Competitive endogenous RNA networks: Decoding the role of long non-coding RNAs and circular RNAs in colorectal cancer chemoresistance.

Colorectal cancer (CRC) is recognized as one of the most common gastrointestinal malignancies across the globe. Despite significant progress in designing novel treatments for CRC, there is a pressing need for more effective therapeutic approaches. Unfortunately, many patients undergoing chemotherapy develop drug resistance, posing a significant challenge for cancer treatment. Non-coding RNAs (ncRNAs) have been found to play crucial roles in CRC development and its response to chemotherapy. However, there are still gaps in our understanding of interactions among various ncRNAs, such as long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs). These ncRNAs can act as either oncogenes or tumour suppressors, affecting numerous biological functions in different cancers including CRC. A class of ncRNA molecules known as competitive endogenous RNAs (ceRNAs) has emerged as a key player in various cellular processes. These molecules form networks through lncRNA/miRNA/mRNA and circRNA/miRNA/mRNA interactions. In CRC, dysregulation of ceRNA networks has been observed across various cellular processes, including proliferation, apoptosis and angiogenesis. These dysregulations are believed to play a significant role in the progression of CRC and, in certain instances, may contribute to the development of chemoresistance. Enriching our knowledge of these dysregulations holds promise for advancing the field of diagnostic and therapeutic modalities for CRC. In this review, we discuss lncRNA- and circRNA-associated ceRNA networks implicated in the emergence and advancement of drug resistance in colorectal carcinogenesis.

Exosomes released by oxidative stress-induced mesenchymal stem cells promote murine mammary tumor progression through activating the STAT3 signaling pathway.

Mesenchymal stem cells (MSCs) may play a pivotal role in shaping the tumor microenvironment (TME), influencing tumor growth. Nonetheless, conflicting evidence exists regarding the distinct impacts of MSCs on tumor progression, with some studies suggesting promotion while others indicate suppression of tumor cell growth. Considering that oxidative stress is implicated in the dynamic interaction between components of the TME and tumor cells, we investigated the contribution of exosomes released by hydrogen peroxide (H2O2)-treated MSCs to murine mammary tumor growth and progression. Additionally, we aimed to identify the underlying mechanism through which MSC-derived exosomes affect breast tumor growth and angiogenesis. Our findings demonstrated that exosomes released by H2O2-treated, stress-induced MSCs (St-MSC Exo) promoted breast cancer cell progression by inducing the expression of vascular endothelial growth factor (VEGF) and markers associated with epithelial-to-mesenchymal transition. Further clarification revealed that the promoting effect of St-MSC Exo on VEGF expression may, in part, depend on activating STAT3 signaling in BC cells. In contrast, exosomes derived from untreated MSCs retarded JAK1/STAT3 phosphorylation and reduced VEGF expression. Additionally, our observations revealed that the activation of the transcription factor NF-κB in BC cells, stimulated with St-MSC Exo, occurs concurrently with an increase in intracellular ROS production. Moreover, we observed that the increase in VEGF secretion into the conditioned media of 4T1 BC, mediated by St-MSC Exo, positively influenced endothelial cell proliferation, migration, and vascular behavior in vitro. In turn, our in vivo studies confirmed that St-MSC Exo, but not exosomes derived from untreated MSCs, exhibited a significant promoting effect on breast tumorigenicity. Collectively, our findings provide new insights into how MSCs may contribute to modulating the TME. We propose a novel mechanism through which exosomes derived from oxidative stress-induced MSCs may contribute to tumor progression and angiogenesis.

Critical regulatory levels in tumor differentiation: Signaling pathways, epigenetics and non-coding transcripts.

Approaches to induce tumor differentiation often result in manageable and therapy-naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non-coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build-up.

Depth of Sequencing Plays a Determining Role in the Characterization of Phage Display Peptide Libraries by NGS.

Next-generation sequencing (NGS) has raised a growing interest in phage display research. Sequencing depth is a pivotal parameter for using NGS. In the current study, we made a side-by-side comparison of two NGS platforms with different sequencing depths, denoted as lower-throughput (LTP) and higher-throughput (HTP). The capacity of these platforms for characterization of the composition, quality, and diversity of the unselected Ph.D.TM-12 Phage Display Peptide Library was investigated. Our results indicated that HTP sequencing detects a considerably higher number of unique sequences compared to the LTP platform, thus covering a broader diversity of the library. We found a larger percentage of singletons, a smaller percentage of repeated sequences, and a greater percentage of distinct sequences in the LTP datasets. These parameters suggest a higher library quality, resulting in potentially misleading information when using LTP sequencing for such assessment. Our observations showed that HTP reveals a broader distribution of peptide frequencies, thus revealing increased heterogeneity of the library by the HTP approach and offering a comparatively higher capacity for distinguishing peptides from each other. Our analyses suggested that LTP and HTP datasets show discrepancies in their peptide composition and position-specific distribution of amino acids within the library. Taken together, these findings lead us to the conclusion that a higher sequencing depth can yield more in-depth insights into the composition of the library and provide a more complete picture of the quality and diversity of phage display peptide libraries.

Propagation Capacity of Phage Display Peptide Libraries Is Affected by the Length and Conformation of Displayed Peptide.

The larger size and diversity of phage display peptide libraries enhance the probability of finding clinically valuable ligands. A simple way of increasing the throughput of selection is to mix multiple peptide libraries with different characteristics of displayed peptides and use it as biopanning input. In phage display, the peptide is genetically coupled with a biological entity (the phage), and the representation of peptides in the selection system is dependent on the propagation capacity of phages. Little is known about how the characteristics of displayed peptides affect the propagation capacity of the pooled library. In this work, next-generation sequencing (NGS) was used to investigate the amplification capacity of three widely used commercial phage display peptide libraries (Ph.D.™-7, Ph.D.™-12, and Ph.D.™-C7C from New England Biolabs). The three libraries were pooled and subjected to competitive propagation, and the proportion of each library in the pool was quantitated at two time points during propagation. The results of the inter-library competitive propagation assay led to the conclusion that the propagation capacity of phage libraries on a population level is decreased with increasing length and cyclic conformation of displayed peptides. Moreover, the enrichment factor (EF) analysis of the phage population revealed a higher propagation capacity of the Ph.D.TM-7 library. Our findings provide evidence for the contribution of the length and structural conformation of displayed peptides to the unequal propagation rates of phage display libraries and suggest that it is important to take peptide characteristics into account once pooling multiple combinatorial libraries for phage display selection through biopanning.

Non-coding RNA-associated competitive endogenous RNA regulatory networks: Novel diagnostic and therapeutic opportunities for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), as the most prevalent liver malignancy, is annually diagnosed in more than half a million people worldwide. HCC is strongly associated with hepatitis B and C viral infections as well as alcohol abuse. Obesity and nonalcoholic fatty liver disease (NAFLD) also significantly enhance the risk of liver cancer. Despite recent improvements in therapeutic approaches, patients diagnosed in advanced stages show poor prognosis. Accumulating evidence provides support for the regulatory role of non-coding RNAs (ncRNAs) in cancer. There are a variety of reports indicating the regulatory role of microRNAs (miRNAs) in different stages of HCC. Long non-coding RNAs (LncRNAs) exert their effects by sponging miRNAs and controlling the expression of miRNA-targeted genes. Circular RNAs (circRNAs) perform their biological functions by acting as transcriptional regulators, miRNA sponges and protein templates. Diverse studies have illustrated that dysregulation of competing endogenous RNA networks (ceRNETs) is remarkably correlated with HCC-causing diseases such as chronic viral infections, nonalcoholic steatohepatitis and liver fibrosis/cirrhosis. The aim of the current article was to provide an overview of the role and molecular mechanisms underlying the function of ceRNETs that modulate the characteristics of HCC such as uncontrolled cell proliferation, resistance to cell death, metabolic reprogramming, immune escape, angiogenesis and metastasis. The current knowledge highlights the potential of these regulatory RNA molecules as novel diagnostic biomarkers and therapeutic targets in HCC.

Identification of a novel colon adenocarcinoma cell targeting peptide using phage display library biopanning.

Phage display is well recognized as a promising high-throughput screening tool for the discovery of novel cancer-targeting peptides. Here, we screened a phage display library of 7-mer random peptides through in vitro biopanning to isolate peptide ligands binding to SW480 human colon adenocarcinoma cells. Three rounds of negative and positive selection caused a remarkable enrichment of colon cancer cell-binding phage clones with a significant enhancement of phage recovery efficiency (about 157-fold). A number of phage clones were picked out from the eluted phages of last selection round and sequenced. According to the results of cell binding assay and phage cell-based ELISA, one of the isolated peptides denoted as CCBP1 (with the sequence HAMRAQP) was indicated to have the highest binding efficiency, selectivity, and specificity toward colon cancer cells with no significant binding to control cells. Peptide competitive inhibition assay revealed that binding of the phage-displayed CCBP1 is competitively inhibited by the same free peptide, suggesting that CCBP1 specific binding to the target cell is independent of the phage context. Taken together, our findings provide support for the notion that CCBP1 binds specifically to colon cancer cells and might be a potential lead candidate for targeted delivery of imaging agents or therapeutic genes/drugs to colon tumors.

A White Plaque, Associated with Genomic Deletion, Derived from M13KE-Based Peptide Library Is Enriched in a Target-Unrelated Manner during Phage Display Biopanning Due to Propagation Advantage.

The nonspecific enrichment of target-unrelated peptides during biopanning remains a major drawback for phage display technology. The commercial Ph.D.TM-7 phage display library is used extensively for peptide discovery. This library is based on the M13KE vector, which carries the lacZα sequence, leading to the formation of blue plaques on IPTG-X-gal agar plates. In the current study, we report the isolation of a fast-propagating white clone (displaying WSLGYTG peptide) identified through screening against a recombinant protein. Sanger sequencing demonstrated that white plaques are not contamination from environmental M13-like phages, but derive from the library itself. Whole genome sequencing revealed that the white color of the plaques results from a large 827-nucleotide genomic deletion. The phenotypic characterization of propagation capacity through plaque count- and NGS-based competitive propagation assay supported the higher propagation rate of Ph-WSLGYTG clone compared with the library. According to our data, white plaques are likely to arise endogenously in Ph.D. libraries due to mutations in the M13KE genome and should not always be viewed as exogenous contamination. Our findings also led to the conclusion that the deletion observed here might be an ancestral mutation already present in the naïve library, which causes target-unrelated nonspecific enrichment of white clone during biopanning due to propagation advantage.

The oncogenic and tumor suppressive roles of RNA-binding proteins in human cancers.

Posttranscriptional regulation is a mechanism for the cells to control gene regulation at the RNA level. In this process, RNA-binding proteins (RBPs) play central roles and orchestrate the function of RNA molecules in multiple steps. Accumulating evidence has shown that the aberrant regulation of RBPs makes  contributions to the initiation and progression of tumorigenesis via numerous mechanisms such as genetic changes, epigenetic alterations, and noncoding RNA-mediated regulations. In this article, we review the effects caused by RBPs and their functional diversity in the malignant transformation of cancer cells that occurs through the involvement of these proteins in various stages of RNA regulation including alternative splicing, stability, polyadenylation, localization, and translation. Besides this, we review the various interactions between RBPs and other crucial posttranscriptional regulators such as microRNAs and long noncoding RNAs in the pathogenesis of cancer. Finally, we discuss the potential approaches for targeting RBPs in human cancers.

Role of miR-142 in the pathogenesis of osteosarcoma and its potential as therapeutic approach.

Osteosarcoma (OS) is the most common primary malignant tumor of the bone with a strong tendency to early metastasis, and occurs in growing bones more commonly in children and adolescents. Considering the limited therapeutic methods and lack of 100% success of these methods, developing innovative therapies with high efficacy and lower side effects is needed. Meanwhile, miRNAs and the studies indicating the involvement of miRNAs in OS development have attracted attentions as a result of the frequent abnormalities in expression of miRNAs in cancer. miRNAs are noncoding short sequences with lengths ranging from 18 to 25 nucleotides that play a very important role in cellular processes, such as proliferation, differentiation, migration, and apoptosis. MiRNAs can have either oncogenic or tumor suppressive role based on cellular function and targets. This review aimed to have overview on miR-142 as a tumor suppressor in OS. Moreover, the genes involved in the disease, such as RAC1, HMAG1, MMP9, MMP2, and E-cadherin, which have irregularities as a result of change in miR-142 expression, and, thereby, result in increasing the proliferation, invasion, and metastasis of the cells in the tissues and OS cells will be discussed.

Down-regulation of the non-coding RNA H19 and its derived miR-675 is concomitant with up-regulation of insulin-like growth factor receptor type 1 during neural-like differentiation of human bone marrow mesenchymal stem cells.

The differentiation of human bone marrow mesenchymal stem cells (BMSCs) into specific lineages offers new opportunities to use the therapeutic efficiency of these pluripotent cells in regenerative medicine. Multiple lines of evidence have revealed that non-coding RNAs play major roles in the differentiation of BMSCs into neural cells. Here, we applied a cocktail of neural inducing factors (NIFs) to differentiate BMSCs into neural-like cells. Our data demonstrated that during neurogenic induction, BMSCs obtained a neuron-like morphology. Also, the results of gene expression analysis by qRT-PCR showed progressively increasing expression levels of neuron-specific enolase (NSE) as well as microtubule-associated protein 2 (MAP-2) and immunocytochemical staining detected the expression of these neuron-specific markers along differentiated BMSC bodies and cytoplasmic processes, confirming the differentiation of BMSCs into neuronal lineages. We also compared differences in the expression levels of the long non-coding RNA (lncRNA) H19 and H19-derived miR-675 between undifferentiated and neurally differentiated BMSCs and found that during neural differentiation down-regulation of the lncRNA H19/miR-675 axis is concomitant with up-regulation of insulin-like growth factor type-1 (IGF-1R), a well-established target of miR-675 involved in neurogenesis. The findings of the current study provide support for the hypothesis that miR-675 may confer functionality to H19, suggesting a key role for this miRNA in the neural differentiation of BSMCs. However, further investigation is required to gain deeper insights into the biological roles of this miRNA in the complex process of neurogenesis.

Biased selection of propagation-related TUPs from phage display peptide libraries.

Phage display is rapidly advancing as a screening strategy in drug discovery and drug delivery. Phage-encoded combinatorial peptide libraries can be screened through the affinity selection procedure of biopanning to find pharmaceutically relevant cell-specific ligands. However, the unwanted enrichment of target-unrelated peptides (TUPs) with no true affinity for the target presents an important barrier to the successful screening of phage display libraries. Propagation-related TUPs (Pr-TUPs) are an emerging but less-studied category of phage display-derived false-positive hits that are displayed on the surface of clones with faster propagation rates. Despite long regarded as an unbiased selection system, accumulating evidence suggests that biopanning may create biological bias toward selection of phage clones with certain displayed peptides. This bias can be dependent on or independent of the displayed sequence and may act as a major driving force for the isolation of fast-growing clones. Sequence-dependent bias is reflected by censorship or over-representation of some amino acids in the displayed peptide and sequence-independent bias is derived from either point mutations or rare recombination events occurring in the phage genome. It is of utmost interest to clean biopanning data by identifying and removing Pr-TUPs. Experimental and bioinformatic approaches can be exploited for Pr-TUP discovery. With no doubt, obtaining deeper insight into how Pr-TUPs emerge during biopanning and how they could be detected provides a basis for using cell-targeting peptides isolated from phage display screening in the development of disease-specific diagnostic and therapeutic platforms.

Combination treatment with dendrosomal nanocurcumin and doxorubicin improves anticancer effects on breast cancer cells through modulating CXCR4/NF-κB/Smo regulatory network.

Despite advantageous antitumor properties of doxorubicin, the considerable cytotoxicity of this chemotherapeutic agent has made it necessary to develop combination treatment strategies. The aim of the current study was to investigate the possible synergism between dendrosomal nanocurcumin (DNC) and doxorubicin in eliciting anticancer effects on MDA-MB-231 metastatic breast cancer cells. The expression levels of CXCL12/CXCR4 axis and Hedgehog pathway genes were evaluated in patient-derived breast carcinoma tissues by qRT-PCR. MTT assay, Annexin V-FITC staining followed by flowcytomety and wound healing assay were used to measure the effects caused by DNC and doxorubicin, alone and in combination, on the viability, apoptosis induction, and migration of MDA-MB-231 cells, respectively. Also, qRT-PCR was exploited to analyze the expression of Smo, NF-κB and CXCR4 in cancer cells. Our results revealed that combination treatment with DNC and doxorubicin leads to significantly decreased viability, increased apoptosis, and reduced migration of breast cancer cells compared with using each drug alone. Also, combination treatment is more efficient that single treatment in reducing the expression levels of NF-κB and Smo transcripts. Our findings provide convincing support for the notion that DNC could synergistically enhance the anticancer effects of doxorubicin on metastatic breast cancer cells by improving its anti-proliferative, pro-apoptotic, and anti-migratory activities. This may be mediated, in part, by downregulating CXCR4, NF-κB, and Smo genes. Overall, the findings of the current study suggest that DNC might be used as a synergistic agent for enhancing therapeutic efficiency and reducing toxic effects of doxorubicin on breast cancer cells.

A polystyrene binding target-unrelated peptide isolated in the screening of phage display library.

Phage display is a powerful methodology for the identification of peptide ligands binding to any desired target. However, the selection of target-unrelated peptides (TUPs) appears as a huge problem in the screening of phage display libraries through biopanning. The phage-displayed peptide TLHPAAD has been isolated both in our laboratory and by another reserach group on completely different screening targets prompting us to hypothesize that it may be a potential TUP. In the current study, we analyzed the binding characteristics and propagation rate of phage clone displaying TLHPAAD peptide (SW-TUP clone). The results of ELISA experiment and phage recovery assay provided strong support for the notion that SW-TUP phage binds to polystyrene with a significantly higher affinity than control phage clones. Furthermore, this polystyrene binding was demonstrated to occur in a concentration- and pH-dependent mode. Characterization of the propagation profile of phage clones within a specified time course revealed no statistically significant difference between the amplification rate of SW-TUP and control phages. Our findings lead us to the conclusion that SW-TUP phage clone with the displayed peptide TLHPAAD is not a true target binder and its selection in biopanning experiments results from its bidning affinity to the polystyrene surface of the solid phase.

Phage display as a promising approach for vaccine development.

Bacteriophages are specific antagonists to bacterial hosts. These viral entities have attracted growing interest as optimal vaccine delivery vehicles. Phages are well-matched for vaccine design due to being highly stable under harsh environmental conditions, simple and inexpensive large scale production, and potent adjuvant capacities. Phage vaccines have efficient immunostimulatory effects and present a high safety profile because these viruses have made a constant relationship with the mammalian body during a long-standing evolutionary period. The birth of phage display technology has been a turning point in the development of phage-based vaccines. Phage display vaccines are made by expressing multiple copies of an antigen on the surface of immunogenic phage particles, thereby eliciting a powerful and effective immune response. Also, the ability to produce combinatorial peptide libraries with a highly diverse pool of randomized ligands has transformed phage display into a straightforward, versatile and high throughput screening methodology for the identification of potential vaccine candidates against different diseases in particular microbial infections. These libraries can be conveniently screened through an affinity selection-based strategy called biopanning against a wide variety of targets for the selection of mimotopes with high antigenicity and immunogenicity. Also, they can be panned against the antiserum of convalescent individuals to recognize novel peptidomimetics of pathogen-related epitopes. Phage display has represented enormous promise for finding new strategies of vaccine discovery and production and current breakthroughs promise a brilliant future for the development of different phage-based vaccine platforms.

Phage display biopanning and isolation of target-unrelated peptides: in search of nonspecific binders hidden in a combinatorial library.

Phage display is known as a powerful methodology for the identification of targeting ligands that specifically bind to a variety of targets. The high-throughput screening of phage display combinatorial peptide libraries is performed through the affinity selection method of biopanning. Although phage display selection has proven very successful in the discovery of numerous high-affinity target-binding peptides with potential application in drug discovery and delivery, the enrichment of false-positive target-unrelated peptides (TUPs) without any actual affinity towards the target remains a major problem of library screening. Selection-related TUPs may emerge because of binding to the components of the screening system rather than the target. Propagation-related TUPs may arise as a result of faster growth rate of some phage clones enabling them to outcompete slow-propagating clones. Amplification of the library between rounds of biopanning makes a significant contribution to the selection of phage clones with propagation advantage. Distinguishing nonspecific TUPs from true target binders is of particular importance for the translation of biopanning findings from basic research to clinical applications. Different experimental and in silico approaches are applied to assess the specificity of phage display-derived peptides towards the target. Bioinformatic tools are playing a rapidly growing role in the analysis of biopanning data and identification of target-irrelevant TUPs. Recent progress in the introduction of efficient strategies for TUP detection holds enormous promise for the discovery of clinically relevant cell- and tissue-homing peptides and paves the way for the development of novel targeted diagnostic and therapeutic platforms in pharmaceutical areas.

PCR amplification of the hrcV gene through specific primers for detecting Pseudomonas syringae pathovars.

Pseudomonas syringae pathovars are important pathogens among phytopathogenic bacteria causing a variety of diseases in plants. These pathogens can rapidly disseminate in a large area leading to infection and destruction of plants. To prevent the incidence of the bacteria, appropriate detection methods should be employed. Routinely serological tests, being time-consuming and costly, are exploited to detect these pathogens in plants, soil, water and other resources. Over the recent years, DNA-based detection approaches which are stable, rapid, specific and reliable have been developed and sequence analysis of various genes are widely utilized to identify different strains of P. syringe. However, the greatest limitation of these genes is inability to detect numerous pathovars of P. syringae. Herein, by using bioinformatic analysis, we found the hrcV gene located at pathogenicity islands of bacterial genome with the potential of being used as a new marker for phylogenetic detection of numerous pathovars of P. syringae. Following design of specific primers to hrcV, we amplified a 440 bp fragment. Of 13 assayed pathovars, 11 were detected. Also, through experimental procedures and bioinformatic analysis it was revealed that the designed primers have the capacity to detect 19 pathovars. Our findings suggest that hrcV could be used as a gene with the merit of detecting more pathovars of P. syringae in comparison with other genes used frequently for detection purposes.

Analysis of Compositional Bias in a Commercial Phage Display Peptide Library by Next-Generation Sequencing.

The principal presumption of phage display biopanning is that the naïve library contains an unbiased repertoire of peptides, and thus, the enriched variants derive from the affinity selection of an entirely random peptide pool. In the current study, we utilized deep sequencing to characterize the widely used Ph.DTM-12 phage display peptide library (New England Biolabs). The next-generation sequencing (NGS) data indicated the presence of stop codons and a high abundance of wild-type clones in the naïve library, which collectively result in a reduced effective size of the library. The analysis of the DNA sequence logo and global and position-specific frequency of amino acids demonstrated significant bias in the nucleotide and amino acid composition of the library inserts. Principal component analysis (PCA) uncovered the existence of four distinct clusters in the naïve library and the investigation of peptide frequency distribution revealed a broad range of unequal abundances for peptides. Taken together, our data provide strong evidence for the notion that the naïve library represents substantial departures from randomness at the nucleotide, amino acid, and peptide levels, though not undergoing any selective pressure for target binding. This non-uniform sequence representation arises from both the M13 phage biology and technical errors of the library construction. Our findings highlight the paramount importance of the qualitative assessment of the naïve phage display libraries prior to biopanning.

CASC11 and PVT1 spliced transcripts play an oncogenic role in colorectal carcinogenesis.

Cancer is fundamentally a genetic disorder that alters cellular information flow toward aberrant growth. The coding part accounts for less than 2% of the human genome, and it has become apparent that aberrations within the noncoding genome drive important cancer phenotypes. The numerous carcinogenesis-related genomic variations in the 8q24 region include single nucleotide variations (SNVs), copy number variations (CNVs), and viral integrations occur in the neighboring areas of the MYC locus. It seems that MYC is not the only target of these alterations. The MYC-proximal mutations may act via regulatory noncoding RNAs (ncRNAs). In this study, gene expression analyses indicated that the expression of some PVT1 spliced linear transcripts, CircPVT1, CASC11, and MYC is increased in colorectal cancer (CRC). Moreover, the expression of these genes is associated with some clinicopathological characteristics of CRC. Also, in vitro studies in CRC cell lines demonstrated that CASC11 is mostly detected in the nucleus, and different transcripts of PVT1 have different preferences for nuclear and cytoplasmic parts. Furthermore, perturbation of PVT1 expression and concomitant perturbation in PVT1 and CASC11 expression caused MYC overexpression. It seems that transcription of MYC is under regulatory control at the transcriptional level, i.e., initiation and elongation of transcription by its neighboring genes. Altogether, the current data provide evidence for the notion that these noncoding transcripts can significantly participate in the MYC regulation network and in the carcinogenesis of colorectal cells.

Identification of dysregulated competing endogenous RNA networks in glioblastoma: A way toward improved therapeutic opportunities.

Glioblastoma is recognized as one of the leading causes of death worldwide. Although there have been considerable advancements in understanding the causative molecular mechanisms of this malignancy, effective therapeutic strategies are still in limited use. It has been revealed that non-coding RNAs (ncRNAs) play critical roles in glioblastoma development, while interactions between the regulatory molecules such as long ncRNAs (lncRNAs), microRNAs (miRNAs), transcribed pseudogenes, and circular RNAs (circRNAs) remain to be fully deciphered. Over the recent years, researchers have discovered a new category of RNA molecules called competing endogenous RNA (ceRNA). This kind of RNA can contribute to molecular interactions in the form of ceRNA networks (ceRNETs). Multiple lines of evidence have demonstrated that dysregulation of various ceRNA networks is involved in glioblastoma development. Therefore, gaining insights into these dysregulations might offer potential for the early diagnosis of glioblastoma patients and identification of efficient therapeutic targets. In this review, we provide an overview of recent discoveries on ceRNA networks and the involvement of dysregulated networks in posing limitations to temozolomide therapy. We also describe signaling pathways relevant to the progression of glioblastoma.