Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been shown to play a critical role in the development of several malignancies. However, the potential molecular mechanism of MALAT1 in glioma remains unclear. In the present study, we found that the expression of MALAT1 was aberrantly increased in both human glioma tissues and cells and associated with poor prognosis in glioma patients. We further found that MALAT1 silencing significantly inhibited glioma cell proliferation while induced cell cycle arrest and apoptosis. In parallel, knockdown of MALAT1 decreased tumor volume in vivo. These results suggested that MALAT1 acts as a functional oncogene, resulting in the oncogenicity in glioma. Nevertheless, the tumor-suppressive effect of MALAT1 silencing was reversed by miR-124. Besides, the relevance of ZEB2 in tumor progression has been studied in several forms of human cancer, and ZEB2 was identified as a target of miR-124 and negatively regulated by miR-124. MALAT1 overexpression or miR-124 inhibitor led to increased expression of ZEB2. In summary, our study depicts a novel pathway of MALAT1/miR-124/ZEB2 that regulates the progression of glioma and might provide a promising strategy for glioma therapy.

Keywords: Glioma; LncRNA; MALAT1; ZEB2; miR-124.

Proinflammatory factor tumor necrosis factor-α (TNF-α) is an important inflammatory mediators in tumor microenvironment and autoimmune diseases, it is highly expressed in many solid tumors and tumor microenvironment, showing a tumor promoting role. However, the molecular mechanisms underlying TNF-α-increased invasion of thyroid cancer are still not fully understood. In order to explore whether TNF-α plays a key role in the process of epithelial mesenchymal transition (EMT) in papillary thyroid carcinoma (PTC), we used TNF-α to induce EMT in different PTC cell lines, and observed the expression of different transcription factors and signal pathways. After TNF-α treatment, in TPC-1, Snail and ZEB2 mRNA levels did not change significantly, while Slug, Twist1, ZEB1 mRNA expression increased. In BCPAP, Snail mRNA level increased significantly (P < 0.01), while Twist1 showed a certain degree of increase only at the concentration of TNF - α 20 ng / ml (P < 0.01), but mRNA of Slug, ZEB1, ZEB2 showed no significant change. The expression of proteins was consistent with genes. The activation of different pathways did not show gene differences, and pathway inhibitors could reduce the invasion and metastasis of cells, but only NF-κB inhibitors could reverse the expression of transcription factors. Expressions of Snail and Slug in different PTC cell lines were dependent on pro-oncogene mutation, but the pathway had no differences. The establishment of this study model can enrich the research on the pathogenesis and metastasis of thyroid cancer, effectively link the inflammatory microenvironment with the occurrence and development of thyroid cancer.

Keywords: EMT; NF-κB; PTC; TNF-α; transcription factors..

Benzalkonium chloride (BAC), an antimicrobial agent in inhalable medications and household sprays, has been reported to be toxic to pulmonary organs. Although cell membrane damage has been considered as the main cytotoxic mechanism of BAC, its concentration- and time-dependent cellular effects on lung epithelium have not been fully understood. In the present study, human lung epithelial (H358) cells were exposed to 0.2-40 μg/mL of BAC for 30 min or 21 days. Cell membranes were rapidly disrupted by 30 min exposure, but 24 h incubation of BAC (4-40 μg/mL) predominantly caused apoptosis rather than necrosis. BAC (2-4 μg/mL) induced mitochondrial depolarization, which may be associated with increased expression of pro-apoptotic proteins (caspase-3, PARP, Bax, p53, and p21), and decreased levels of the anti-apoptotic protein Bcl-2. The protein expression levels of IRE1α, BiP, CHOP, and p-JNK were also elevated by BAC (2-4 μg/mL) suggesting the possible involvement of endoplasmic reticulum stress in inducing apoptosis. Long-term (7-21 days) incubation with BAC (0.2-0.6 μg/mL) did not affect cell viability but led to epithelial-mesenchymal transition (EMT) as shown by the decrease of E-cadherin and the increase of N-cadherin, fibronectin, and vimentin, caused by the upregulation of EMT transcription factors, such as Snail, Slug, Twist1, Zeb1, and Zeb2. Therefore, we conclude that apoptosis could be an important mechanism of acute BAC cytotoxicity in lung epithelial cells, and chronic exposure to BAC even at sub-lethal doses can promote pulmonary EMT.

Bladder cancer (BCa) is one of the most common urinary malignancies in the world. Growing evidence suggests that epithelial-to-mesenchymal transition (EMT) is a major contributor for BCa metastasis. lncRNA small nucleolar RNA host gene 16 (SNHG16) has been reported as a tumor promoter in many cancers. This study aims to investigate the function and mechanism of SNHG16 on EMT in BCa. Quantitative RT-PCR (qRT-PCR) was used to determine the expression of SNHG16 in human BCa tissues and TGF-β-induced cells. Western blot (WB) was performed to evaluate the expression of EMT-related proteins. Transwell assay was exerted to assess the migration and invasion ability of SNHG16 in BCa. RNA pull-down assay was conducted to confirm the RNA-RNA interaction. The precise mechanism by which SNHG16 regulated EMT process in BCa was also explored. SNHG16 was found up-regulated in TGF-β-induced BCa cells and BCa tissues. Transwell assay showed that overexpression of SNHG16 significantly promoted the migration and invasion of BCa cells, whereas knock-down of SNHG16 caused the opposite effects. Then, the interaction between SNHG16 and miR-200a-3p was verified by dual-luciferase reporter assay and RNA pull-down assay. And the effects of knock-down or overexpression of SNHG16 on migration and invasion were reversed by co-transfecting miR-200a-3p inhibitors or mimics. This study first demonstrated that SNHG16 was responsible for EMT of BCa cells via miR-200a-3p/ ZEB1/ZEB2 axis. These results provided a potential therapeutic strategy for BCa treatment, especially in metastatic BCa.

Early Infantile Epileptic Encephalopathy (EIEE) presents shortly after birth with frequent, severe seizures, a burst-suppression EEG pattern, and progressive disturbance of cerebral function. We present a case of EIEE associated with a de novo missense variant in ZEB2. Heterozygous truncating mutations or deletions in ZEB2 are known to cause Mowat-Wilson syndrome (MWS), which is characterized by seizures with onset in the second year of life, distinctive dysmorphic facial features and malformations that were absent in this patient. This unique case expands the range of phenotypes associated with variants in ZEB2 and indicates that this gene should be included in the molecular investigation of EIEE cases.

It is one of the important events that trophoblast cells within the placental folds differentiate into two types that differ in cell shape during placental development in pigs. This study showed that all the trophoblast cells were of similar shape between Yorkshire and Chinese Meishan pigs on day 26 of gestation; thereafter, the trophoblast cells located at the top of the placental folds became high columnar, while those cells at the base of the placental folds were cuboidal on day 50 of gestation. Additionally, on day 95 of gestation, all the trophoblast cells in Meishan pigs became cuboidal, but the trophoblast cells located at the top of the placental folds in Yorkshire pigs still remained columnar. The membranous E-cadherin and β-catenin were strongly co-expressed by the high columnar trophoblast cells but very weakly expressed by those cuboidal cells. Consistently, the expression pattern of ZEB2, the E-cadherin repressor, was inversely correlated with that of E-cadherin in the two types of trophoblast cells in the two breeds. Furthermore, electrophoretic mobility shift assays demonstrated the binding of ZEB2 to the E-cadherin promoter in nuclear extracts from porcine placental tissue. These findings suggest a ZEB2-dependent mechanism of trophoblast cell differentiation during placental development in pigs.

Mowat-Wilson syndrome (OMIM 235730) is a genetic condition characterized by moderate-to-severe intellectual disability, a recognizable facial phenotype, and multiple congenital anomalies. The striking facial phenotype in addition to other features such as severely impaired speech, hypotonia, microcephaly, short stature, seizures, corpus callosum agenesis, congenital heart defects, hypospadias, and Hirschsprung disease are particularly important clues for the initial clinical diagnosis. All molecularly confirmed cases with typical MWS have a heterozygous loss-of-function mutation in the zinc finger E-box protein 2 (ZEB2) gene, also called SIP1 (Smad-interacting protein 1) and ZFHX1B, suggesting that haploinsufficiency is the main pathological mechanism. Approximately 80% of mutations are nonsense and frameshift mutations (small insertions or deletions). About half of these mutations are located in exon eight. Here, we report the first Indonesian patient with Mowat-Wilson syndrome confirmed by molecular analysis.

Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations. The cause of MWS is a de novo mutation in the ZEB2 gene. This report describes a Turkish boy who was clinically diagnosed with MWS and had his diagnosis confirmed by molecular analysis of the ZEB2 gene. The investigation identified a heterozygous complex rearrangement in exon 8 of ZEB2, specifically a 48-nucleotide deletion and a 44-nucleotide insertion that caused a frameshift. MWS is a relatively newly identified disorder, and even MWS patients without Hirschsprung disease can be diagnosed easily based on clinical findings alone.

Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome characterised by unique facial features and congenital anomalies such as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and urinary tract anomalies. Some cases also present epilepsy, growth retardation and microcephaly. The syndrome is caused by mutations or deletions of the ZEB2 gene at chromosome 2q22-q23. MWS was first described in 1998 and until now approximately 180 cases have been reported worldwide. We report the first three molecularly confirmed Danish cases with MWS.

Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene rarely diagnosed prenatally and with little fetal description reported. It is mainly characterized by moderate-to-severe intellectual disability, epilepsy, facial dysmorphism and various malformations including Hirschsprung disease and corpus callosum anomalies. Here we report a fetal case of MWS well described, suspected at standard autopsy. The association of a corpus callosum hypoplasia with a histological Hirschsprung disease and a typical facial gestalt allowed the guiding of genetic testing. Classical fetopathological examination still keeps indications in cases of syndromic association in the era of virtual autopsy.

Smad-interacting protein-1 (Sip1) [Zinc finger homeobox (Zfhx1b), Zeb2] is a transcription factor implicated in the genesis of Mowat-Wilson syndrome (MWS) in humans. MWS is a rare genetic autosomal dominant disease caused by a mutation in the Sip1 gene (aka Zeb2 or Zfhx1b) mapped to 2q22.3 locus. MWS affects 1 in every 50-100 newborns worldwide. It is characterized by mental retardation, small stature, typical facial abnormalities as well as disturbances in the development of the cardio-vascular and renal systems as well as some other organs. Sip1 mutations cause abnormal neurogenesis in the brain during development as well as susceptibility to epileptic seizures. In the current study we investigated the role of the Sip1 gene in the activity of NMDA-, AMPA- and KA- receptors. We showed that a particular Sip1 mutation in the mouse causes changes in the activity of both NMDA- and AMPA- receptors in the neocortical neurons in vitro. We demonstrate that neocortical neurons that have only one copy of Sip1 (heterozygous, Sip1fI/wt), are more sensitive to both NMDA- and AMPA- receptors agonists as compared to wild type neurons (Sip1wt/wt). This is reflected in higher amplitudes of agonist induced Ca2+ signals as well as a lower half maximal effective concentration (ЕC50). In contrast, neurons from homozygous Sip1 mice (Sip1fI/fI), demonstrate higher resistance to these respective receptor agonists. This is reflected in lower amplitudes of Ca2+-responses and so a higher concentration of receptor activators is required for activation.

Individuals with Mowat-Wilson syndrome (MWS; OMIM#235730) have characteristic facial features, a variety of congenital anomalies such as Hirschsprung disease, and intellectual disabilities caused by mutation or deletion of ZEB2 gene. This deletion or cytogenetic abnormality has been reported primarily from Europe, Australia and the United States, but not in Korea. Here we report a patient with characteristic facial features of MWS, developmental delay and spasticity. High resolution microarray analysis revealed 0.9 Mb deletion of 2q22.3 involving two genes: ZEB2 and GTDC1. This case shows the important role of high resolution microarray in patients with unexplained psychomotor retardation and/or facial dysmorphism. Knowledge about the most striking clinical signs and implementation of effective molecular tests like microarray could significantly increase the detection rate of new cases of MWS in Korea. This is the first reported case of MWS in Korea.

UNASSIGNED

The Forkhead transcription family member FOXA2 plays a fundamental role in hepatocellular carcinoma (HCC) progression, but the precise interaction factor and molecular regulation of FOXA2 are not fully understood.

UNASSIGNED

In this study, we found that FOXA2 could interact with sirtuin 6 (SIRT6) directly in vivo and in vitro. We explored that the expressions of FOXA2 and SIRT6 were significantly downregulated in human HCC and HCC cell lines.

UNASSIGNED

Functionally, cell counting kit-8 assay and Transwell® assay were performed; we demonstrated that the knockdown of FOXA2 and SIRT6 promoted HepG2 cells and Huh7 cells proliferation and invasion in vitro.

UNASSIGNED

Mechanically, using luciferase reporter assay and fast chromatin immunoprecipitation assay, we showed that FOXA2 and SIRT6 regulated the expression of ZEB2 from transcription level. ZEB2 suppression was involved in the anti-oncogenesis effect of FOXA2 and SIRT6. The negative correlation between the expressions of ZEB2 and FOXA2 or SIRT6 was observed in the tissues of HCC patients.

UNASSIGNED

Our findings indicated that the coordination function of FOXA2 and SIRT6 played a critical role in HCC progression and may serve as potential drug candidates for HCC.

The transcription factors Twist, Snail, Slug, ZEB1 and ZEB2 regulate epithelial-mesenchymal transition (EMT) and their expression has been associated with a poor prognosis in several cancer entities. The aim of this analysis was to investigate in parallel the expression of all of these transcription factors in head and neck squamous cell carcinomas (HNSCCs) in order to gain insight into their possible co-expression.

Tumor tissue samples were immunohistochemically stained using antibodies against these transcription factors. The staining intensity and cellular distribution of the immunoreactivity was recorded.

In general, transcription factor immunoreactivity was noted in the nucleus of both cancer and stromal cells. The highest immunoreactivity was observed for Twist. Snail, Slug, ZEB1 and ZEB2 showed a much lesser immunoreactivity in cancer cells and they were expressed independently from each other.

Twist is the major transcription factor active in HNSCC; the other transcription factors of EMT seem to be of less importance in this tumor entity.

Objective- It is unclear to what extent genetic susceptibility variants are shared between peripheral artery disease (PAD) and coronary heart disease (CHD), both manifestations of atherosclerotic vascular disease. We investigated whether common and low-frequency/rare variants in loci associated with CHD are also associated with PAD. Approach and Results- Targeted sequencing of 41 genomic regions associated with CHD in genome-wide association studies was performed in 1749 PAD cases (65±11 years, 61% men) and 1855 controls (60±11 years, 56% men) of European ancestry. PAD cases had a resting/postexercise ankle-brachial index ≤0.9, or history of lower extremity revascularization; controls had no history of PAD. We tested the association of common (defined as minor allele frequency ≥5%) variants with PAD assuming an additive genetic model with adjustment for age and sex. To identify low-frequency/rare variants (minor allele frequency <5%) associated with PAD, we conducted gene-level analyses using sequence kernel association test and permutation test. After Bonferroni correction, we found common variants in SH2B3, ABO, and ZEB2 to be associated with PAD ( P<4.5×10^-5). At the gene level, the strongest associations were for LPL and SH2B3. Conclusions- Targeted sequencing of 41 genomic regions associated with CHD revealed several common variants/genes to be associated with PAD, highlighting the basis of shared genetic susceptibility between CHD and PAD.

The identification of the rare but recurrent t(2; 14)(q22; q32) translocation involving the ZEB2 locus in T-cell acute lymphoblastic leukemia, suggested that ZEB2 is an oncogenic driver of this high-risk subtype of leukemia. ZEB2, a zinc finger E-box homeobox binding transcription factor, is a master regulator of cellular plasticity and its expression is correlated with poor overall survival of cancer patients. Recent loss- and gain-of-function in the mouse revealed important roles of ZEB2 during different stages of hematopoiesis, including the T-cell lineage. Here, we summarize the roles of ZEB2 in T-cells, their development, and malignant transformation to T-ALL.

Background/aim: Both pediatric glioblastoma (pGB) and adult glioblastoma (aGB) are clinically devastating, and are known to have different molecular pathogenesis. Here, we focused on the role of ZEB2 in pGB and aGB.

Materials and methods: Following transfection with ZEB2 siRNA into pGB cells (KNS42) and aGB cells (U87 and U373), cell proliferation, migration and invasion, and cell cycle progression were evaluated.

Results: Targeted inhibition of ZEB2 induced up-regulation of E-cadherin expression and down-regulation of vimentin expression. Furthermore, it reduced invasion and migration of both pGB and aGB cells. Interestingly, in pGB cells, but not in aGB cells, silencing of ZEB2 reduced cell proliferation and viability, and affected the cell cycle progression of tumor cells.

Conclusion: Inhibition of ZEB2 altered the mesenchymal features and reduced the migration and invasive ability of both pGB and aGB cells. ZEB2 effects were different in pGB and aGB cells regarding proliferation and cell cycle progression, suggesting that different underlying molecular mechanisms drive progression in these two types of tumors.

Keywords: Adult glioblastoma (aGB); pediatric glioblastoma (pGB); zinc finger E-box-binding homeobox 2 (ZEB2).

Purpose: Previously, we found that long non-coding RNA (lncRNA) MEG3 may act as a tumour suppressor in retinoblastoma. Overall, however, little is known about the role of lncRNAs in retinoblastoma. Here, we aimed to determine the expression and clinical significance of lnc00152 in retinoblastoma.

Methods: Lnc00152 and its downstream targets were selected using GEO datasets. The level of lnc00152 in primary patient samples was determined using RT-qPCR. Odds ratios of invasion and metastasis were calculated using logistic regression analysis. Recurrence-free survival was assessed using Cox regression analysis. Scratch wound healing, transwell and tumorigenesis assays were used to determine migration and invasion abilities of retinoblastoma cells in vitro and in vivo. Levels of EMT-related proteins were measured using Western blotting. Binding sites between lnc00152 and its targets were validated using dual-luciferase reporter and RNA pull-down assays. Lnc00152 activating transcription factors were determined using ChIP assays.

Results: We found that Lnc00152 was significantly up-regulated in retinoblastoma tumour tissues, and was a risk factor for tumour invasion, metastasis and recurrence. Lnc00152 overexpressing retinoblastoma cells exhibited a tendency to transform into mesenchymal cells, with significantly increased migration and invasion capacities, significantly decreased E-cadherin expression levels, and significantly increased N-cadherin, SOX9 and ZEB2 expression levels. In addition, we found that lnc00152, which was activated by Sp1, could inhibit miR-30d as an endogenous miRNA 'sponge', thereby regulating the expression of SOX9 and ZEB2.

Conclusions: Our data indicate that Lnc00152 may be associated with retinoblastoma invasion, metastasis and prognosis. In addition, we conclude that Lnc00152, which can be activated by Sp1, can induce EMT via the miR-30d/SOX9/ZEB2 pathway and, by doing so, promote the invasion and metastasis of retinoblastoma cells.

Keywords: EMT; Retinoblastoma; Sp1 protein; lnc00152; lncRNA; miR-30d.

BACKGROUND

Mowat Wilson syndrome (MWS) is an uncommon association of Hirschsprung's disease (HSCR). Phenotypic features may develop with time, causing initial difficulties in diagnosis. MWS results from haploinsufficiency of the Zinc finger E-box-binding homeobox 2 (ZEB2) gene, and molecular diagnosis of ZEB2 mutation is required to confirm the diagnosis. We report the first confirmed cases of MWS in three children with the typical facial features, mental retardation, absent corpus callosum, epilepsy, and HSCR and novel Zeb2 variations on DNA analysis.

METHODS

Clinical features were monitored. DNA extracted from peripheral blood was subjected to bidirectional sequencing analysis following PCR DNA amplification. ZEB2 gene results were compared to the ZEB2 reference sequence (ENS00000169554) for variation. Bioinformatic investigation of novel gene variants was via the "Blastx" program function available via the National Center for Biotechnology Information (http://www.bioinfo.org/NPInter/blast/blast_link.cgi).

RESULTS

Clinical follow-up showed that the phenotypic features were not all present at birth but developed with time in 2 surviving patients. Several Zeb2 variations were detected in the promoter region of the ZEB2 gene of which 2 were novel (-56A/T 1174 11A/12A). In addition, a novel heterozygous single nucleotide insertion in exon 2 of ZEB2 in one patient results in a frameshift causing deletion of the first 8 amino acids of the ZEB2 protein and an alteration of amino acids 9 (G9A), 11 (R11G), and 12 (C12A). In the third patient, a novel single nucleotide deletion exon 8 (1784delC Het) results in a frameshift at amino acid 595 of translated protein. This shortens protein from 1214 to 594 amino acids and affects the functionality of the critical ZEB2 protein.

CONCLUSIONS

MWS is an important link to recognise clinically. It underlines the functionality of the Zeb2 gene in certain syndromic Hirschsprung's disease. These variations probably contribute to the clinical features of the Mowat Wilson phenotype in Hirschsprung's disease but should be confirmed in further research.

BACKGROUND

Brain hypoplasia and mental retardation in Down syndrome (DS) can be attributed to a severe and selective disruption of neurogenesis. Secondary disruption of the transcriptome, as well as primary gene dosage imbalance, is responsible for the phenotype. MicroRNA (miRNA) expression is relatively abundant in brain tissue. Perturbed miRNA expression might contribute to the cellular events underlying the pathology in DS.

METHODS

MiRNA expression profiles in the cerebrum of Ts65Dn mice, a DS model, were examined with a real-time RT-PCR array. MiRNA target gene expression was detected by real-time quantitative PCR and Western blotting. Based on the prediction of their cerebrum-specific targets, the functions of the misregulated miRNAs were annotated by Gene Ontology (GO) enrichment analysis.

RESULTS

A total of 342 miRNAs were examined. Among them, 20 miRNAs showed decreased expression in the brains of Ts65Dn mice, and some of these belonged to the same family. Two known targets of the miR-200 family, Lfng and Zeb2, were specifically selected to compare their expression in the cerebrum of Ts65Dn mice with those of euploids. However, no significant difference was found in terms of mRNA and protein expression levels of these genes. By enrichment analysis of the cerebrum-specific targets of each miRNA, we found that 15 of the differential miRNAs could significantly affect target genes that were enriched in the GO biological processes related to nervous system development.

CONCLUSIONS

Perturbed expression of multiple functionally cooperative miRNAs contributes to the cellular events underlying the pathogenesis of DS.

Following cardiac injury, fibroblasts are activated and are termed as myofibroblasts, and these cells are key players in extracellular matrix (ECM) remodeling and fibrosis, itself a primary contributor to heart failure. Nutraceuticals have been shown to blunt cardiac fibrosis in both in-vitro and in-vivo studies. However, nutraceuticals have had conflicting results in clinical trials, and there are no effective therapies currently available to specifically target cardiac fibrosis. We have previously shown that expression of the zinc finger E box-binding homeobox 2 (Zeb2) transcription factor increases as fibroblasts are activated. We now show that Zeb2 plays a critical role in fibroblast activation. Zeb2 overexpression in primary rat cardiac fibroblasts is associated with significantly increased expression of embryonic smooth muscle myosin heavy chain (SMemb), ED-A fibronectin and α-smooth muscle actin (α-SMA). We found that Zeb2 was highly expressed in activated myofibroblast nuclei but not in the nuclei of inactive fibroblasts. Moreover, ectopic Zeb2 expression in myofibroblasts resulted in a significantly less migratory phenotype with elevated contractility, which are characteristics of mature myofibroblasts. Knockdown of Zeb2 with siRNA in primary myofibroblasts did not alter the expression of myofibroblast markers, which may indicate that Zeb2 is functionally redundant with other profibrotic transcription factors. These findings add to our understanding of the contribution of Zeb2 to the mechanisms controlling cardiac fibroblast activation.

Non-small-cell lung cancer (NSCLC) is an aggressive neoplasm with a poor survival and novel therapies are urgently needed. The study of deregulated micro- RNAs (dereg-miRs) could constitute a strategy helping to detect specific genes playing a relevant role in the disease. Thus, the oncoproteins encoded by these genes could be exploited as novel therapeutic targets to be inhibited by small molecules, aptamers, or monoclonal antibodies.

The present review is focused on candidate genes having convincing biological evidences to be both bona fide targets for dereg-miRs and playing a role in NSCLC progression. These genes were evaluated according to the molecular pathway they belong. Moreover, in the attempt to provide an even broader list of candidate therapeutic targets for NSCLC, the full list of genes was analyzed using the online tool Interactome DB.

Among the identified targets, some of them belong to p53 or MAP kinase signaling pathways, and others include caspases, MCL1, and BCL2L2 (playing a role in apoptosis), ZEB1, ZEB2, and USP25 (epithelial-to-mesenchymal transition), EZH2, SOX9, and HOXA5 (differentiation), Paxillin, LIMK1 and MTDH (cytoskeleton remodeling), and HDGF (angiogenesis). In addition, other targets, such as TIMP-2, PIM-1, and components of the IGF-signaling pathways were suggested following the interactome analysis.

Studies on dereg-miRs helped to identify a set of genes whose encoded proteins could constitute candidates for future therapeutic approaches.