remains unclear. Here we find that DGCR8 is modified by SUMO1 at the major site K⁷⁰⁷, which can be promoted by its ERK-activated phosphorylation. SUMOylation of DGCR8 enhances the protein stability by preventing the degradation via the ubiquitin proteasome pathway. More importantly, SUMOylation of DGCR8 does not alter its association with Drosha, the MC activity and miRNA biogenesis, but rather influences its affinity with pri-miRNAs. This altered affinity of DGCR8 with pri-miRNAs seems to control the direct functions of pri-miRNAs in recognition and repression of the target mRNAs, which is evidently linked to the DGCR8 function in regulation of tumorigenesis and cell migration. Collectively, our data suggest a novel mechanism that SUMOylation of DGCR8 controls direct functions of pri-miRNAs in gene silencing.

• Animals
• Carcinogenesis
• Cell Line
• Cell Movement
• Cells, Cultured
• Humans
• Lysine/metabolism
• Mice
• Mice, Nude
• MicroRNAs/metabolism
• Neoplasms/metabolism
• Neoplasms/physiopathology
• Phosphorylation
• Protein Stability
• RNA-Binding Proteins/chemistry
• RNA-Binding Proteins/metabolism
• SUMO-1 Protein/metabolism
• Sumoylation
• Ubiquitination