Critical involvement of circular RNAs in virus-associated cancers.

Virus-related cancer is cancer where viral infection leads to the malignant transformation of the host's infected cells. Seven viruses (e.g., human papillomavirus (HPV), Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T-lymphotropic virus (HTLV), and Merkel cell polyomavirus (MCV)) that infect humans have been identified as an oncogene and have been associated with several human malignancies. Recently, growing attention has been attracted to exploring the pathogenesis of virus-related cancers. One of the most mysterious molecules involved in carcinogenesis and progression of virus-related cancers is circular RNAs (circRNA). These emerging non-coding RNAs (ncRNAs), due to the absence of 5' and 3' ends, have high stability than linear RNAs and are found in some species across the eukaryotic organisms. Compelling evidence has revealed that viruses also encode a repertoire of circRNAs, as well as dysregulation of these viral circRNAs play a critical role in the pathogenesis and progression of different types of virus-related cancers. Therefore, understanding the exact role and function of the virally encoded circRNAs with virus-associated cancers will open a new road for increasing our knowledge about the RNA world. Hence, in this review, we will focus on emerging roles of virus-encoded circRNAs in multiple cancers, including cervical cancer, gastric cancer, Merkel cell carcinoma, nasopharyngeal carcinoma, Kaposi cancer, and liver cancer.

Prevalence of Co-infection by Human Papillomavirus, Epstein- Barr Virus and Merkel Cell Polyomavirus in Iranian Oral Cavity Cancer and Pre-malignant Lesions.

Human papillomavirus (HPV) is recognized as the most important risk factor in oral cavity cancer and pre-malignant lesions; however, the etiological association of concomitant infection with other oncogenic viruses as a co-factor has not been definitively proven. The present study aimed to determine the prevalence of co-infection with HPV, Epstein-Barr virus (EBV) and Merkel Cell PolyomaVirus (MCPyV) in oral cavity lesions in Iranian patients. One hundred and fourteen oral cavity samples, including 33 oral squamous cell carcinoma, 28 oral lichen planus, 16 oral epithelial dysplasia and 37 oral irritation fibromas were analyzed for the HPV, EBV and MCPyV infection by quantitative real-time PCR. According to histological features 32.5% and 28.9% of cases were oral irritation fibroma and oral squamous cell carcinoma, respectively. Infection with at least two viruses was detected in 21.1% of patients. In this group, co-infection with HPV/EBV was identified in 37.5% of cases, HPV/MCPyV in 29.2%, EBV/MCPyV in 12.5%, and HPV/EBV/MCPyV in 20.8%. There was no statistically significant difference between multiple infections and anatomical locations of cancer. The prevalence of triple viral infection (HPV/EBV/MCPyV) in well differentiated tumors was higher than EBV or MCPyV single infection. This study revealed that co-infection of HPV, EBV and MCPyV can be detected in both malignant and non-malignant oral cavity tissues, and co-infection with all three viruses in well differentiated tumors can be shown as a synergistic hypothesis of the pathogenic role of these viruses in oral malignant transformation.

Higher viral load of Epstein-Barr virus in gastric cancer compared with non-cancerous gastroduodenal tissues.

Introduction: Epstein-Barr Virus (EBV)-associated gastric cancer is a distinct molecular subtype of gastrointestinal carcinomas as defined by the Cancer Genome Atlas. Methods: In the present study 237 samples from Iranian patients diagnosed with gastric cancer and gastroduodenal disease were retrospectively examined for EBV infection by quantitative Real-Time PCR. Results: Of the 237 samples tested, EBV DNA was detected in 37 samples (15.6%), in 13 of the 81 gastric cancer cases (16%), and 24 of the 156 non-cancerous samples (15.4%). The EBV infection rate was found higher in patients with gastric ulcer (35%) and duodenal ulcer (21.9%) compared to patients with gastric cancer (16%) and gastritis (19.6%). The EBV-encoded small RNA (EBER) copy number in the gastric cancer group (mean = 2.14×10-1 with range of 2.14×10-2 to 4.10×10-1 copies/ cell) was higher than gastroduodenal diseases group (mean = 1.39×10-2 with range 1.11×10-3 to 2.35×10-2 copies/ cell), and this difference was statistically significant (P >0.001). Conclusion: The higher number of copies of EBV-EBER in the gastric cancer group compared to the non-cancer group confirmed the possible role of EBV in inducing cancer.

The role of human endogenous retroviruses (HERVs) in Multiple Sclerosis and the plausible interplay between HERVs, Epstein-Barr virus infection, and vitamin D.

Multiple Sclerosis (MS) is one of the chronic inflammatory diseases with neurological disability in the central nervous system (CNS). Although the exact cause of MS is still largely unknown, both genetic and environmental factors are thought to play a role in disease risk. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome whose expression is associated with MS. HERVs are normally silenced or expressed at low levels, although their expression is higher in MS than in the healthy population. Several studies highlighted the plausible interaction between HERVs and other MS risk factors, including viral infection like Epstein-Barr viruses and vitamin D deficiency which may lead to high expression of HERVs in these patients. Understanding how HERVs act in this scenario can improve our understanding towards MS etiology and may lead to the development of antiretroviral therapies in these patients. Here in this review, we try to examine the different HERVs expression implicated in MS and their association with EBV infection and vitamin D status.

Prevalence of Merkel Cell Polyomavirus (MCPyV) in the Oral Cavity Biopsies in Northern Iran.

OBJECTIVE: Infection with human tumor viruses is one of the hypothesized causes of cancer. The current investigation aimed to explore the presence and quantitative analysis of a new human tumor virus, Merkel cell polyomavirus (MCPyV) in tissue samples of 114 patients with oral cavity lesions including oral squamous cell carcinoma (OSCC), oral lichen planus (OLP), Dysplasia and oral irritation fibroma (OIF) in Northern Iran. METHODS: From 114 formalin fixed paraffin embedded samples; 35 with SCC, 29 with OLP, 14 with dysplasia and 36 with OIF were cut, deparaffinized and DNA was extracted. Quantitative detection of MCPyV large T antigen was performed by absolute quantitative Real-Time PCR. RESULT: MCPyV DNA was detected in 30.6% (n: 11/36) of IF, 24.1% (n; 7/29) of OLP, 21.4% (n:3/14) of dysplasia and 20% (n;7/35) of OSCC samples. The mean MCPyV DNA copy number was 2.32×10-2 ± 3.97 ×10-2, 2.02×10-2 (SD=3.13×10-2), 2.69×10-4 (SD=2.51×10-4), and 2.56×10-4 (SD=6.73×10-4) per cell in OSCC, dysplasia and both of OLP and OIF samples, respectively (P=0.76). CONCLUSION: This study provides the first data from Iran regarding the presence of MCPyV genome in oral cavity lesions and oral cancer. These results also emphasize that MCPyV has an active role in the occurrence of oral lesions and progression to cancer. Further studies should be carried out to clarify the role of MCPyV in oral cavity lesions.

Detection of Epstein-Barr virus encoded small RNA genes in oral squamous cell carcinoma and non-cancerous oral cavity samples.

BACKGROUND: Epstein-Barr Virus (EBV) is a human oncogenic virus that can lead to cancer in lymphoid and epithelial cells and is one of the hypothesized causes of oral cavity lesions including oral squamous cell carcinoma (OSCC), but the etiological association remains undetermined. The present investigation aimed to explore the EBV presence, viral load, and EBV-encoded small RNA (EBER) sequence variation in tissue samples of patients with OSCC and other oral cavity lesions including oral lichen planus (OLP), and oral irritation fibroma (OIF). METHODS: In total, 88 oral cavity samples (23 with OSCC, 29 with OLP, and 36 with OIF diagnosis) were examined by Real-Time PCR technique and some of them were sequenced. RESULTS: Viral EBER sequence was detected in 6 out of the 23 OSCC (31.4%), 6 out of the 29 OLP (20.7%), and 3 out of the 36 OIF cases (8.3%). The mean EBV copy number was higher in OSCC samples (1.2 × 10-2 ± 1.3 × 10-2 copies/cell) compared to OLP (2.2 × 10-3 ± 2.6 × 10-3 copies/cell) and OIF (2.4 × 10-4 ± 2.0 × 10-4 copies/cell) samples, although this difference was not statistically significant (P = 0.318). The EBER gene was amplified and sequenced in 5 OSCC, 3 OLP, and 2 OIF samples with high EBV viral load. One OSCC, two OLP, and two OIF isolates showed different nucleotide variations compared with EBV-WT and AG876 prototype sequences: C6834T, C6870T, C6981T, C7085T, C7085G, and C7094T. CONCLUSION: In our study the presence of more than one genome copies per tumor cell indicates the possible role of EBV infection in oral cancers. However, more studies should be conducted to clarify the role of EBV in OSCC carcinogenesis.

The critical role of mesenchymal stromal/stem cell therapy in COVID-19 patients: An updated review.

New coronavirus disease 2019 (COVID-19), as a pandemic disaster, has drawn the attention of researchers in various fields to discover suitable therapeutic approaches for the management of COVID-19 patients. Currently, there are many worries about the rapid spread of COVID-19; there is no approved treatment for this infectious disease, despite many efforts to develop therapeutic procedures for COVID-19. Emerging evidence shows that mesenchymal stromal/stem cell (MSC) therapy can be a suitable option for the management of COVID-19. These cells have many biological features (including the potential of differentiation, high safety and effectiveness, secretion of trophic factors and immunoregulatory features) that make them suitable for the treatment of various diseases. However, some studies have questioned the positive role of MSC therapy in the treatment of COVID-19. Accordingly, in this paper, we will focus on the therapeutic impacts of MSCs and their critical role in cytokine storm of COVID-19 patients.

Prevalence and viral load determination of BK polyomavirus among Iranian patients with brain tumors.

BACKGROUND: Due to persistent infections of human central nervous system (CNS), polyomaviruses have been identified as one of the risk factors for brain tumor development. Human BK virus is of significant interest due to its experimental neuro-oncogenic potential and the possible association with CNS neoplasms. However, the results of different studies are discrepant. In the present study, we aimed to investigate the prevalence of BK virus genome and quantify BK viral load in Iranian patients with primary and metastatic brain malignancies. METHODS: To assess the prevalence of BK virus sequences, a total of 58 fresh brain tumors were examined by quantitative real-time PCR. The BK viral load was determined as viral copy number per cell. RESULTS: Of the 58 brain tumor samples BK tumor antigen (TAg) sequences were detected in 26 (44.8%) of cases. In primary brain tumors, BK virus sequences were recognized more frequently in schwannomas (15.5%) and meningiomas (12.1%). The mean BK virus TAg copy number in positive cases was 0.20×10-3±0.27×10-3 (range 0.01×10-3- 0.8×10-3) copies per cell. CONCLUSION: Taken together, in the present study low copy numbers of BK virus TAg gene was detected in brain tumor cells, which can indicate that BK virus may contribute to tumor induction by indirect mechanisms or neuro-persistence of this virus without any pathological consequences.

Critical review of Epstein-Barr virus microRNAs relation with EBV-associated gastric cancer.

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is regarded as the most prevalent malignant tumor triggered by EBV infection. In recent years, increasing attention has been considered to recognize more about the disease process's exact mechanisms. There is accumulating evidence that showing epigenetic modifications play critical roles in the EBVaGC pathogenesis. MicroRNAs (miRNAs), as critical epigenetic modulators, are single-strand short noncoding RNA (length ~ <200 bp), which regulate gene expression through binding to the 3'-untranslated region (3'-UTR) of target RNA transcripts and either degrade or repress their activities. In the latest research on EBV, it was found that this virus could encode miRNAs. Mechanistically, EBV-encoded miRNAs are involved in carcinogenesis and the progression of EBV-associated malignancies. Moreover, these miRNAs implicated in immune evasion, identification of pattern recognition receptors, regulation of lymphocyte activation and lethality, modulation of infected host cell antigen, maintain of EBV infection status, promotion of cell proliferation, invasion and migration, and reduction of apoptosis. As good news, not only has recent data demonstrated the crucial function of EBV-encoded miRNAs in the pathogenesis of EBVaGC, but it has also been revealed that aberrant expression of exosomal miRNAs in EBVaGC has made them biomarkers for detection of EBVaGC. Regarding these substantial characterizes, the critical role of EBV-encoded miRNAs has been a hot topic in research. In this review, we will focus on the multiple mechanisms involved in EBVaGC caused by EBV-encoded miRNAs and briefly discuss their potential application in the clinic as a diagnostic biomarker.