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Epstein–Barr virus (EBV) is associated with various human malignancies. An association between EBV infection and oral squamous cell carcinoma (OSCC) has recently been reported. We established EBV-positive OSCC cells and demonstrated that EBV infection promoted OSCC progression. However, the mechanisms by which EBV promotes OSCC progression remain poorly understood. Therefore, we performed metabolic analyses of EBV-positive OSCC cells and established a xenograft model to investigate the viral contribution to OSCC progression. Here, we demonstrated that EBV infection induced mitochondrial stress by reducing the number of mitochondrial DNA (mtDNA) copies. Microarray data from EBV-positive OSCC cells showed altered expression of glycolysis-related genes, particularly the upregulation of key genes involved in the Warburg effect, including LDHA, GLUT1, and PDK1. Furthermore, lactate production and LDH activity were elevated in EBV-positive OSCC cells. EBV infection significantly upregulated the expression levels of cancer stem cell (CSC) markers such as CD44 and CD133 in the xenograft model. In this model, tumor growth was significantly increased in EBV-positive SCC25 cells compared with that in uninfected cells. Furthermore, tumorigenicity increased after serial passages of EBV-positive SCC25 tumors. This study revealed the oncogenic role of EBV in OSCC progression by inducing the Warburg effect and cancer stemness. [ABSTRACT FROM AUTHOR]

The Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that affects the world's popula-tion with chikungunya disease. Adaptation of the viral life cycle to their host cells' environment is a key step for establishing their infection and pathogenesis. Recently, the accumulating evidence advocates a principal role of extracellular vesicles (EVs), including exosomes, in both the infection and pathogenesis of infectious diseases. However, the participation of exosomes in CHIKV infec-tion and transmission is not well clarified. Here, we demonstrated that the CHIKV RNA and pro-teins were captured in exosomes, which were released by viral-infected epithelial cells. A viral genomic element in the isolated exosomes was infectious to naïve mammalian epithelial cells. The assay of particle size distribution and transmission electron microscopy (TEM) revealed CHIKV-derived exosomes with a size range from 50 to 250 nm. Treatments with RNase A, Triton X-100, and immunoglobulin G antibodies from CHIKV-positive patient plasma indicated that in-fectious viral elements are encompassed inside the exosomes. Interestingly, our viral plaque for-mation also exhibited that infectious viral elements might be securely transmitted to neighboring cells by a secreted exosomal pathway. Taken together, our recent findings emphasize the evidence for a complementary means of CHIKV infection and suggest the role of exosome-mediated CHIKV transmission. [ABSTRACT FROM AUTHOR]

Simple Summary: There is still limited knowledge of the critical pathogenic processes by which HPV16 induces oral carcinogenesis. Therefore, we aimed to illuminate the oncogenic role of HPV16 in the context of oral squamous cell carcinomas (OSCCs). Using human tongue keratinocyte cells, we demonstrated that HPV16 E6 promotes LTα1β2 and LTβR expression, thus promoting the lymphotoxin signaling pathway and leading to suppression of the transporter associated with the antigen-processing complex (TAPs; TAP1 and TAP2). Additionally, in vitro, we also demonstrated regulation of the antigenic peptide-loaded machinery in HPV-infected OSCC tissues through analysis of the transcriptomic profiles of the head and neck squamous cell carcinoma (HNSCC) cohort from the TCGA database, which was validated using fresh biopsied specimens. Thus, our study enhances the proposed functional role of HPV16 E6-associated immune-evasive properties in oral epithelial cells, revealing a possible mechanism underlying the development of HPV-mediated OSCCs. Infection by high-risk human papillomaviruses (hrHPVs), including HPV type 16 (HPV16), is a major risk factor for oral squamous cell carcinomas (OSCCs). However, the pathogenic mechanism by which hrHPVs promote oral carcinogenesis remains to be elucidated. Here, we demonstrated that the suppression of a transporter associated with the antigen-processing complex (TAPs; TAP1 and TAP2), which is a key molecule in the transportation of viral antigenic peptides into MHC class-I cells, is affected by the E6 protein of HPV16. Mechanistically, HPV-mediated immune evasion is principally mediated via the signal-transduction network of a lymphotoxin (LT) pathway, in particular LTα1β2 and LTβR. Our analysis of transcriptomic data from an HNSCC cohort from the Cancer Genome Atlas (TCGA) indicated that expression of TAP genes, particularly TAP2, was downregulated in HPV-infected cases. We further demonstrated that LTα1β2 and LTβR were upregulated, which was negatively correlated with TAP1 and TAP2 expression in HPV-positive clinical OSCC samples. Taken together, our findings imply that HPV16 E6 regulates the machinery of the antigenic peptide-loading system and helps to clarify the role of oncogenic viruses in the context of oral carcinoma. [ABSTRACT FROM AUTHOR]

Regardless of the prophylactic vaccine accessibility, persistent infections of high-risk human papillomaviruses (hr-HPVs), recognized as an etiology of cervical cancers, continues to represent a major health problem for the world population. An overexpression of viral early protein 6 (E6) is linked to carcinogenesis. E6 induces anti-apoptosis by degrading tumor suppressor proteins p53 (p53) via E6-E6-associated protein (E6AP)-mediated polyubiquitination. Thus, the restoration of apoptosis by interfering with the E6 function has been proposed as a selective medicinal strategy. This study aimed to determine the activities of andrographolide (Androg) on the disturbance of E6-mediated p53 degradation in cervical cancer cell lines using a proteomic approach. These results demonstrated that Androg could restore the intracellular p53 level, leading to apoptosis-induced cell death in HPV16-positive cervical cancer cell lines, SiHa and CaSki. Mechanistically, the anti-tumor activity of Androg essentially relied on the reduction in host cell proteins, which are associated with ubiquitin-mediated proteolysis pathways, particularly HERC4 and SMURF2. They are gradually suppressed in Androg-treated HPV16-positive cervical cancer cells. Collectively, the restoration of p53 in HPV16-positive cervical cancer cells might be achieved by disruption of E3 ubiquitin ligase activity by Androg, which could be an alternative treatment for HPV-associated epithelial lesions. [ABSTRACT FROM AUTHOR]

The Epstein–Barr virus (EBV) is a human herpesvirus associated with various cancers. The number of reports that describe infection of EBV in oral squamous carcinoma cells is increasing. However, there is no available in vitro model to study the possible role of EBV in the development of oral squamous cell carcinoma. Herein, we report establishment of a latent EBV infection of well-differentiated HSC1 cells and poorly differentiated SCC25 cells. Viral copy numbers per cell in EBV-infected HSC1 and SCC25 cells are 2 and 5, respectively. Although the EBV copy number was small, spontaneous viral replication was observed in EBV-infected HSC1 cells. Contrarily, infectious viral production was not observed in EBV-infected SCC25 cells, despite containing larger number of EBV genomes. Chemical activation of cells induced expression of viral lytic BZLF1 gene in EBV-infected HSC1 cells, but not in EBV-infected SCC25 cells. EBV infection activated proliferation and migration of HSC1 cells. However, EBV-infection activated migration but not proliferation in SCC25 cells. In conclusion, EBV can infect squamous cells and establish latent infection, but promotion of cell proliferation and of lytic EBV replication may vary depending on stages of cell differentiation. Our model can be used to study the role of EBV in the development of EBV-associated oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]