[LncRNAs: new approach in cancer therapy]

LncRNAs are non-coding transcripts with more than 200 nucleotides in length which interact to other molecules through their particular molecular structures and affect on numerous molecular processes. Key functions of lncRNAs in a great variety of cell pathways have been significantly studied. These molecules are expressed in many various cell types, but their decreased or increased expression has been reported in different diseases, especially cancer. Published papers have introduced lncRNAs and their crucial roles in primary steps of tumorigenesis, tumor development and apoptosis. lncRNAs importance in cancer occurrence is so remarkable that level measurement of some of them may be a considerable aid in diagnosis or prognosis of related cancer. Furthermore, a variety of new therapeutic approaches are innovated based on inhibition or enhancement of lncRNAs functions for alleviation disease severity however, they are conceivable only in research concept. In the current article, these approaches and their related molecular basis are conveyed by the use of the newest reliable resources

Pharmacogenomics and cancer stem cells

In oncology, Pharmacogenomics is still considered to be the best strategy to personalize cancer therapy. Although, its clinical application is still limited to a few genes, And also in a number of cancers, the correlation between genotype and clinical outcome have been promising. However, since the current pharmacogenomie studies do not take into account the emerging role of cancer stem cells [CSCs] in drug sensitivity and resistance, Favorable results were not achieved. CSCs are the only tumor-initiating cells within a malignancy; due to this CSCs are at the apex of human cancer hierarchy system. But genetic variants affecting their activity in some specific signal-transduction pathways are generally neglected in current pharmacogenomie studies. Moreover, in several malignancies, CSCs represent a rare sub-population; therefore, whole tumor profiling might mask CSC gene expression patterns. This article reviews current evidence on CSC chemoresistance and shows how common genetic variations in CSC-related genes may predict individual response to anticancer agents. Furthermore, this article provides insights into the design of pharmacogenomie studies to address the clinical usefulness of CSC genetic profiling

[lncRNAs roles in cancer occurrence]

Cancer is a complex condition in which gene expression is disrupted. Genetic factors involved in cancer pathology have been studied significantly. However, evidences have documented that a considerable fraction of susceptibility to cancer is not attributable to changes in protein coding sequences. Discovery and identification of a vast repertory of long noncoding RNAs [lncRNAs] with more than 200 nucleotides in human have been associated to unveiling their roles in tumorigenesis. Importance of lncRNAs, as either tumor suppressive or oncogenic agents, has been demonstrated in various common cancers. Recent studies indicate that several risk loci contributing to cancer pathogenesis are transcripted to lncRNAs which have critical roles in cancer incidence. Fundamental mechanisms of lncRNAs functions in a variety of gene expression levels involving epigenetic modification and transcriptional or post-transcriptional regulation, as well as interaction of these RNAs with other critical molecules such as DNA and some of proteins with definitive roles in cell fate have been described previously in detail by authors. Since a remarkable part of cancer pathogenesis has been reported in related to lncRNAs, the current review article discusses about association of some lncRNAs with specific tumors, effects of lncRNAs on cancer incidence and their importance in providing diagnostic and prognostic opportunities

[lncRNAs: significance and function mechanisms]

In mammals, the majority of products of gene expression are non-coding ribonucleotide sequences. They include short and long RNA molecules with sizes ranging of tens to hundreds of nucleotides. Among them, the molecules with more than 200 nucleotides are called long non-coding RNAs or lncRNAs. While LncRNAs functions depend on their unique molecular structures, they play important roles in regulating gene expression at epigenetic, transcriptional and post-transcriptional levels. Interacting with other biological molecules such as DNA, RNA and protein, LncRNAs have been found to play important roles in normal cell physiological activities. Activation of transcription factors, guidance of ribonucleoprotein complexes, aggregation of partner proteins, regulation of alternative processing, cooperation in chromatin remodeling, facilitation of genomic imprinting, maintaining of multipotential state and control of nucleus/cytoplasm traffic are some of crucial approaches Implemented by LncRNAs. Modern technologies have been developed to identify lncRNA molecules, and many relevant databases have been designated to facilitate research and academic exchange of data concerning them. In this review article, signification, identification, classification, biological evolution, genomic position, configuration, expression, localization and remarkable functions of LncRNAs have been discussed

[Targeted Genome Editing With Engineered Nucleases- a New Approach in Gene Therapy]

Nowadays, targeted genome engineering is one of the most important advances in genetic engineering. This process is based on the function of engineered endonucleases. These tools can make desirable genetic changes through creating double strand breaks followed by homologous recombination or nonhomologous end joining mechanisms in a specific site on genome. Genome editing endonucleases have strong ability in understanding the gene performance and gene therapy applications. Meganucleases are the first group of these tools which are naturally found in all creatures and play a crucial role in the targeted genome engineering. zinc finger endonucleases [ZFNs] are the second class made using fusion of a series of DNA recognition Zinc finger domains with catalytic domain of FokI enzyme. Another class of these nucleases includes Transcription activator like-effector nucleases [TALENs] in which, DNA recognition domains are derivatives of transcription activator like-effector proteins from Xanthomonas species, plant pathogen bacteria? fused with catalytic domain of FokI enzyme, like previous class. The last class of these engineered endonucleases, modeled on bacterial adaptive immune system which are called CRISPR/Cas. In this system, Cas9 endonuclease is recruited to the target sequence by a guide RNA that pairs with target DNA and then the enzyme cuts the DNA. In this review, characteristics of the four endonucleases mentioned above and some advances in this area for enhancing its efficiency and specificity in basic and practical researches will discuss through personal experiences and up to date references.

[Genetic instability and centrosome abnormality in cancer]

Genetic instability is an important issue in cancer and including two important types of chromosome instability and microsatellite instability. Centrosome abnormality is a leading cause of chromosome instability. Centrosome plays as a microtubule organizing center [MTOC] to determine number, polarity and organization of interphase and metaphase microtubule. Centrosomes take part in cytoplasm organization, cell polarity and chromosome distribution to daughter cells. Numbers and function of centrosomes are regulated by genetic factors and polar mitotic apparatus. Cancer cells display a wide range of centrosome abnormality in in vitro and in vivo. Together, in this article we review recent and basic concepts of centrosome abnormality in cancer cells

[Genetic variants of susceptible genes to schizophrenia and their role on disease progress]

Schizophrenia is a severe psychiatric disorder that has a lifetime prevalence of 1% in the most studied population. Schizophrenia is a multifactorial disorder that is characterized by the contribution of multiple susceptibility genes that could act in conjunction with epigenetic processes and environmental factors. Linkage and association studies have shown a number of candidate risk genes including Nerugulin 1, Disrupted in schizophrenia, Disbyndin and Epsin 4 that have associated with schizophrenia. However, their biological function remains elusive. 'Disrupted in schizophrenia 1' [DISC1], a gene locus originally identified at the first in a large Scottish family, showing a heavy burden of major mental illnesses associated with a balanced t[1;11][q42.1;q14.3] chromosome translocation. Substantial genetic and biological research on DISC1 has been displayed in past decade that DISC1 is now recognized as a genetic risk factor for a spectrum of psychiatric disorders and it impacts on many aspects of central nervous system [CNS] function, including neurodevelopment, neurosignaling, and synaptic functioning. Evidences emerged from genetic studies have shown a relationship between DISC1 and quantitative traits, including working memory, cognitive aging, gray matter volume in the prefrontal cortex, and abnormalities in hippocampal structures as well as function. DISC1 interacts with numerous proteins, also involved in neuronal migration, neurite outgrowth, cytoskeletal modulation, and signal transduction, some of which have been reported as independent genetic susceptibility factors for psychiatric morbidity. Here, we studied association of genetic variants of several susceptibility genes to schizophrenia, specially DISC1 and its intractor proteins and their effect on functional and structural of the brain in human and in the mouse

Differential expression of human homeodomain TGIFLX in brain tumor cell lines

Glioblastoma is the most common and the most lethal primary brain cancer. This malignancy is highly locally invasive, rarely metastatic and resistant to current therapies. Little is known about the distinct molecular biology of glioblastoma multiforme [GBM] in terms of initiation and progression. So far, several molecular mechanisms have been suggested to implicate in GBM development. Homeodomain [HD] transcription factors play central roles in the expression of genomic information in all known eukaryotes. The TGIFX homeobox gene was originally discovered in human adult testes. Our previous study showed implications of TGIFLX in prostate cancer and azoospermia, although the molecular mechanism by which TGIFLX acts is unknown. Moreover, studies reported that HD proteins are involved in normal and abnormal brain developments. We examined the expression pattern of TGIFLX in different human brain tumor cell lines including U87MG, A172, Daoy and 1321N1. Interestingly, real time RT-PCR and western blot analysis revealed a high level of TGIFLX expression in A172 cells but not in the other cell lines. We subsequently cloned the entire coding sequence of TGIFLX gene into the pEGFP-N1 vector, eukaryotic expressionvector encoding eGFP, and transfected into the U-87 MG cell line. The TGIFLX-GFP expression was confirmed by real time RT-PCR and UV-microscopic analysis. Upon transfection into U87 cells, fusion protein TGIFLX-GFP was found to locate mainly in the nucleus. This is the first report to determine the nuclear localization of TGIFLX and evaluation of its expression level between different brain tumor cell lines. Our data also suggest that TGIFLX gene dysregulation could be involved in the pathogenesis of some human brain tumors

[Molecular genetics and gene therapy in esophageal cancer: a review article]

With approximately 386,000 deaths per year, esophageal cancer is the 6th most common cause of death due to cancer in the world. This cancer, like any other cancer, is the outcome of genetic alterations or environmental factors such as tobacco smoke and gastro-esophageal reflux. Tobacco smoking is a major etiologic factor for esophageal squamous cell carcinoma in western countries, and it increases the risk by approximately 3 to 5 folds. Chronic gastro-esophageal reflux usually leads to the replacement of squamous mucosa by intestinal-type Barrett's metaplastic mucosa which is considered the most important factor causing esophageal adenocarcinoma. In contrast to esophageal adenocarcinoma, different risk factors and mechanisms, such as mutations in oncogenes and tumor suppressor genes, play an important role in causing esophageal squamous cell carcinoma. Molecular studies on esophageal cancers have revealed frequent genetic abnormalities in esophageal squamous cell carcinoma and adenocarcinoma, including altered expression of p53, p16, cyclin D1, EGFR, E-cadherin, COX-2, iNOS, RARs, Rb, hTERT, p21, APC, c-MYC, VEGF, TGT-alpha and NF-kappa B. Many studies have focused on the role of different polymorphisms such as aldehyde dehydrogenase 2 and alcohol dehydrogenase 2 in causing esophageal cancer. Different agents including bestatin, curcumin, black raspberries, 5-lipoxygenase [LOX] and COX-2 inhibitors have been found to play a role in inhibiting esophageal carcinogenesis. Different gene therapy approaches including p53 and p21WAF1 replacement gene therapies and therapy by suicide genes have also been experimented. Moreover, efforts have been made to use nanotechnology and aptamer technology in this regard

Polymorphism analysis of malaria susceptibility biomarkers in G6PD deficiency patients

Several studies suggested that some traits and polymorphisms in human genome such as G6PD deficiency and other genes have protective effects on susceptibility to malaria infection. In present study we investigated the prevalence of TNF alpha -244G -> A, TNF alpha -308G->A,TNF alpha -238G->A, NOS2-954G->C, MBL54G->A, MBL 57G->A, MBLIVS-I-5G->A polymorphisms and G6PD variants [Mediterranean, Chatham, Cosenza, A-[202,376] in 315 subjects with G6PD deficiency and 10 malaria patient. All the 315 subjects were selected from five provinces [Pars, Khuzestan, Esfahan, Yazd and Kerman] and screened by PCR-RFLP method. TheNOS2-954G->A consisted GG[40.31%], GC[53.01%], and CC[6.66%] where as TNF alpha -308 consisted GG[68.8%], AG[31.11%] contents. The TNF alpha -244 showed GG[94.60%], AG[5.39%] genotypes and the TNF alpha -238 had GG[92.69%], AG[6.66%], AA[0.63%] genotypes. The MBL54 polymorphism had GG[75.55%], AG [24.44%], AA[0.63%] genotypes. In MBL 57, had GG[95.23%], AG[4.76%], AA [0.63%] genotypes. The G6PD variants was indicated that Mediterranean mutation in Pars, Khuzestan, Esfahan, Yazd and Kerman provinces was 79.4%, 58%, 83/8%, 64% and 63% respectively and also, the Chatham mutation was 8.8%, 8% 4.5%,3.6% and 0% respectively. Analysis of other four mutations [Cosenza, Arures and A-202 and A-367] showed that none of them had those mutations. Our results suggested that genotypes which causes protection against malaria or reduction of risk for celebral malaria and death has the maximum prevalence in samples taken from the five provinces, but in the kolmogorov-smiranov test results, only NOS2-954G->C supported the theory of relation between these polymorphisms and protection against malaria

Immunobiological consequences of sulfur mustard contamination

Sulfur mustard has been employed in chemical warfare in certain regions including Iran. The short and long term biological effects of sulfur mustard contamination have been studied in both basic and clinical aspects. Sulfur mustard has been shown to induce a vast array of pathological effects in affected persons. In addition to skin, lung, eyes and gastrointestinal disturbances, sulfur mustard has been shown to induce hematological complications and a severe suppression of the immune system. The short and long term immunological [both cellular and humoral], hematological, genetic and biochemical consequences of persons exposed to sulfur mustard are extensively reviewed here. The long term complications of these patients indicate the need to develop effective preventive and therapeutic strategies in the clinic. These strategies may be based upon immunopotentiating intervention and therapy