The AP‐1 pathway; A key regulator of cellular transformation modulated by oncogenic viruses

Cancer progression is critically associated with modulation of host cell signaling pathways. Activator protein‐1 (AP‐1) signaling is one such pathway whose deregulation renders the host more susceptible to cancer development. Oncogenic viruses, including hepatitis B virus, hepatitis C virus, human papilloma virus, Epstein‐Barr virus, human T‐cell lymphotropic virus type 1, and Kaposi's sarcoma‐associated herpes virus, are common causes of cancer. This review discusses how these oncoviruses by acting through various aspects of the host cell signaling machinery such as the AP‐1 pathway might affect oncoviral tumorigenesis, replication, and pathogenesis. The review also briefly considers how the pathway might be targeted during infections with these oncogenic viruses.     

The Wnt pathway: a key network in cell signalling dysregulated by viruses

Viruses are obligate parasites dependent on host cells for survival. Viral infection of a cell activates a panel of pattern recognition receptors that mediate antiviral host responses to inhibit viral replication and dissemination. Viruses have evolved mechanisms to evade and subvert this antiviral host response, including encoding proteins that hijack, mimic and/or manipulate cellular processes such as the cell cycle, DNA damage repair, cellular metabolism and the host immune response. Currently, there is an increasing interest whether viral modulation of these cellular processes, including the cell cycle, contributes to cancer development. One cellular pathway related to cell cycle signalling is the Wnt pathway. This review focuses on the modulation of this pathway by human viruses, known to cause (or associated with) cancer development. The main mechanisms where viruses interact with the Wnt pathway appear to be through (i) epigenetic modification of Wnt genes; (ii) cellular or viral miRNAs targeting Wnt genes; (iii) altering specific Wnt pathway members, often leading to (iv) nuclear translocation of β‐catenin and activation of Wnt signalling. Given that diverse viruses affect this signalling pathway, modulating Wnt signalling could be a generalised critical process for the initiation or maintenance of viral pathogenesis, with resultant dysregulation contributing to virus‐induced cancers. Further study of this virus–host interaction may identify options for targeted therapy against Wnt signalling molecules as a means to reduce virus‐induced pathogenesis and the downstream consequences of infection. Copyright © 2016 John Wiley & Sons, Ltd.     

Anti-Jagged-1 immunotherapy in cancer

Notch signaling is a highly conserved pathway and it plays an essential role in regulating cellular proliferation, differentiation, and apoptosis. The human Notch family includes four receptors, Notch 1–4, and five ligands, delta-like ligand 1 (DLL1), delta-like ligand 3 (DLL3), delta-like ligand 4 (DLL4), Jagged-1 (JAG1), and Jagged-2 (JAG2). It is widely known, that Notch signaling components are often mutated and have deregulated expression in many types of cancer and other diseases. Thus, various therapeutic approaches targeting receptors and ligands of the Notch pathway are being investigated. Human JAG1 is closely related to tumor biology among the Notch ligands, and recent studies have shown potential for monoclonal antibodies targeting JAG1 in cancer therapy. Therefore, this review focuses on current reports on the significance of JAG1 directed cancer treatment, emphasizing immunotherapy.     

Viral etiology of sporadic cases of parotitis among children in Korea during 2013‐2014

Recent years have seen a high incidence of mumps, which is generally diagnosed based on clinical features, especially parotitis, without laboratory confirmation in Korea. To better understand the epidemiology of mumps in Korean children, we investigated sporadic suspected mumps cases with parotitis. In total, 237 buccal swabs or throat swabs collected from children with parotitis who had been clinically diagnosed with mumps were tested using real‐time PCR for the detection of six viruses (Epstein‐Barr virus, Human herpesvirus 6, Mumps virus, Human parainfluenza virus‐1, ‐2, ‐3, Human adenovirus, Human bocavirus). Among 237 parotitis cases, 87 (36.7%) were positive for at least one virus; a single infection was observed in 73 (83.9%) cases, and co‐infections were detected in 14 (16.1%) cases. Epstein‐Barr virus was most frequent (20.7%), followed by human herpesvirus 6 (8.0%), mumps virus (5.5%), human parainfluenza virus‐3 (4.6%), human adenovirus (4.2%), and human bocavirus (0.4%). These data suggested that the sporadic suspected mumps in the children might be related to other respiratory viruses rather than to the mumps virus. Our findings also indicate the limitation of clinical diagnosis without laboratory confirmation for mumps and thus highlight the importance of laboratory testing in suspected mumps cases.     

Are human polyomaviruses co‐factors for cancers induced by other oncoviruses?

Presently, 12 human polyomaviruses are known: BK polyomavirus (BKPyV), JCPyV, KIPyV, WUPyV, Merkel cell polyomavirus (MCPyV), HPyV6, HPyV7, Trichodysplasia spinulosa‐associated polyomavirus, HPyV9, HPyV10, STLPyV and HPyV12. In addition, the non‐human primate polyomavirus simian virus 40 (SV40) seems to circulate in the human population. MCPyV was first described in 2008 and is now accepted to be an etiological factor in about 80% of the rare but aggressive skin cancer Merkel cell carcinoma. SV40, BKPyV and JCPyV or part of their genomes can transform cells, including human cells, and induce tumours in animal models. Moreover, DNA and RNA sequences and proteins of these three viruses have been discovered in tumour tissue. Despite these observations, their role in cancer remains controversial. So far, an association between cancer and the other human polyomaviruses is lacking. Because human polyomavirus DNA has been found in a broad spectrum of cell types, simultaneous dwelling with other oncogenic viruses is possible. Co‐infecting human polyomaviruses may therefore act as a co‐factor in the development of cancer, including those induced by other oncoviruses. Reviewing studies that report co‐infection with human polyomaviruses and other tumour viruses in cancer tissue fail to detect a clear link between co‐infection and cancer. Directions for future studies to elaborate on a possible auxiliary role of human polyomaviruses in cancer are suggested, and the mechanisms by which human polyomaviruses may synergize with other viruses in oncogenic transformation are discussed. Copyright © 2014 John Wiley & Sons, Ltd.     

Notch信号通路及其在肺癌发生中的作用

Notch信号通路存在于多种动物体内,是许多细胞信号转导通路的交汇点,不仅对正常组织、细胞的分化、发育起重要作用,而且和一些肿瘤的发生、发展相关。Notch信号在肺癌中的作用多样，在不同类型肺癌中呈现出不同的促癌或抑癌功能。了解Notch和肺癌的关系有利于进一步阐明肺癌发生机制,提出预防和治疗肺癌的新途径，为肿瘤基因治疗提供一个新的有希望的靶点。     

Notch1 modulates mesenchymal stem cells mediated regulatory T‐cell induction

Notch1 signaling is involved in regulatory T (Treg)‐cell differentiation. We previously demonstrated that, when cocultured with CD3⁺ cells, mesenchymal stem cells (MSCs) induced a T‐cell population with a regulatory phenotype. Here, we investigated the molecular mechanism underlying MSC induction of human Treg cells. We show that the Notch1 pathway is activated in CD4⁺ T cells cocultured with MSCs. Inhibition of Notch1 signaling through GSI‐I or the Notch1 neutralizing antibody reduced expression of HES1 (the Notch1 downstream target) and the percentage of MSC‐induced CD4⁺CD25^highFOXP3⁺ cells in vitro. Moreover, we demonstrate that FOXP3 is a downstream target of Notch signaling in human cells. No crosstalk between Notch1 and TGF‐β signaling pathways was observed in our experimental system. Together, these findings indicate that activation of the Notch1 pathway is a novel mechanism in the human Treg‐cell induction mediated by MSCs.     

Human ligands of the Notch receptor

During development, the Notch signaling pathway is essential for the appropriate differentiation of many cell types in organisms across the phylogenetic scale, including humans. Notch signaling is also implicated in human diseases, including a leukemia and two hereditary syndromes known as Alagille and CADASIL. To generate tools for pursuing the role of the Notch pathway in human disease and development, we have cloned and analyzed the expression of three human homologues of the Notch ligands Delta and Serrate, human Jagged1 (HJ1), human Jagged2 (HJ2), and human Delta1 (H-Delta-1), and determined their chromosomal localizations. We have also raised antibodies to HJ1, and used these antibodies in conjunction with in situ hybridization to examine the expression of these ligands in normal and cancerous cervical tissue. We find that, as reported previously for Notch, the ligands are up-regulated in certain neoplastic tissues. This observation is consistent with the notion that Notch signaling is an important element in these pathogenic conditions, raising the possibility that modulation of Notch activity could be used to influence the fate of the cells and offering a conceivable therapeutic avenue.     

Human virus-specific CD8+ T cells: diversity specialists

Summary: Human viruses elicit functionally highly diverse CD8⁺ T‐cell responses. This variation, which manifests in the memory or latency stage, includes differences in expansion requirements, migratory properties, homeostatic maintenance mechanisms, and constitutive effector properties, and it may reflect specific adaptations of the human immune system to challenges posed by individual pathogens. Longitudinal follow‐up of individuals after primary virus infections has revealed how divergent virus‐specific CD8⁺ T cells may develop from the initially expanded virus‐specific T‐cell effector pool. Recent findings have shown that CD8⁺ T cells reactive toward latent viruses may depend on other mechanisms for their homeostatic maintenance than T cells specific for cleared viruses. Whereas the latter can respond to the homeostatic cytokine interleukin‐7 (IL‐7), many persistent virus‐specific T cells, recognizing latent herpesviruses such as Epstein–Barr virus and cytomegalovirus (CMV), lack IL‐7 receptor α (IL‐7Rα) and depend on viral antigens to persist. Finally, CMV is unique in that it generates a vast pool of resting virus‐specific T cells with constitutive cytolytic effector function. The putative role of functionally diverse CD8⁺ T cells in protective immunity to persistent viruses is discussed in this review.     

Dengue virus up‐regulates expression of notch ligands Dll1 and Dll4 through interferon‐β signalling pathway

The Notch signalling pathway is involved in multiple cellular processes and has been recently indicated to modulate the host immune response. However, the role of the Notch pathway in dengue virus (DENV) infection remains unknown. Our study has screened the expression profile of Notch receptors, ligands and target genes in human monocytes, macrophages and dendritic cells in response to DENV infection. The real‐time PCR data showed that Notch ligand Dll1 was significantly induced in DENV‐infected monocytes; and receptor Notch4, ligands Dll1 and Dll4, and target Hes1 were dramatically enhanced in DENV‐infected macrophages and dendritic cells. In macrophages, induction of Dll1 and Dll4 mediated by DENV2 was increased by treatment with interferon‐β (IFN‐β), and was impaired by neutralization of IFN‐β. The DENV‐induced Dll1 and Dll4 expression level was decreased by silencing key innate immune molecules, including Toll‐like receptor 3 (TLR3), MyD88, RIG‐I and IPS‐I. In IFN‐receptor‐depleted macrophages, the Dll1 and Dll4 induction was significantly alleviated. Functionally, activation of Notch signalling by Dll1 in CD4⁺ T cells enhanced the expression of a T helper type 1 (Th1) cytokine IFN‐γ, while Notch activation in macrophages had no direct effect on replication of DENV. Our data revealed that the expressions of Notch ligands in antigen‐presenting cells were differentially induced by DENV via innate immune signalling, which is important for Th1/Th2 differentiation during adaptive immune response.     

In Brief: Notch signalling in health and disease

The Notch pathway controls many aspects of development and is mutated in various human cancers. Remarkably, Notch function changes during the development of cellular hierarchies and can be either oncogenic or tumour‐suppressive, depending on cellular context. Notch dysregulation is also important in cardiovascular disease and disorders of immunity. This mini‐review outlines key features of the Notch signalling pathway and emerging data linking it to human diseases. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Gamma-secretase complex-dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma

The γ-secretase complex is a presenilin-dependent aspartyl protease involved in the intramembranous cleavage of various type I transmembrane proteins. As a type I transmembrane protein, CD147 is highly expressed in hepatoma cells and promotes cell proliferation, migration, and invasion. However, the direct underlying mechanism of how CD147 promotes cancer cell proliferation is unknown. Here, we demonstrated that CD147 undergoes an intramembranous cleavage by the γ-secretase at lysine 231 to release its intracellular domains (ICDs). The nuclear translocation of the CD147ICD regulated Notch1 expression by directly binding to the NOTCH1 promoter and promoted the activation of the Notch signaling pathway. Simultaneously, overexpression of CD147ICD promoted cancer cell proliferation via Notch1 signaling. In 102 cases of human hepatocellular carcinoma (HCC) tissues, patients with a high positive rate of nuclear CD147ICD expression had a significantly poor overall survival compared with patients with a low positive rate of nuclear CD147ICD expression. We confirmed that nuclear CD147ICD predicted a poor prognosis in human HCC. The combined therapy of the γ-secretase complex inhibitor and CD147-directed antibody showed better efficacy than monotherapy in orthotopic transplantation HCC mouse models. In conclusion, CD147 is cleaved by the γ-secretase and releases CD147ICD to the cell nucleus, promoting Notch1 expression via direct binding to the NOTCH1 promoter. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Curcumin inhibits the survival and metastasis of prostate cancer cells via the Notch‐1 signaling pathway

Prostate cancer is one of the most common malignancies in men, and it urgently demands precise interventions that target the signaling pathways implicated in its initiation, progression, and metastasis. The Notch‐1 signaling pathway is closely associated with the pathophysiology of prostate cancer. This study investigated the antitumor effects and mechanisms of curcumin, which is a well‐known natural compound from curcuminoids, in prostate cancer cells. Viability, proliferation, and migration were analyzed in two prostate cancer cell lines, DU145 and PC3, after curcumin treatment. Whether the Notch‐1 signaling pathway is involved in the antitumor effects of curcumin was examined. Curcumin inhibited the survival and proliferation of PC3 and DU145 cells in a dose‐ and time‐dependent manner and inhibited DU145 migration. Curcumin did not affect the expression of Notch‐1 or its active product NICD, but it did inhibit the expression of MT1‐MMP and MMP2 proteins in DU145 cells. We found that curcumin inhibited the DNA‐binding ability of NICD in DU145 cells. In conclusion, curcumin inhibited the survival and metastasis of prostate cancer cells via the Notch‐1 signaling pathway.     

Prevalence of EBV,CMV, and HPV in oral squamous cell carcinoma patients in the Pakistani population

Many studies have proposed an important role of viruses in the pathogenesis of oral cancer. The present study aimed to find out the prevalence of Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human papillomavirus (HPV) among patients with oral squamous cell carcinoma (OSCC) in a Pakistani cohort. We investigated tissue samples obtained from 58 patients with OSCC using the polymerase chain reaction assay. No sample was positive for HPV. EBV was identified in 15 patients (25.86%), and CMV in three patients (5.17%). Coinfection with one or more viruses was detected in two cases and was coinfection with EBV and CMV. These results suggest a low prevalence of these viruses in OSCC patients in the Pakistani population compared to most other countries where the prevalence of these viruses has been reported in the past. Nevertheless, further studies are necessary to determine the potential role of EBV and the possible importance of CMV as an infection cofactor in oral cancer.     

NOTCH signaling pathway and non-coding RNAs in cancer

Malignant tumors, known as cancer, seriously threaten human life and health. Cancer has the characteristics of abnormal cell differentiation, proliferation, invasion and metastasis. As a result, cancer often accompanied by poor prognosis and a lower survival rate. Notch signaling pathway is a highly conserved system in many multicellular organisms, and which has been proved to play a biological role in many cancers. In recent years, increasing evidence has shown that non-coding RNA can not only activate or inhibit NOTCH pathway, but also regulate the occurrence and development of cancer through NOTCH pathway. Therefore, we focus on the cancer-NOTCH-non-coding RNA axis in this review, and provide new ideas for cancer therapy.     

Notch信号通路相关蛋白在前列腺癌中的表达及临床意义

目的 本研究旨在探讨Notch信号通路相关蛋白在前列腺癌中的表达及临床意义.方法 采用实时定量PCR(Q-PCR)和Western blotting方法检测135例新鲜前列腺癌病理组织标本及临近非肿瘤组织标本中Notch 1、Notch 3及Hes1 mRNA和蛋白表达情况.同时采用免疫组化方法检测135例前列腺癌病理组织标本与临近非肿瘤组织标本中Notch 1、Notch 3及Hes 1蛋白表达情况,并分析各蛋白表达与前列腺癌患者临床病理因素的关系.结果 135例新鲜前列腺癌病理组织标本Q-PCR及Western blotting结果表明,与临近非肿瘤组织相比,前列腺癌组织中Notch 1、Notch 3及Hes 1 mRNA和蛋白表达均上调(P均＜0.05).免疫组化的结果表明,59.26％(80/135)前列腺癌样本为Notch 1阳性,高于临近非肿瘤组织17.78％ (24/135)(P＜0.05);65.19％(88/135)前列腺癌样本为Notch 3阳性,高于临近非肿瘤组织22.22％(30/135) (P＜ 0.05);62.22％ (84/135)前列腺癌样本为Hes 1阳性,高于临近非肿瘤组织17.78％(24/135)(P＜0.05).统计分析证实Notch 1蛋白表达与前列腺癌的肿瘤转移密切相关(x2=7.532,P=0.003);Notch 3蛋白表达与前列腺癌的肿瘤转移密切相关(x2=7.532,P=0.003);Hes 1蛋白表达与前列腺癌的肿瘤大小密切相关(x2=6.781,P=0.012).结论 Notch信号通路相关蛋白Notch 1、Notch 3及Hes 1在前列腺癌患者组织中表达升高,Notch信号通路的激活可能在前列腺癌发生、发展过程中起重要作用.