TRIM26 restricts Epstein-Barr virus infection in nasopharyngeal epithelial cells through K48-linked ubiquitination of HSP-90ß.

The tripartite interaction motif (TRIM) family of proteins is known for their antiviral activity through different mechanisms, such as interfering with viral components, regulating immune responses, and participating in autophagy-mediated defense pathways. In this study, we investigated the role of tripartite interaction motif 26 (TRIM26), which is encoded by a major histocompatibility complex (MHC) gene, in regulating Epstein-Barr virus (EBV) infection of nasopharyngeal epithelial cells. We found that TRIM26 expression was induced upon EBV infection and that it indirectly targeted EphA2, a crucial epithelial receptor for EBV entry. Our results showed that TRIM26 interacted with heat shock protein 90-beta (HSP-90ß) and promoted its polyubiquitination, which led to its degradation via the proteasome pathway. This, in turn, affected EphA2 integrity and suppressed EBV infection. These findings suggest that TRIM26 could be a valuable target for developing therapeutic interventions against EBV infection and its associated pathogenesis.

Advancing therapeutic strategies for Epstein-Barr virus-associated malignancies through lytic reactivation.

Epstein-Barr virus (EBV) is a widespread human herpes virus associated with lymphomas and epithelial cell cancers. It establishes two separate infection phases, latent and lytic, in the host. Upon infection of a new host cell, the virus activates several pathways, to induce the expression of lytic EBV antigens and the production of infectious virus particles. Although the carcinogenic role of latent EBV infection has been established, recent research suggests that lytic reactivation also plays a significant role in carcinogenesis. In this review, we summarize the mechanism of EBV reactivation and recent findings about the role of viral lytic antigens in tumor formation. In addition, we discuss the treatment of EBV-associated tumors with lytic activators and the targets that may be therapeutically effective in the future.

Roles of Foxp3 in the occurrence and development of cervical cancer.

OBJECTIVE: This study aimed to evaluate the relationship between forkhead box P3 (Foxp3) expression and clinicopathological characteristics of cervical cancer and to explore the influence of Foxp3 on the biological behaviors of cervical cancer cells. METHODS: In this study, immunohistochemistry, lentivirus mediated transfection, Transwell assay; CCK-8 assay, real-time PCR and flow cytometry were employed to confirm the roles of Foxp3 in the occurrence and development of cervical cancer. RESULTS: Foxp3 and p16(INK4a) were highly expressed in the cervical cancer and their expressions were related to the FIGO stage, tumor size, lymph node metastasis and serum SCC. Foxp3 had a high expression in the cervical cancer cells, tumor interstitium and metastatic lymph nodes. Foxp3 expression was positively related to p16(INK4a) expression in the cervical cancer. Foxp3 expression in the cervical cancer was negatively related to the prognosis: high Foxp3 expression predicted a poor prognosis. Silencing of Foxp3 was able to inhibit the proliferation and invasiveness of cervical cancer cells, promote their apoptosis, and induce the change in cell cycle. Silencing of Foxp3 also reduced the mRNA and protein expressions of p16(INK4a) in cervical cancer cells. CONCLUSION: Foxp3 is highly expressed in the cervical cancer, and able to facilitate the proliferation and invasiveness of cervical cancer, change cell cycle and inhibit their apoptosis, resulting in the occurrence, development and metastasis of cervical cancer.

Sex-determining region Y-related high mobility group box (SOX)-2 is overexpressed in cervical squamous cell carcinoma and contributes cervical cancer cell migration and invasion in vitro.

Sex-determining region Y-related high mobility group box 2 (SOX-2) is a key pluripotency-associated transcription factor and may be implicated in the pathogenesis of cervical squamous cell carcinoma (SCC). The aim of this study was to explore SOX-2 expression in cervical SCC tissues and to examine whether and how SOX-2 regulates the malignant behaviors of cervical SCC cells in vitro. We here found that SOX-2 expression in the examined cervical SCC tissues was higher than that in the normal cervical and cervical intraepithelial neoplasia (CIN) tissues. Higher protein level of SOX-2 (nuclear positive staining cells ≥50 %) was detected in 34.9 % (29 out of 83 cases) of cervical SCC patients. We also noted that 100 % of well-differentiated and 66.7 % of moderately differentiated cervical SCCs showed lower SOX-2 expression (nuclear positive staining cells <50 %), while 58.8 % of poorly differentiated tumors had higher SOX-2 expression (P < 0.05). Furthermore, the migratory and invasive capabilities of SiHa cervical cancer cells were enhanced when SOX-2 was upregulated whereas suppressed when SOX-2 was downregulated. Also, the phosphorylation levels of protein kinase B (Akt) and extracellular regulated protein kinases (ERK) 1/2 were increased in SOX-2-overexpressed cancer cells but decreased in SOX-2-depleted cells. Additionally, LY294002 (Akt pathway inhibitor) or U0126 (ERK pathway inhibitor) significantly suppressed SOX-2-overexpression-induced migration and invasion in SiHa cells. Our results indicate that differentially expressed SOX-2 is associated with tumor differentiation (P < 0.05) and that SOX-2 contributes to the migratory and invasive behaviors of cervical SCC in vitro.

Expression and effects of high-mobility group box 1 in cervical cancer.

We investigated the significance of high- mobility group box1 (HMGB1) and T-cell-mediated immunity and prognostic value in cervical cancer. HMGB1, forkhead/winged helix transcription factor p3 (Foxp3), IL-2, and IL-10 protein expression was analyzed in 100 cervical tissue samples including cervical cancer, cervical intraepithelial neoplasia (CIN), and healthy control samples using immunohistochemistry. Serum squamous cell carcinoma antigen (SCC-Ag) was immunoradiometrically measured in 32 serum samples from 37 cases of squamous cervical cancer. HMGB1 and SCC-Ag were then correlated to clinicopathological characteristics. HMGB1 expression tends to increase as cervical cancer progresses and it was found to be significantly correlated to FIGO stage and lymph node metastasis. These findings suggest that HMGB1 may be a useful prognostic indicator of cervical carcinoma. In addition, there were significant positive relationships between HMGB1 and FOXP3 or IL-10 expression (both p<0.05). In contrast, HMGB1 and IL-2 expression was negatively correlated (p<0.05). HMGB1 expression may activate Tregs or facilitate Th2 polarization to promote immune evasion of cervical cancer. Elevated HMGB1 protein in cervical carcinoma samples was associated with a high recurrence of HPV infection in univariate analysis (p<0.05). HMGB1 expression and levels of SCC-Ag were directly correlated in SCC (p<0.05). Thus, HMGB1 may be a useful biomarker for patient prognosis and cervical cancer prediction and treatment.

Clinical significance of Wnt-11 and squamous cell carcinoma antigen expression in cervical cancer.

The purpose of the study was to determine the expression patterns of Wnt-11 and squamous cell carcinoma antigen in cervical cancer tissues and to explore their clinical significance and correlation with clinicopathological parameters. The expression of Wnt-11 and squamous cell carcinoma antigen was detected in 127 cervical cancer tissues, 21 cervical intraepithelial neoplasia, as well as in 20 healthy controls by immunohistochemistry, and the relationship of Wnt-11 and squamous cell carcinoma antigen expression with clinicopathological parameters was analyzed. Both Wnt-11 and squamous cell carcinoma antigen were more commonly expressed in cervical cancer than in cervical intraepithelial neoplasia and in normal cervical tissue (respectively; P < 0.05); further, Wnt-11 and squamous cell carcinoma antigen expression in cervical cancer were positively correlated (r = 0.271, P < 0.05). In comparing the expression with clinicopathological parameters of tumor samples, Wnt-11 and squamous cell carcinoma antigen were both associated with FIGO stage, lymph node metastasis, and tumor size (P < 0.05), but not with patient age, pathological type, or differentiation. Increased Wnt-11 protein levels in cervical carcinoma samples were associated with a poor outcome in univariate and multivariate analysis. Wnt-11 and squamous cell carcinoma antigen are related to the malignancy degree and metastasis of cervical cancer, and thus may play a coordinating role in the occurrence and progression of cervical cancer. The study indicated that Wnt-11 may be a useful prognostic indicator for cervical carcinoma.

[Correlation study of HPV-16 existential status with Th17/Treg cytokines].

OBJECTIVE: To explore the relationship between the presence of HPV-16 DNA and the expression Treg surface marker Foxp3(+), peripheral blood levels of Th17/Treg cell-associated cytokines and explore their roles and significance in cervical cancer progression. METHODS: Between January 2012 and October 2012 at Shengjing Hospital of China Medical University, a total of 142 HPV16 positive patients were divided into cervical cancer (CC, n = 60), cervical intraepithelial neoplasia (CIN, n = 65) and control group (n = 17). Cervical liquid-based cytological (LBC) samples were collected to detect E2 and E6 genes of HPV type 16 using multiple real-time polymerase chain reaction (PCR). E2/E6 ratio was used to evaluate the physical status of HPV-16 DNA in host cell genome. The SP immunohistochemical method was used to detect the expressions of FOXP3 in cervical lesions. The concentrations of Th17/Treg cell-associated cytokines were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Under the same status of HPV16 DNA in vivo, the levels of Foxp3(+), transforming growth factor-ß (TGF-ß) and interleukin-10 (IL-10) were significantly higher than those of the control group (P < 0.01) while the levels of interleukin-17 (IL-17) and interleukin-21 (IL-21)were significantly lower than those of the control group (P < 0.05) . In the same disease, HPV16 DNA integration rate grew with the increases of Foxp3(+), TGF-ß and IL-10 while IL-17 and IL-21 were opposite. In the different status of HPV16 type DNA, the expression of Foxp3(+) was closely correlated with Federation International of Gynecology and Obstetrics (FIGO) stage, histological grade and lymphnode metastasis (P < 0.05) except for age (P > 0.05). CONCLUSION: Treg cytokines, HPV16 integration rate and severity of cervical lesions are positively correlated while Th17 cytokines show opposite effects. Th17/Treg cell-associated cytokines may play an important role in the occurrence and development of cervical cancer.