Role of the VEGF in virus-associated cancers.

The role of numerous risk factors, including consumption of alcohol, smoking, having diet high in fat and sugar and many other items, on caner progression cannot be denied. Viral diseases are one these factors, and they can initiate some signalling pathways causing cancer. For example, they can be effective on providing oxygen and nutrients by inducing VEGF expression. In this review article, we summarised the mechanisms of angiogenesis and VEGF expression in cancerous tissues which are infected with oncoviruses (Epstein-Barr virus, Human papillomavirus infection, Human T-lymphotropic virus, Kaposi's sarcoma-associated herpesvirus, Hepatitis B and hepatitis C virus).

The evaluation of human endogenous retroviral env expression in normal and cancerous tissues of the breast.

Background: Both internal and external risk factors can accelerate the progression of breast cancer which is the reason why clinicians have tried to find new biomarkers for this health problem. Human endogenous retrovirus-W (HERV-W) can be one of these biomarkers, as it has been mentioned that some genes of this virus are able to have either higher or lower expression in numerous cancerous cells. In this study, we aimed to compare HERV-W envelope expression in breast cancer tissues and normal ones since its effects on this malignancy have not been clear. Materials and Methods: We collected 46 breast cancer tissues and their normal adjacent ones. After extracting the RNA of breast samples, we evaluated the expression of HERV-W envelope syncytin-1 and 2 using quantitative real-time polymerase chain reaction (PCR) in different kinds of breast cancer stages. Results: Data showed that more than 13% of patients had a family history of breast cancer; moreover, approximately half of the tissues were estrogen receptor or progesterone receptor positive. Lymph node metastasis was seen in 52% of the patients, and about 40% of tumors were larger than 2 cm. Real-time PCR showed that syncytin-1 and 2 had upward regulation with (*P < 0.05) and (**P < 0.01), respectively. Conclusion: As the expression of HERV-W Env (syncytin-1, syncytin-2) was higher in breast cancerous tissues in comparison with normal ones, we believe that these genes may have a role to play in monitoring patients suffering from this type of cancer. However, further studies are needed to confirm this hypothesis.

The prevalence of varicella zoster virus, herpes simplex virus type 2, and human papillomavirus in breast cancerous tissues and their adjacent ones in Iran.

Background: Breast cancer is the second type of cancer in the world. Some internal and external risk factors, especially infection diseases, can progress breast cancer. As the relation between varicella zoster virus (VZV), human papillomavirus (HPV), herpes simplex virus type 2 (HSV-2), and breast cancer has not been understood, it was attempting to find the effect of these viruses and breast cancer in this study. Materials and Methods: We collected 40 breast cancer and 50 healthy adjacent tissues from Taleghani and Imam Hossein Hospital, Tehran, Iran, in 3 years starting in 2017. After extracting DNA from breast tissues, multiplex polymerase chain reaction (PCR), nested PCR, and PCR were done to analyze the prevalence of HSV-2, VZV, and HPV. Results: Our results showed that HPV may be one of the important causes of breast cancer. Nested PCR illustrated nine breast cancerous tissues (mean age: 43) and three healthy adjacent ones (mean age: 41) were infected by HPV. Phylogenetic analysis illustrated that all of the infected HPV cancerous and healthy tissues were HPV 18 (except two healthy samples infected with HPV 6). Nevertheless, there were not any infected tissues by HSV-2 and VZV. Conclusion: It seems that HPV virus type 18 can have high prevalence in breast cancerous tissues in comparison with healthy adjacent ones, and it is likely to have an effect on breast cancer progression. However, the opposite trend is true for HSV-2 and VZV as we did not find any differences between different kinds of breast tissues.

Detection of Major Human Herpesviruses in Iranian Patients with Suspected Encephalitis Using Multiplex Polymerase Chain Reaction.

BACKGROUND: The Herpesviridae family plays a significant etiological role in central nervous system viral infections during primary infection or reactivation from a latent form. Early detection is crucial because prescribing some antivirals can prevent severe side effects or life-threatening conditions. METHODS: In this study, 251 CSF specimens were collected from patients with clinical suspicion of viral encephalitis in Pars Hospital, Tehran, Iran. DNA was extracted, and a multiplex PCR was designed to investigate the presence of herpes simplex virus-1, herpes simplex virus-2, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus. RESULTS: Overall, 59 cases of the 251 CSF samples were positive for multiplex PCR (23.5%). The most frequent positive findings were EBV and HSV, with a prevalence of 10.3% and 8.7% (5.5% HSV-1 and 3.1% HSV-2), respectively. Four co-infections were also seen in this study. CONCLUSIONS: This multiplex PCR assay detects simultaneously different herpesviruses in CSF samples of patients with suspected encephalitis in 2 rounds of PCR amplification; therefore, it is a reliable and cost-saving diagnostic method for evaluating patients infected with herpesvirus with neurological disorders.

Detection of human papillomavirus genotypes, herpes simplex, varicella zoster and cytomegalovirus in breast cancer patients.

BACKGROUND: The role of viruses as a cause of breast cancer (BC) has been significantly investigated in recent years. Human papillomavirus (HPV) has been detected in invasive breast carcinomas, while most studies have only focused on the detection of viral DNA, we aimed to examine the prevalence and genotypes of HPV among Iranian BC patients. We also examined the presence of herpes simplex-1 (HSV-1), herpes simplex-2 (HSV-2), varicella zoster virus (VZV), and cytomegalovirus (CMV) in these samples. METHODS: We collected and analyzed 70 Formalin-Fixed Paraffin-Embedded (FFPE) blocks including 59 BC samples, and 11 benign breast lesions as control from Iranian patients using nested PCR. Real-time PCR utilized as a confirming test to nested PCR findings. Genotyping of HPV positive samples was performed, the samples were also subjected to a multiplex PCR to detect HSV-1, HSV-2, VZV, and CMV in BC. RESULTS: Papillomavirus DNA was present in 7 of 59 BC samples (11.8%); while none was detected in control samples. The most prevalent type was HPV18, followed by HPV 6. All HPV positive patients had high tumor grades (II/ III) with a histologic diagnosis of ductal carcinoma. The patient age range was 33 to 73 years with a median of 51 years. Most of HPV positive patients had low levels of education. HPV16 was not detected. Also, 5 of 59 BC specimens (8.47%), were positive for HSV-1. But none of the samples were positive for HSV-2, VZV, and CMV. CONCLUSIONS: Our results suggest a carcinogenesis role for High-risk HPV (HPV18) in breast tumors. Our findings of HSV-1 and low-risk HPV (HPV6) in BCs may propose a cancer-causing role for them. Further large-scale studies are warranted to assess the significance of our findings.

Histone deacetylases in virus-associated cancers.

Oncogenic viruses are one of the most important causes of cancer worldwide. The pathogens contribute to the establishment of human malignancies by affecting various cellular events. Epigenetic mechanisms, such as histone modification methylation/demethylation, are one of the most critical events manipulated by oncogenic viruses to drive tumorigenesis. Histone modifications are mediated by histone acetylation and deacetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Dysregulation of HDACs activity affects viral tumorigenesis in several ways, such as manipulating tumor suppressor and viral gene expression. The present review aims to describe the vital interactions between both cancer-caused/associated viruses and the HDAC machinery, particularly by focusing on those viruses involved in gastrointestinal tumors, as some of the most common viral-mediated cancers.

Detection of Enterovirus, Herpes Simplex, Varicella Zoster, Epstein-Barr and Cytomegalovirus in cerebrospinal fluid in meningitis patients in Iran.

BACKGROUND: Despite medical advances, central nervous system (CNS) diseases put a pressure on the health care system. A number of risk factors, especially infectious agents can accelerate the progression of meningitis. As viruses probably account for most cases of meningitis, the diagnosis of them can reduce antibiotic prescriptions. Among various types of infectious diseases, the relationship between two important virus families, including Picornaviridae and Herpesviridae, and meningitis has attracted attraction. METHODS: In this study, one hundred and two samples were collected from patients who experienced symptoms, such as the loss of consciousness, seizures, muscle weakness, fever, headache, rash, and severe dementia, between November 2018 and September 2019. After RNA and DNA extraction, the prevalence of Enterovirus (EV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes simplex virus type 1 (HSV-1), Herpes simplex virus type 2 (HSV-2), and Varicella zoster virus (VZV) was evaluated using PCR, multiplex PCR, and nested PCR. RESULTS: Results indicated that there were two VZV DNA-positive specimens, while six and five samples were infected with HSV-1 and EBV, respectively. CONCLUSION: We reported that the prevalence of EBV, HSV-1, and VZV in patients, suffering from meningitis cannot be ignored; however, further investigation is needed.

Detection of extensively drug-resistant and hypervirulent Klebsiella pneumoniae ST15, ST147, ST377 and ST442 in Iran.

In this study, we focused on the emergence of extensively drug-resistant (XDR), pandrug-resistant (PDR), and hypervirulent Klebsiella pneumoniae (hvKP) in Iran. During 2018 to 2020 a total of 52 K. pneumoniae isolates were collected from different clinical specimens. The hvKP isolates were identified by PCR amplification of virulence and capsular serotype-specific genes. Hypermucoviscous K. pneumoniae (hmKP) were identified by string test. Carbapenem-resistant hvKP (CR-hvKP), multidrug-resistant hvKP (MDR-hvKP), extensively drug-resistant hvKP (XDR-hvKP), and pandrug-resistant hvKP (PDR-hvKP) were determined by disc diffusion method, Carba-NP test and PCR method. XDR-hvKP isolates were typed by multilocus sequence typing (MLST). Among all K. pneumoniae isolates 14 (26.9%) were identified as hvKP and 78.6% (11/14) of them were hmKP however, none of the classic K. pneumoniae (cKP) isolates were hmKP. The predominant capsular serotype of hvKP was K2 (42.85%) followed by K1 (35.71%). The prevalence of MDR-hvKP, XDR-hvKP and PDR-hvKP isolates were 6 (42.9%), 5 (35.7%) and 1 (7.1%), respectively. ESBL production was found in 85.7% of hvKP isolates and most of them carried bla TEM gene (78.6%) and 6 isolates (42.9%) were CR-hvKP. Among hvKP isolates, 1 (7.1%), 2 (14.3%), 3 (21.4%), 8 (28.6%), and 11 (78.6%) carried bla NDM-6, bla OXA-48, bla CTX-M, bla SHV, and bla TEM genes, respectively. According to MLST analysis, 2, 1, 1, and 1 XDR-hvKP isolates belonged to ST15, ST377, ST442, and ST147, respectively. The occurrence of such isolates is deeply concerning due to the combination of hypervirulence and extensively drug-resistance or pandrug-resistance.

The evaluation of Human papilloma virus and human herpes viruses (EBV, CMV, VZV HSV-1 and HSV-2) in semen samples.

There are a number of risk factors, especially viral diseases, which can lead to infertility. Among the various viral infections, much attention has been given to the role of the Papillomaviridae and Herpesviridae. After collecting 82 semen samples (37 teratospermia, 2 asthenozoospermia, 2 oligoasthenospermia, 1 oligospermia, 6 asthenoteratospermia and 34 normal semen samples), and washing them, the DNA from both freshly ejaculated spermatozoon and washed spermatozoa was extracted. Subsequently, the prevalence of EBV, CMV, HSV-1, HSV-2, VZV and HPV was evaluated using Multiplex PCR and Nested PCR. In this study, 1 normal and 5 abnormal semen samples were infected with HSV-1 (1 normal, 4 teratospermia and 1 oligoasthenospermia). In addition, there were 2 VZV-positive samples (both were teratozoospermia). Nested PCR indicated that 1 asthenozoospermia, 1 asthenoteratospermia, 3 teratospermia and 4 normal samples were HPV positive (including 8 HPV-18 and 1 HPV-33). Among 9 HPV-positive subjects, 3 samples were negative after washing the infected samples. The prevalence of EBV, CMV, VZV, HSV-1 and HSV-2 remained unchanged prior to and after washing. Maybe sperm washing can be useful to eliminate HPV infection from semen samples, but further investigation is required because of the small number of samples.

Exploiting yoeB-yefM toxin-antitoxin system of Streptococcus pneumoniae on the selective killing of miR-21 overexpressing breast cancer cell line (MCF-7).

Toxin-antitoxin (TA) systems are two-component genetic modules widespread in bacterial and archaeal genomes, in which the toxin module is rendered inactive under resting conditions by its antitoxin counterpart. Under stress conditions, however, the antitoxin is degraded, freeing the toxin to exert its lethal effects. Although not evolved to function in eukaryotes, some studies have established the lethal activity of these bacterial toxins by inducing apoptosis in mammalian cells, an effect that can be neutralized by its cognate antitoxin. Inspired by the way the toxin can become active in eukaryotes cells, we produced an engrained yoeB-yefM TA system to selectively kill human breast cancer cells expressing a high level of miR-21. Accordingly, we generated an engineered yefM antitoxin gene with eight miR-21 target sites placed in its 3'untranslated region. The resulting TA system acts autonomously in human cells, distinguishing those that overexpress miR-21, killed by YoeB, from those that do not, remaining protected by YefM. Thus, we indicated that microRNA-control of the antitoxin protein of bacterial TA systems constitutes a novel strategy to enhance the selective killing of human cancer cells by the toxin module. The present study provides significant insights for developing novel anticancer strategies avoiding off-target effects, a challenge that has been pursued by many investigators over the years.

Global estimate of phenotypic and genotypic ganciclovir resistance in cytomegalovirus infections among HIV and organ transplant patients; A systematic review and meta-analysis.

Human cytomegalovirus (CMV), an opportunistic pathogen belonging to Herpesviridae family, is considered as one of the major causes of morbidity and mortality among wide variety of patients, particularly in transplant recipients and HIV positive patients. As this virus can be resistant to treatment, frequency of CMV in patients who receive organ transplantation and people suffering from AIDS was studied between 1980 and 2019. Medline (via PubMed), Embase, Web of Science, and the Iranian Database were reviewed, and Comprehensive Meta-Analysis (V2.0, Biostat) software analyzed all data. Finally, we used Cochran's Q-statistic to encounter heterogeneity between different studies. Meta-analyses indicated, GCV resistance was 14.1% (95% CI 11.2-17.7); however, in patients suffering from AIDS and organ transplantation were 19.5% (95% CI 14.7-25.4) and 11.4% (95% CI 8.1-15.8), respectively. There were increasing rates in the prevalence of GCV resistance in CMV among transplant recipients, and HIV positive patients. Therefore, evaluation of these refractory infections is beneficial.

Aneuploidy and oncoviruses.

Seven oncogenic viruses are known for tumorigenesis and contribute to 12% of all human cancers. The oncogenic factors, the target tissue, and pathology of cancer vary among these viruses with several mechanisms proposed for the initiation and development of cancer. Aneuploidy in cells is associated with anomalies in chromosome number that can be a hallmark of cancer, a disease defined by expanded proliferative potential. In this review, we summarize the different mechanisms of aneuploidy and furthermore discuss recent findings of the role of viral oncoproteins in inducing cellular aneuploidy that might facilitate tumorigenesis. Improved understanding of viral oncogenesis may help to find new strategies for controlling virus-associated cancers.

DNA methyltransferases in virus-associated cancers.

Human tumor viruses are either casually linked or contribute in the development of human cancers. Viruses can stimulate oncogenesis through affecting diverse biological pathways in human cells. Growing data have demonstrated frequent involvement of one of the most characteristic parts of cellular epigenetic machinery, DNA methylation, in the oncogenesis. DNA methylation of cellular genes is catalyzed by DNA methyltransferases (DNMTs) as a key effector enzyme in this process. Dysregulation of DNMTs can cause aberrant gene methylation in promoter of cancer-related genes including tumor suppressor genes, resulting in gene silencing. In this regard, the role of tumor viruses is remarkable. Here, in this review, we used published information to elucidate whether tumor viruses are able to manipulate DNMT regulation, and if so, what are its consequences in the process of oncogenesis. This essay also aims to shed light on which cellular pathways have been engaged by viruses to induce DNMTs.

The roles of FOX proteins in virus-associated cancers.

Forkhead box (FOX) proteins play a crucial role in regulating the expression of genes involved in multiple biological processes, such as metabolism, development, differentiation, proliferation, apoptosis, migration, invasion, and longevity. Deregulation of FOX proteins is commonly associated with cancer initiation, progression, and chemotherapeutic drug resistance in many human tumors. FOX proteins deregulate through genetic events and the perturbation of posttranslational modification. The purpose of the present review is to describe the deregulation of FOX proteins by oncoviruses. Oncoviruses utilize various mechanisms to deregulate FOX proteins, including alterations in posttranslational modifications, cellular localization independently of posttranslational modifications, virus-encoded miRNAs, activation or suppression of a series of cell signaling pathways. This deregulation can affect proliferation, metastasis, chemotherapy resistance, and immunosuppression in virus-induced cancers and help to chronic viral infection, development of gluconeogenic responses, and inflammation. Since the PI3K/Akt/mTOR signaling pathway is the upstream FOXO, suppressing it can cause FOXO function to return, and this can be one of the reasons for patients to recover from the infection of the viruses used to treat these inhibitors. Hence, FOX proteins could serve as prognosis markers and target therapy specifically in cancers caused by oncoviruses.

Serum and tissue miRNAs: potential biomarkers for the diagnosis of cervical cancer.

BACKGROUND: Finding new biomarkers for the early detection of cervical cancer is an essential requirement in this field. In this study, we aimed to evaluate the expression level of potential biomarkers in progression of cervical cancer in patients with cervical cancer compared to normal subjects. METHODS: The expression levels of tissue and serum miRNAs, including miR-9, miR-192 and miR-205, were investigated in 36 normal, 18 precancer, and 18 cervical cancer samples using real-time polymerase chain reaction. RESULTS: The results showed the higher significant expressions of miR-9, miR-192 and miR-205 in the tissue of cancer samples than those in the normal samples. Moreover, the miR-192 and miR-205 expression were significantly increased in the cancer group in comparison with the precancer group. Examination of serum samples revealed the increase in the expression level in the cancer groups than in the normal samples, for miR-9, miR-192 and miR-205 and the expressions of miR-9, miR-192 and miR-205 were significantly up-regulated in the precancer group in comparison with the normal group. Also the expression of miR-205 was remarkably increased in the cancer group in comparison with the precancer group. The receiver operating characteristic (ROC) analyses showed the highest area under the curve value for miR-192. CONCLUSIONS: Given the increased expression level of miR-192 in cancer and in precancerous tissue and serum compared with the normal tissue and serum validated by analysing the ROC curve, miR-192 can be used as potential biomarker for the early detection of cervical cancer.

Viruses as key modulators of the TGF-ß pathway; a double-edged sword involved in cancer.

Transforming growth factor-ß (TGF-ß) signaling pathway is a key network in cell signaling that controls vital processes such as proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and migration, thus acting as a double-edged sword in normal development and diseases, in particular organ fibrosis, vascular disorders, and cancer. Early in tumorigenesis, the pathway exerts anti-tumor effects through suppressing cell cycle and inducing apoptosis, while during late stages, it functions as a tumor promoter by enhancing tumor invasiveness and metastasis. This signaling pathway can be perturbed by environmental and genetic factors such as microbial interference and mutation, respectively. In this way, the present review describes the modulation of the TGF-ß pathway by oncogenic human viral pathogens and other viruses. The main mechanisms by which viruses interferes with TGF-ß signaling seems to be through (1) the alteration of either TGF-ß protein expression or activation, (2) the modulation of the TGF-ß receptors or SMADs factors (by interfering with their levels and functions), (3) the alteration of none-SMAD pathways, and (4) indirect interaction with the pathway by the modulation of transcriptional co-activator/repressor and regulators of the pathway. Given the axial role of this pathway in tumorigenesis, it can be regarded as an attractive target for cancer therapy. Hence, further investigations on this subject may represent molecular targets among either TGF-ß signaling molecules or viral factors for the treatment and management of viral infection consequences such as cancer.

Relationship of human herpes virus 6 and multiple sclerosis: A systematic review and meta-analysis.

Infection with human herpes viruses has been suggested to contribute to multiple sclerosis (MS), while interaction between human herpes 6 (HHV6) and MS remain unclear yet. Here, we conducted a meta-analysis on the relationship of HHV6 infection and MS. All related studies were collected from major databases. The analyses were performed by STATA 14 and Comprehensive Meta-Analysis V2.0 softwares. Pooled odds ratios (ORs) and 95%CIs were calculated from the raw data of the including studies by the random effects models when I2 > 50% and fix model when I2 < 50%. Thirty nine studies were included in the meta-analysis that 34 studies used molecular assays and 7 studies used serological assays for diagnosis of HHV6 infected cases. The relationship of HHV6 and MS was significant in healthy control group by yielding a summary OR of (2.23 [1.5-3.3], p = 0.06). A significant HHV6 association with MS were in the studies with >6 score that used serum/blood sample with OR of (6.7 [95%CI 4.8-8.6], p < 0.00001) and in serological studies, IgM positive titer in other neurological diseases (OND) control group was significant with OR of (8.3 [95%CI 3-24.07], p < 0.00001). This study has been showed that there were significant relationship between MS and HHV6 infection.

Role of viruses in gastrointestinal cancer.

Gastrointestinal cancers are a global public health problem, which represent a vast majority of all cancer-caused deaths in both men and women. On the other hand, viral pathogens have been long implicated as etiological factors in the onset of certain human cancers, including gastrointestinal tumors. In this regard, Human Papilloma Virus (HPV), Epstein-Barr Virus (EBV), and John Cunningham Virus (JCV) have been more strongly suggested to be involved in gastrointestinal carcinogenesis; so that, the association of HPV with oropharyngeal and anal cancers and also the association of EBV with gastric cancer have been etiologically confirmed by epidemiological and experimental investigations. Although, the association of other viruses is less evident, but may rely on co-factors for their oncogenic roles. Therefore, to improve the prevention and treatment of these classes of cancer, their association with viral agents as potential risk factors should be investigated with care. In this respect, the present review has focused on the existing literature on the subject of viral involvement in gastrointestinal tumorgenesis, by covering and discussing various gastrointestinal cancers, corresponding viral agents and their oncogenic aspects and then summarizing evidences either supporting or rejecting a causal role of these pathogens in gastrointestinal malignancies.

The role of Nrf2 transcription factor in viral infection.

The nuclear factor erythroid 2 related factor 2 (Nrf2) is a major regulator of intracellular inducible defense systems against harmful endogenous and exogenous substances in the body. Under normal conditions Nrf2 is mainly binds to keap1 and located in the cytoplasm. However, in response to oxidative and electrophile stress, Nrf2 translocated to the nucleus and link to anti-oxidant response elements to induce the transcription of cytoprotective genes. Most viruses cause oxidative stress and increase the activity of radicals and reactive oxygen species (ROS), subsequently, the cellular protection system activates the Nrf2 and increases the expression of cytoprotective genes. However, in some cases, the activation of Nrf2 is not ROS-dependent, and is carried out directly via the ROS-independent pathway. Many viruses cause the activation of Nrf2, which is involved in the pathogenesis and the progression of the virus infection and even in its chronic form. However, some viruses inhibit the activation of Nrf2, in which case the virus also benefits of this mechanism to maintain the homeostasis of the cell. However, the challenge between the Nrf2/ARE signaling pathway of and viral infections is unknown in some cases, and in order to know more details in this regard, a more detailed seems necessary.

Anoikis resistance and oncoviruses.

Anoikis is known as a special type of programmed cell death which occurs in response to loss of correct cell-extracellular matrix (ECM) connections. This process could be as pivotal event in normal development and tissue homeostasis and found as important mechanism in cancer invasiveness and metastasis. The persistent infection with oncoviruses including EBV (Epstein Bar virus), HPV (Human Papillomaviruses), HBV (Hepatitis B virus), KSHV (Human herpesvirus 8), HTLV-1 (Human T-lymphotropic virus-1), and HCV (Hepatitis C virus) accounted as one of main risk factor for cancer progression. Some of them play critical roles in metastasis, especially in anoikis resistance which could contribute to metastasis of tumor cells. The better understanding of effects of oncoviruses on anoikis could contribute to finding of effective therapeutic platforms for treatment of virus-associated cancers. This paper highlighted effects of these oncoviruses on anoikis protection in cancer.