miRNAs and exosomal miRNAs in lung cancer: New emerging players in tumor progression and therapy response.

Non-coding RNAs have shown key roles in cancer and among them, short RNA molecules are known as microRNAs (miRNAs). These molecules have length less than 25 nucleotides and suppress translation and expression. The functional miRNAs are produced in cytoplasm. Lung cancer is a devastating disease that its mortality and morbidity have undergone an increase in recent years. Aggressive behavior leads to undesirable prognosis and tumors demonstrate abnormal proliferation and invasion. In the present review, miRNA functions in lung cancer is described. miRNAs reduce/increase proliferation and metastasis. They modulate cell death and proliferation. Overexpression of oncogenic miRNAs facilitates drug resistance and radio-resistance in lung cancer. Tumor microenvironment components including macrophages and cancer-associated fibroblasts demonstrate interactions with miRNAs in lung cancer. Other factors such as HIF-1α, lncRNAs and circRNAs modulate miRNA expression. miRNAs have also value in the diagnosis of lung cancer. Understanding such interactions can pave the way for developing novel therapeutics in near future for lung cancer patients.

Biological and therapeutic viewpoints towards role of miR-218 in human cancers: Revisiting molecular interactions and future clinical translations.

Understanding the exact pathogenesis of cancer is difficult due to heterogenous nature of tumor cells and multiple factors that cause its initiation and development. Treatment of cancer is mainly based on surgical resection, chemotherapy, radiotherapy and their combination, while gene therapy has been emerged as a new kind of therapy for cancer. Post-transcriptional regulation of genes has been of interest in recent years and among various types of epigenetic factors that can modulate gene expression, short non-coding RNAs known as microRNAs (miRNAs) have obtained much attention. The stability of mRNA decreases by miRNAs to repress gene expression. miRNAs can regulate tumor malignancy and biological behavior of cancer cells and understanding their function in tumorigenesis can pave the way towards developing new therapeutics in future. One of the new emerging miRNAs in cancer therapy is miR-218 that increasing evidence highlights its anti-cancer activity, while a few studies demonstrate its oncogenic function. The miR-218 transfection is promising in reducing progression of tumor cells. miR-218 shows interactions with molecular mechanisms including apoptosis, autophagy, glycolysis and EMT, and the interaction is different. miR-218 induces apoptosis, while it suppresses glycolysis, cytoprotective autophagy and EMT. Low expression of miR-218 can result in development of chemoresistance and radio-resistance in tumor cells and direct targeting of miR-218 as a key player is promising in cancer therapy. LncRNAs and circRNAs are nonprotein coding transcripts that can regulate miR-218 expression in human cancers. Moreover, low expression level of miR-218 can be observed in human cancers such as brain, gastrointestinal and urological cancers that mediate poor prognosis and low survival rate.

Progress in targeting PTEN/PI3K/Akt axis in glioblastoma therapy: Revisiting molecular interactions.

Glioblastoma (GBM) is one of the most malignant cancers of central nervous system and due to its sensitive location, surgical resection has high risk and therefore, chemotherapy and radiotherapy are utilized for its treatment. However, chemoresistance and radio-resistance are other problems in GBM treatment. Hence, new therapies based on genes are recommended for treatment of GBM. PTEN is a tumor-suppressor operator in cancer that inhibits PI3K/Akt/mTOR axis in diminishing growth, metastasis and drug resistance. In the current review, the function of PTEN/PI3K/Akt axis in GBM progression is evaluated. Mutation or depletion of PTEN leads to increase in GBM progression. Low expression level of PTEN mediates poor prognosis in GBM and by increasing proliferation and invasion, promotes malignancy of tumor cells. Moreover, loss of PTEN signaling can result in therapy resistance in GBM. Activation of PTEN signaling impairs GBM metabolism via glycolysis inhibition. In contrast to PTEN, PI3K/Akt signaling has oncogenic function and during tumor progression, expression level of PI3K/Akt enhances. PI3K/Akt signaling shows positive association with oncogenic pathways and its expression similar to PTEN signaling, is regulated by non-coding RNAs. PTEN upregulation and PI3K/Akt signaling inhibition by anti-cancer agents can be beneficial in interfering GBM progression. This review emphasizes on the signaling networks related to PTEN/PI3K/Akt and provides new insights for targeting this axis in effective GBM treatment.

Extremely Low Frequency Magnetic Fields Induce mTOR and Hsa_Circ_100338 Expression Changes in Gastric Cancer and Normal Fibroblast Cell Lines.

OBJECTIVE: Extremely low-frequency magnetic field (ELF-MF) exposure, as a targeted tumor therapy, presents several potential advantages. In this research, we investigated effects of different ELF-MF intensities on cell viability and expression levels of the mammalian target of rapamycin (mTOR) and hsa_circ_100338 in the normal fibroblast (Hu02) and human gastric adenocarcinoma (AGS) cell lines. MATERIALS AND METHODS: In this experimental study, cell lines of AGS and Hu02, were cultured under the exposure of ELFMF with magnetic flux densities (MFDs) of 0.25, 0.5, 1 and 2 millitesla (mT) for 18 hours. The 3-(4, 5-dimethylthiazoyl-2- yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the cell viability. Relative expression of mTOR and hsa_circ_100338 RNAs was estimated by quantitative real-time polymerase chain reaction (qRT-PCR) technique. RESULTS: Viability of the normal cells was significantly increased at MFDs of 0.5, 1 and 2 mT, while viability of the tumor cells was significantly decreased at MFD of 0.25 and increased at MFD of 2 mT. Expression level of mTOR was significantly increased at the all applied MFDs in the normal cells, while it was significantly decreased at MFDs of 0.25 and 0.5mT in the tumor cells. MFDs of 1 and 2 mT in tumor cells inversely led to the increase in mTOR expression. hsa_circ_100338 was downregulated in MFD of 0.25 mT and then it was increased parallel to the increase of MFD in the normal and tumor cells. CONCLUSION: Results of the present study indicated that ELF-MF at MFDs of 0.25 and 0.5 mT can lead to decrease in the both mTOR and hsa_circ_100338 expression levels. Given the role of mTOR in cell growth, proliferation and differentiation, in addition to the potential role of hsa_circ_100338 in metastasis, expression inhibition of these two genes could be a therapeutic target in cancer treatment.

EVALUATION OF BCL2 AND ITS REGULATORY MIRS, MIR-15-B AND MIR-16 EXPRESSION CHANGES UNDER THE EXPOSURE OF EXTREMELY LOW-FREQUENCY ELECTROMAGNETIC FIELDS ON HUMAN GASTRIC CANCER CELL LINE.

In this research, changes in the expression of B-cell lymphoma 2 (BCL2), miR-15-b and miR-16 in human adenocarcinoma gastric cancer cell line (AGS) following the exposure to magnetic flux densities (MFDs) of 0.2 and 2 mT continuously and discontinuously (1.5 h on/1.5 h off) for 18 h were investigated. Changes in the cell viability were evaluated by the MTT assay. Real-time PCR was used to evaluate the expression changes of BCL2, miR-15-b and miR-16. The results showed that extremely low frequency electromagnetic field (ELF-EMF) could significantly reduce the viability of AGS cells in the continuous MFD of 2 mT. The BCL2 expression was significantly decreased following the exposure to continuous MFDs of 0.2 and 2 mT and discontinuous MFD of 2 mT. The expressions of miR-15-b and miR-16 were significantly increased in continuous and discontinuous MFD of 2 mT. According to the results, weak and moderate extremely low-frequency electromagnetic fields can change the expressions of BCL2, miR-15-b and miR-16.

Up-regulation of miR-144 and miR-375 in the human gastric cancer cell line following the exposure to extremely low-frequency electromagnetic fields.

PURPOSE: Recently, therapeutic effects of extremely low-frequency electromagnetic field (ELF-EMF) as complementary and alternative medicine, used in the oncology field to control disease symptoms. Micro RNAs (miRs) are responsible for the post-transcriptional regulation of gene expression in the cell. This study aimed to evaluate the expression changes of miR-144 and miR-375 in the human gastric adenocarcinoma cell line (AGS) under the exposure of ELF-EMF. MATERIALS AND METHODS: AGS cells were exposed to magnetic flux densities of 0.2 and 2 mT for 18 h, continuously and discontinuously (1.5 h on/1.5 h off). Cell viability was evaluated by MTT assay. Changes of miR-144 expression levels in AGS cells immediately after exposure and 18 and 36 h after the exposure cut-off was calculated by QRT-PCR. RESULTS: The cell viability of AGS cells was decreased under the exposure of 0.2 and 2 mT EMFs when compared to the control. Up-regulation of miR-144 and miR-375 were observed in AGS cells under the exposure of magnetic fields. CONCLUSIONS: The results indicated that the miR levels were significantly decreased 18 and 36 h after finishing the exposure, but not reached the normal range. The results of this investigation indicated that weak and moderate intermittent 50 Hz ELF-EMFs can induce changes in miRNA expression.

Changes in NOTCH1 gene and its regulatory circRNA, hsa_circ_0005986 expression pattern in human gastric adenocarcinoma and human normal fibroblast cell line following the exposure to extremely low frequency magnetic field.

The effect of an extremely low-frequency magnetic field (ELF-MFs) on the expression levels of NOTCH1 and its regulatory circular RNA (circ-RNA) in gastric cancer has not yet investigated. This study aimed to find the expression changes of NOTCH1 and its regulatory circ-RNA, hsa_circ_0005986, in human gastric adenocarcinoma cell line (AGS) and human normal fibroblast (Hu02) cells fallowing the exposure to discontinuously magnetic flux densities (MFDs) of 0.25, 0.5 ,1 and 2 millitesla (mT) for 18h in comparison to unexposed cells. In addition, the effect of various MFDs on viability of tumor and normal cells was investigated. The cell viability was evaluated by MTT assay. The relative expression of NOTCH1and hsa_circ_0005986 mRNAs was analyzed by quantitative Real-time PCR. The viability of tumor cells was decreased under the exposure of MFs, while the normal cells viability was increased. NOTCH1 was significantly down-regulated in AGS cells and up-regulated in Hu02 cells at all MFDs. The expression changes of NOTCH1 in tumor and  normal cells was depended to the MFD of MFs. According to our results, the tumor and normal cells show different behavior at the molecular level in various MFDs in terms of NOTCH1 and hsa_circ_0005986 expression level. Decrease in tumor cell survival following the exposure to ELF-MFs may be the result of decreased in the expression level of NOTCH1 and its Reg-circ-RNA. These magnetic field-reducing effects on cancer cell survival through the change on the expression of genes involved in the proliferation and progression of cancer can be a new key in cancer treatment.

Association between adipokine and myeloperoxidase levels in patients with coronary artery disease.

The adipokines, leptin and adiponectin, have a prominent role in the pathogenesis of coronary artery disease (CAD). The inflammatory enzyme, myeloperoxidase (MPO) also has an important role in the pathogenesis of CAD. Association of the adipokines with MPO remains to be resolved in patients with CAD. In this case-control study, 100 patients with CAD and 100 control subjects were appropriately recruited. Angiographic evaluation assigned the presence of CAD. Plasma leptin, adiponectin and MPO concentrations were measured using immunoassay methods. Other conventional cardiovascular risk factors were also recorded. Leptin and MPO concentrations were significantly increased in CAD patients compared to control subjects (25.38 ± 5.91 ng/ml vs. 3.68 ± 1.95 ng/mL and 52.85 ± 12.90 ng/mL vs.  23.00 ± 3.60 ng/mL, P=0.001, respectively). In contrast, adiponectin was significantly decreased in CAD patients compared to control subjects (5.62 ± 1.15 µg/mL vs. 9.25 ± 1.8, P = 0.001). There was a strong positive association between leptin and MPO concentrations only in CAD patients (P = 0.01). In contrast, a significant inverse association was found between adiponectin and MPO concentrations in CAD patients (P = 0.01). The associations also were significant after adjustment for other conventional risk factors (P = 0.001). Considering the presence of significant association between leptin and MPO, as well as adiponectin and MPO in patients with CAD, it may be inferred that the contribution of the adipokines in the pathogenesis of CAD may be, in part, through affecting the MPO concentration.

Elevated level of microRNA-21 in the serum of patients with colorectal cancer.

In patients with colorectal cancer, circulating micro RNA-21 (miR-21) is overexpressed and may act as a potential diagnostic and prognostic biomarker. In the present study, serum miR-21 level was determined in patients with colorectal cancer and control subjects in an attempt to explore its potential clinical diagnostic and prognostic value. Serum levels of miR-21 were measured in 40 patients with colorectal adenocarcinoma and 40 control subjects using a quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) assay. Serum miR-21 levels were compared in the colorectal cancer patients and control subjects. Furthermore, the association between serum miR-21 level and the clinical stages of tumors was also examined in the patients. Serum miR-21 level was significantly elevated in colorectal adenocarcinoma patients relative to control subjects (P=0.0001), and it was revealed as a potential diagnostic biomarker for differentiating the patients from control subjects. Increased levels of serum miR-21 were associated with clinical stages of tumors in the patients (P=0.01). These results indicated that serum miR-21 levels could serve as a reliable diagnostic and prognostic biomarker for colorectal adenocarcinoma.

Association of plasma leptin, homocysteine and nitric oxide levels with the presence and unstability of coronary artery disease.

AIM: Leptin and total homocysteine (tHcy) may participate in the pathogenesis of coronary artery disease (CAD) through nitric oxide (NO) depletion. We sought to investigate whether leptin, tHcy and NO are suitable predictors of CAD. PATIENTS & METHODS: This study contained 50 control subjects and 50 stable and 50 unstable angina patients. Plasma leptin, tHcy and NO levels were determined using enzyme immunoassay, HPLC fluorescence and spectrophotometric methods, respectively. Other conventional risk factors were also determined. RESULTS: Leptin and tHcy levels were highest in unstable angina patients, followed by stable angina patients and then controls (p < 0.001). Controls had significantly higher NO than patients (p <0.001). Leptin and tHcy had a positive and NO a negative association with the presence of CAD. CONCLUSIONS: Some athrogenic effects of leptin may be mediated by affecting tHcy and NO levels. Plasma leptin, tHcy and NO levels showed significant contribution to CAD prediction and discrimination.

Serum paraoxonase 1 activity is associated with fatty acid composition of high density lipoprotein.

INTRODUCTION: Cardioprotective effect of high density lipoprotein (HDL) is, in part, dependent on its related enzyme, paraoxonase 1 (PON1). Fatty acid composition of HDL could affect its size and structure. On the other hand, PON1 activity is directly related to the structure of HDL. This study was designed to investigate the association between serum PON1 activity and fatty acid composition of HDL in healthy men. METHODS: One hundred and forty healthy men participated in this research. HDL was separated by sequential ultracentrifugation, and its fatty acid composition was analyzed by gas chromatography. PON1 activity was measured spectrophotometrically using paraxon as substrate. RESULTS: Serum PON1 activity was directly correlated with the amount of stearic acid and dihomo-gamma-linolenic acid (DGLA). PON1/HDL-C was directly correlated with the amount of miristic acid, stearic acid, and DGLA and was inversely correlated with total amount of ω 6 fatty acids of HDL. CONCLUSION: The fatty acid composition of HDL could affect the activity of its associated enzyme, PON1. As dietary fats are the major determinants of serum lipids and lipoprotein composition, consuming some special dietary fatty acids may improve the activity of PON1 and thereby have beneficial effects on health.

Association between HDL particles size and myeloperoxidase/ paraoxonase-1 (MPO/PON1) ratio in patients with acute coronary syndrome.

Myeloperoxidase (MPO) and paraoxonase-1 (PON1) are inflammatory and anti-inflammatory enzymes, respectively that have been involved in the pathogenesis of coronary artery disease (CAD). In this study we sought to evaluate the relations of MPO and PON1 with high density lipoprotein (HDL) mean size in patients with acute coronary syndrome (ACS). Collectively, 50 control subjects and 50 patients with ACS were participated in this study. MPO level and PON1 activity was determined using immunoassay and colorimetric methods, respectively. HDL mean size was determined by a dynamic light scattering methodology. Other clinical risk factors were also determined by standard methods. The MPO/PON1 ratio amount was significantly higher in patients with ACS (1.49±1.10) than in control subjects (0.21±0.14) (P<0.01). There was a significant correlation between MPO/PON1 ratio and HDL mean size in patients with ACS. Amount of the enzymes and their relations to HDL particle size in patients with ACS may play a part in the pathogenesis of ACS. Also, MPO/PON1 ratio may be a robust predictor of ACS.

Evaluation of the effects of weak and moderate static magnetic fields on the characteristics of human low density lipoprotein in vitro.

It has been suggested that exposure to electromagnetic fields may be a risk factor for cardiovascular disease in humans. Low density lipoprotein (LDL) modifications such as peroxidation and aggregation have been implicated in the pathogenesis of atherosclerosis. The present study investigated the effects of weak (0.125-0.5 mT) and moderate (1-4 mT) static magnetic fields (SMFs) on LDL oxidation, aggregation and zeta potential in vitro. Our results demonstrated that magnetic flux densities of 0.25 and 0.5 mT decreased, and magnetic flux densities of 3 and 4 mT increased the zeta potential and LDL oxidation in comparison with the control samples. All doses of SMFs increased the LDL aggregation in a time- and dose-dependent manner. It is concluded that SMFs can alter the susceptibility of LDL to oxidation and this alteration is dependent on the applied magnetic flux density. The SMF, in addition to its role in the production and stabilization of free radicals and promotion of lipid peroxidation, may influence the metabolism of lipoproteins and their interaction with other molecules such as apolipoproteins, enzymes and receptors through the alteration of the LDL zeta potential and its particles tendency to aggregation.