Importance of long non-coding RNAs in the pathogenesis, diagnosis, and treatment of prostate cancer.

Long non-coding RNAs (lncRNAs) are regulatory transcripts with essential roles in the pathogenesis of almost all types of cancers, including prostate cancer. They can act as either oncogenic lncRNAs or tumor suppressor ones in prostate cancer. Small nucleolar RNA host genes are among the mostly assessed oncogenic lncRNAs in this cancer. PCA3 is an example of oncogenic lncRNAs that has been approved as a diagnostic marker in prostate cancer. A number of well-known oncogenic lncRNAs in other cancers such as DANCR, MALAT1, CCAT1, PVT1, TUG1 and NEAT1 have also been shown to act as oncogenes in prostate cancer. On the other hand, LINC00893, LINC01679, MIR22HG, RP1-59D14.5, MAGI2-AS3, NXTAR, FGF14-AS2 and ADAMTS9-AS1 are among lncRNAs that act as tumor suppressors in prostate cancer. LncRNAs can contribute to the pathogenesis of prostate cancer via modulation of androgen receptor (AR) signaling, ubiquitin-proteasome degradation process of AR or other important signaling pathways. The current review summarizes the role of lncRNAs in the evolution of prostate cancer with an especial focus on their importance in design of novel biomarker panels and therapeutic targets.

Sex-based Dysregulation of Inflammation-related Genes in Periodontitis.

Periodontitis is a chronic inflammatory condition affecting a large population all over the world. This condition is linked with abnormal expression of numerous genes. We measured levels of CYFIP1, KDR, RABGGTA, RABGGTB and FOXD2 in gingival tissue and circulation of people with periodontitis and healthy controls. KDR was more expressed in tissue samples of female patients compared with female controls (Ratio of mean expression (RME) =4.16, P=0.02). However, this gene was less expressed in the blood of female patients compared with female control subjects (RME=0.12, P=0.04). RABGGTB was less expressed in the blood of male patients compared with male controls (RME=0.20, P=0.02). Finally, FOXD2 was less expressed in total blood samples compared with total controls (RME=0.3, P<0.001) and in blood samples of female patients compared with female control subjects (RME=0.02, P<0.001). RABGGTA had the best area under curve (AUC) value in differentiation of patients' tissues from normal tissues (AUC=0.60, sensitivity=0.37, specificity=0.92). In distinction of abnormal blood samples from controls, FOXD2 had the best performance (AUC=0.85, sensitivity=0.66, specificity=0.91). In brief, we demonstrated a sex-dependent dysregulation of KDR, RABGGTB and FOXD2 genes in circulation or tissue of patients with periodontitis.

Assessment of expression of oxytocin-related lncRNAs in schizophrenia.

BACKGROUND: Schizophrenia is a neuropsychiatric disorder characterized by a variety of clinical manifestations. This disorder has a complex inheritance. Oxytocinegic system has been shown to be implicated in the pathophysiology of schizophrenia. This system can alter social cognition through direct interaction with dopaminergic signaling, facilitating brain-stimulation reward, reduction of defense mechanism and stress reactivity, and modulation of social information processing through enhancing the greatness of social incentives. Long non-coding RNAs (lncRNAs) can affect activity of oxytocinegic system, thus contributing in the etiology of this disorder. METHODS: We designed the current study to appraise dysregulation of nine oxytocin-associated mRNAs and lncRNAs in the venous blood of patients with schizophrenia. RESULTS: Expression of FOS was up-regulated in total patients compared with total control group (Expression ratio (95% CI)= 13.64 (5.46-34.05), adjusted P value<0.0001) and in female patients compared with female control group (Expression ratio (95% CI)=32.13 (5.81-176), adjusted P value<0.0001). Such pattern was also seen for Lnc-FOXF1 (Expression ratio (95% CI)= 6.41 (2.84-14.3), adjusted P value<0.0001 and Expression ratio (95% CI)= 14.41 (3.2-64.44), adjusted P value<0.0001, respectively). ITPR1 was down-regulated in total patients compared with total controls (Expression ratio (95% CI)= 0.22 (0.076-0.67), adjusted P value=0.0079). ROC curve analyses demonstrated that FOS had the best AUC value among other genes in differentiation between patients and controls (AUC=0.78). CONCLUSION: The above-mentioned results imply dysregulation of oxytocin-related genes in the circulatory blood of patients with schizophrenia.

Association between genetic variants and risk of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a complex multi-gene disorder. In the current study, we genotyped six single nucleotide polymorphisms (SNPs) within MOCOS, NINJ2 and AKT1 genes in a cohort of Iranian patients with this disorder and healthy controls. C allele of rs1057251 has been found to increase risk of OCD (OR (95% CI) =6.39 (4.64-8.79), P value <0.001). This SNP has been associated with risk of OCD in codominant model (OR (95% CI) = 69.53 (25.02-193.21) and 147 (34.2-631.75) for TC and CC genotypes, respectively, P value <0.0001). The rs1057251 was also associated with risk of OCD in dominant (OR (95% CI) = 72.87 (26.28-202.03), P value <0.0001), recessive (OR (95% CI) = 7.43 (2.49-22.19), P value =0.0002), overdominant (OR (95% CI) = 20.2 (11.1-36.76), P value <0.0001) and log-additive (OR (95% CI) = 20.87 (13.83-56.14), P value <0.0001) models. The rs3809263 within NINJ2 was also associated with risk of OCD. The A allele of this SNP has been found to confer risk of OCD (OR (95% CI) =3.28 (2.41-4.48), P value <0.001). This SNP was associated with risk of OCD in codominant (P value <0.0001), dominant (P value <0.0001), overdominant (OR (95% CI) = 9.28 (5.23-16.46), P value<0.0001) and log-additive (OR (95% CI) = 5.25 (3.4-8.1), P value <0.0001) models. Other SNPs were not associated with risk of OCD in any inheritance model. Taken together, rs1057251 and rs3809263 can be considered as risk loci for OCD in Iranian population.

Dysregulation of NF-κB-Associated LncRNAs in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a long-standing neurodevelopmental condition with prominent effects on social behavior of affected children. This disorder has been linked with neuroinflammatory responses. NF-κB has been shown to affect these responses in the orbitofrontal cortex of patients with ASD, thus being implicated in the pathogenesis of ASD. We measured expression of some NF-κB-associated lncRNAs and mRNAs (DILC, ANRIL, PACER, CHAST, ADINR, DICER1-AS1, HNF1A-AS1, NKILA, ATG5 and CEBPA) in the peripheral blood of ASD kids vs. healthy children. Expression quantities of ADINR, ANRIL, DILC, NKILA and CHAST were meaningfully higher in ASD cases compared with healthy kids (Posterior Beta = 1.402, P value < 0.0001; Posterior Beta = 2.959, P value < 0.0001; Posterior Beta = 0.882, P value = 0.012; Posterior Beta = 1.461, P value < 0.0001; Posterior Beta = 0.541, P value = 0.043, respectively). The Bonferroni corrected P values for these lncRNAs remained significant except for CHAST and DILC. Expression levels of other genes were not considerably different between cases and controls. Expressions of ATG5, DICER-AS1 and DILC were correlated with age of ASD patients (P < 0.0001). Among ASD cases, the most robust correlation has been detected between ADINR and NKILA (r = 0.87, P < 0.0001). Expression of none of genes has been correlated with age of healthy children. Among this group of children, expression levels of ADINR and CHAST were robustly correlated (r = 0.83, P < 0.0001). ANRIL had the greatest AUC value (AUC = 0.857), thus the best diagnostic power among the assessed genes. NKILA ranked the second position in this regard (AUC = 0.757). Thus, NF-κB-associated lncRNAs might partake in the pathogenesis of ASD.

Dysregulation of lncRNAs in circulation of patients with periodontitis: results of a pilot study.

BACKGROUND: Periodontitis is a chronic inflammatory disorder with a complex etiology. Long non-coding RNAs (lncRNAs) have been shown to affect pathoetiology of periodontitis. We aimed at identification of expression of five lncRNAs, namely Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 in the circulation and gingival tissues of these patients compared with healthy controls. METHODS: In a pilot case-control study, we compared expressions of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 lncRNAs between blood and tissue samples of patients with periodontitis and healthy controls using real time quantitative PCR technique. The present work was performed on samples got from 26 patients with periodontitis and 28 controls. Female/male ratio was 16/10 and 12/16 in cases and controls, respectively. RESULTS: There was no significant difference in the expressions of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 genes between affected and unaffected tissues. However, expressions of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 genes were significantly lower in the blood samples of patients when compared with control samples (Ratio of mean expression = 0.16, 0.14, 0.13, 0.10 and 0.14, respectively). Subsequently, we compared expressions of these lncRNAs between patients and controls in a sex-based manner. Expressions of Linc00667, FENDRR and DIRC3 genes were significantly lower in female patients compared with female controls (RME = 0.09, 0.07 and 0.10, respectively). Yet, there was no significant difference in expression of any of mentioned lncRNAs among male subgroups. Consistent with the similar levels of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 in tissue samples of patients and controls, none of them could separate these two sets of samples. However, AUC values for of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 expression levels in blood samples were 0.66, 0.72, 0.70, 0.72, 0.70 and 0.68, respectively with FENDRR having the best sensitivity value. CONCLUSION: Taken together, lncRNAs might be involved in the pathologic events in the circulation of patients with periodontitis.

Abnormal expression of NF-κB-related transcripts in blood of patients with inflammatory peripheral nerve disorders.

The NF-κB family includes some transcription factors which have important functions in the regulation of immune responses, therefore participating in the pathophysiology of inflammatory conditions such as peripheral neuropathies. We have quantified expression of a number of NF-κB-related transcripts in patients with Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP) versus healthy subjects. These transcripts have been previously shown to be functionally related with this family of transcription factors. Expressions of ATG5, DICER-AS1, PACER, DILC, NKILA and ADINR have been increased in both CIDP and GBS patients compared with controls. However, expression of ATG5 was not different between female CIDP cases and female controls. Moreover, expression of PACER was not different between male GBS cases and male controls. Expression levels of CHAST and CEBPA were not different between patients and controls. Expression of none of the assessed genes was different between GBS and CIDP cases. Significant correlations have been revealed between expression amounts of NF-κB-related transcripts both among CIDP/ GBS patients and among controls except for NKILA/ATG5, ADINR/ATG5 and PACER/ATG5 and DICER-AS1/ATG5 pairs among controls whose expression levels have not been correlated. In the patient group, CEBPA/PACER, CHAST/PACER and CHAST/DICER-AS1 pairs had the most robust correlations (r = 0.94). Among controls, NKILA/ADINR pair had the most strong correlation (r = 0.78). ADINR and DICER-AS1 levels could differentiate CIDP cases from controls with 100% sensitivity and specificity. In differentiation of GBS cases from controls, these two transcripts had the AUC values of 0.99 and 1. Combination transcript levels of NF-κB-related transcripts similarly detects CIDP and GBS cases from healthy controls with 100% sensitivity and specificity. Therefore, NF-κB-related transcripts are possibly involved in the pathophysiology of inflammatory peripheral nerve disorders and can be used as diagnostic markers for these conditions.

A Comprehensive Review on the Role of Non-Coding RNAs in the Pathophysiology of Bipolar Disorder.

AIM: Bipolar disorder is a multifactorial disorder being linked with dysregulation of several genes. Among the recently acknowledged factors in the pathophysiology of bipolar disorder are non-coding RNAs (ncRNAs). METHODS: We searched PubMed and Google Scholar databases to find studies that assessed the expression profile of miRNAs, lncRNAs and circRNAs in bipolar disorder. RESULTS: Dysregulated ncRNAs in bipolar patients have been enriched in several neuron-related pathways such as GABAergic and glutamatergic synapses, morphine addiction pathway and redox modulation. CONCLUSION: Altered expression of these transcripts in bipolar disorder provides clues for identification of the pathogenesis of this disorder and design of targeted therapies for the treatment of patients.

MicroRNAs as important contributors in the pathogenesis of colorectal cancer.

Colorectal cancer (CRC) is the third most fatal and fourth most frequently diagnosed neoplasm in the world. Numerous non-coding RNAs have been shown to contribute in the development of CRC. MicroRNAs (miRNAs) are among the mostly assessed non-coding RNAs in CRC. These transcripts influence expression and activity of TGF-ß, Wnt/ß-catenin, MAPK, PI3K/AKT and other CRC-related pathways. In the context of CRC, miRNAs interact with long non-coding RNAs to influence CRC course. Stool and serum levels of miRNAs have been used to distinguish CRC patients from healthy controls, indicating diagnostic roles of these transcripts in CRC. Therapeutic application of miRNAs in CRC has been assessed in animal models, yet has not been verified in clinical settings. In the current review, we have provided a recent update on the role of miRNAs in CRC development as well as diagnostic and prognostic approaches.

Altered expression of STAT genes in periodontitis.

Signal Transducer and Activator of Transcription (STAT) pathway is functionally located downstream of Janus kinases proteins and can integrate signals from diverse pathways, thus regulating several aspects of immune responses. Although contribution of STAT proteins in the pathogenesis of several inflammatory conditions has been confirmed, their role in the development of periodontitis has been less appraised. Thus, we assessed levels of STAT transcripts in the periodontal tissues and circulation of affected individuals compared with the corresponding controls. Expression of STAT1 was remarkably lower in tissues samples of patients compared with control tissues (Ratio of mean expression (RME) = 0.15, SE = 0.99, P value = 0.01). Expression of STAT3 was lower in total periodontitis tissues compared with total control tissues (RME = 0.20, SE = 0.95, P value = 0.02). Expression of STAT6 was higher in total periodontitis tissues compared with total control tissues (RME = 0.5.38, SE = 0.74, P value < 0.001). Expressions of other STAT genes were statistically similar in tissues obtained from cases and controls. Moreover, blood levels of all STAT genes were statistically similar between patients and controls. Correlation analysis demonstrated significant correlations between tissues levels of individual STAT genes as well as between their blood levels. However, tissue and blood levels of each STAT gene were not correlated. The current investigation potentiates the role of certain STAT genes in the development of this immune-related condition and warrants functional assays to clarify the mechanism.

Expression of BDNF-Associated lncRNAs in Treatment-Resistant Schizophrenia Patients.

Long non-coding RNAs (lncRNAs) play a decisive role in the development of the central nervous system and modulation, differentiation, and function of neurons. Thus, any abnormal pattern of expression of these transcripts might alter normal development leading to neuropsychiatric disorders. In this regard, transcripts of brain-derived neurotrophic factor (BDNF) and four BDNF-associated lncRNAs (BDNF-AS, MIR137HG, MIAT, and PNKY) were evaluated in the peripheral blood of schizophrenia (SCZ) patients as well as normal subjects. The results indicated that the relative expression (RE) of PNKY was higher in SCZ patients as compared with controls (posterior beta of RE = 2.605, P value = 0.006) and in female patients compared with female controls (posterior beta of RE = 2.831, P value < 0.0001). BDNF expression was also higher in SCZ patients when compared with controls (posterior beta of RE = 0.64, P value < 0.036). Finally, a correlation was detected between the disease status and gender in terms of BDNF-AS expression (P value = 0.026). An inverse correlation was also found between levels of PNKY and age in the control group (r = - 0.30, P value < 0.0001). Expressions of BDNF and all lncRNAs were correlated with each other in both patients and controls. PNKY had the best diagnostic power among all assessed genes in the identification of disease status (area under curve = 0.78). BDNF, BDNF-AS, MIR137HG, and MIAT genes could discriminate SCZ patients from normal subjects with diagnostic power of 71%, 72%, 67%, and 68%, respectively. The current investigation suggests the possibility of the application of transcript levels of lncRNAs as an SCZ diagnostic marker. However, it warrants further studies in larger sample sizes.

Expression of NF-κB associated lncRNAs in schizophrenia.

NF-κB signaling pathway has important roles in the regulation of growth and development of nervous system. This pathway has also been shown to participate in the pathogenesis of schizophrenia. Meanwhile, activity of NF-κB signaling pathway is regulated by several factors including non-coding RNAs (lncRNAs). In the current study, we evaluated expression of nine NF-κB-related lncRNAs namely DILC, ANRIL, PACER, CHAST, ADINR, DICER1-AS1, HNF1A-AS1, H19 and NKILA as well as two mRNA coding genes namely ATG5 and CEBPA in the peripheral blood of patients with schizophrenia compared with matched healthy subjects. Expressions of these genes were assessed by real time PCR technique. Expression of PACER was lower in patients with schizophrenia compared with controls (Posterior beta = - 0.684, P value = 0.049). On the other hand, expressions of CHAST, CEBPA, H19, HNF1A-AS1 and DICER1-AS1 were higher in patients compared with controls (Posterior beta = 0.39, P value = 0.005; Posterior beta = 0.844, P value < 0.0001; Posterior beta = 0.467, P value < 0.0001; Posterior beta = 1.107, P value = 0.005; Posterior beta = 0.176, P value = 0.044, respectively). We also appraised the diagnostic power of transcript quantities of CHAST, CEBPA, DICER1-AS1, H19 and HNF1A-AS1 in distinguishing between patients with schizophrenia and controls through depicting ROC curves. Based on the area under curve (AUC) values, CEBPA had the best diagnostic power (AUC = 0.948, P < 0.0001), followed by H19 (AUC = 0.815, P < 0.0001). Taken together, our study demonstrated dysregulation of NF-κB-related lncRNAs and genes in the peripheral blood of patients with schizophrenia and their potential as peripheral markers for this psychiatric condition.

The roles of miRNAs' clinical efficiencies in the colorectal cancer pathobiology: A review article.

MiRNAs (microRNAs) are defined as micro directors and regulators of gene expression. Since altered miRNA expression is signified in the pathobiology of diverse cancers such as colorectal cancers (CRCs), these molecules are described as therapeutic targets, either. Manipulation of miRNAs could lead to further therapy for chemo and radio-resistant CRCs. The usage of microRNAs has indicated prominent promise in the prognosis and diagnosis of CRC, because of their unique expression pattern associated with cancer types and malignancies. Nowadays, many researchers are analyzing the correlation between miRNA polymorphisms and cancer risk. With continuous incompatibility in colorectal cancer (CRC) miRNAs expression data, it is critical to move toward the content of a "pre-laboratory" analysis to speed up efficient accuracy medicine and translational study. Pathway study for the highest expressed miRNAs- regulated target genes resulted in the identification of a considerable number of genes associated with CRC pathway including PI3K, TGFß, and APC. In this review, we aimed to collect fruitful information about miRNAs and their potential roles in CRC, and provide a meta-analysis of the most frequently studied miRNAs in association with the disease.

Association Analysis Between the rs1899663 Polymorphism of HOTAIR and Risk of Psychiatric Conditions in an Iranian Population.

Recent studies have shown contribution of long non-coding RNAs (lncRNAs) in the pathogenesis of a number of psychiatric disorders. In the current study, we investigated the association between a single nucleotide polymorphism in the lncRNA HOX transcript antisense intergenic RNA (HOTAIR) and risk of diverse neuropsychiatric conditions in Iranian population. The selected polymorphism (rs1899663) is an intronic variant of this lncRNA which has been associated with several cancers in different populations. This SNP was genotyped in 323 individuals with methamphetamine addiction, 55 children with attention-deficit hyperactive disorder (ADHD), 138 patients with bipolar disorder 1 (BPD1), 86 patients with BPD2, 53 patients with major depressive disorder (MDD), and 194 patients with schizophrenia (SCZ). There was no significant association between rs1899663 genotypes and risk of methamphetamine addiction or SCZ in any assessed inheritance model. There was a significant association between rs1899663 SNP and risk of BPD1 in allelic, co-dominant, and dominant models (P values of 0.003, 0.009, and 0.003, respectively). The T allele of this SNP conferred risk of BPD1 (OR (95% CI) = 1.70 (1.20-2.41)). This SNP was associated with risk of BPD2 in allelic and dominant models (P values of 0.02 and 0.04). The T allele of this SNP was revealed to be the risk allele for BPD2 as well (OR (95% CI) = 1.61 (1.09-2.40)). Besides, the mentioned SNP was associated with susceptibility to MDD in allelic and dominant models (P values of 0.01 and 0.03). Finally, the rs1899663 was associated with risk of ADHD in allelic, co-dominant, and dominant models (P values of 3.6E-4, 0.002, and 1.2E-4, respectively). The current investigation highlights the role of rs1899663 in conferring risk of BPD1, BPD2, MDD, and ADHD and suggests a similar underlying genetic background for these conditions.