Cancer initiation and proliferation is regulated by both epigenetic and genetic events with epigenetic modifications being increasingly identified as important targets for cancer research. DNA methylation catalyzed by DNA methyltransferases (DNMTs) is one of the essential epigenetic mechanisms that control cell proliferation, apoptosis, differentiation, cell cycle, and transformation in eukaryotes. Recent progress in epigenetics revealed a deeper understanding of the mechanisms of tumorigenesis and provided biomarkers for early detection, diagnosis, and prognosis in cancer patients. Although DNA methylation biomarker possesses potential contributing to precision medicine, there are still limitations to be overcome before it reaches clinical setting. Hence, the current status of DNA methylation biomarkers was reviewed and the future use in clinic was also predicted.

PD-L1 (programmed cell death 1 ligand 1) is a key driver of tumor-mediated immune suppression and targeting it with antibodies can induce therapeutic responses. Given the costs and associated toxicity of PD-L1 blockade, alternative therapeutic strategies are needed.Using reverse-phase protein arrays to assess drugs in use or likely to enter trials, we performed a candidate drug screen for inhibitors of PD-L1 expression and identified verteporfin as a possible small molecule inhibitor. Verteporfin suppressed basal and interferon (IFN)induced PD-L1 expression in vitro and in vivo through golgi-related autophagy and disruption of the STAT1-IRF1-TRIM28 signaling cascade, but not affecting the proinflammatory CIITA-MHC II cascade. Within the tumor microenvironment, verteporfin inhibited PD-L1 expression, which associated with enhanced T-lymphocyte infiltration. Inhibition of Chromatin-associated enzyme poly (ADP-ribose) polymerase 1 (PARP1) induced PD-L1 expression in high endothelial venules (HEVs) in tumors and when combined with verteporfin enhanced therapeutic efficacy. Thus, verteporfin effectively targets PD-L1 through transcriptional and posttranslational mechanisms, representing an alternative therapeutic strategy for targeting PD-L1.

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BackgroundNasopharyngeal carcinoma (NPC) is an Epstein-Barr virus–associated malignancy that is most common in East Asia, Africa, and Alaska. Radiotherapy is the main treatment option; unfortunately, disease response to concurrent radiotherapy and chemotherapy varies among patients with NPC, and in many cases, NPC becomes resistant to radiotherapy. Our previous studies indicated that Jab1/CSN5 was overexpressed and plays a role in the pathogenesis and radiotherapy resistance in NPC. Therefore, it is important to seek for innovative therapeutics targeting Jab1/CSN5 for NPC. In this study, we explored the antitumor effect of a curcumin analogue T83 in NPC, and found T83 exhibits antitumor activity and induces radiosensitivity through inactivation of Jab1 in NPC.MethodsNPC cell viability and proliferation were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. Cell cycle distribution was detected with use of flow cytometry. Apoptosis was examined by using the Annexin V/propidium iodide staining assay and cleavage poly(ADP-ribose polymerase (PARP) and cleavage caspase-3 expression. Jab1 expression was examined by Western blotting.ResultsA growth inhibitory effect was observed with T83 treatment in a dose- and time-dependent manner. T83 significantly induced G2/M arrest and apoptosis in NPC. In addition, T83 inhibited Jab1 expression and sensitized NPC cells to radiotherapy.ConclusionOur data indicate that T83 exhibits potent inhibitory activity in NPC cells and induces radiotherapy sensitivity. Thus, T83 has translational potential as a chemopreventive or therapeutic agent for NPC.

In this retrospective study, the correlation between pre- and post-treatment plasma Epstein-Barr virus (EBV) DNA and circulating immune subsets as well as the prognostic implications was investigated in nasopharyngeal carcinoma (NPC) patients. Patients (n=356) were diagnosed and received comprehensive treatment at the First People's Hospital of Foshan from 2006 to 2010. Pre- and post-treatment plasma EBV DNA load and circulating immune subsets (percentage of CD3+ T cell, CD3+ CD4+ T cells, CD3+ CD8+ T cells, CD19+ B cells and CD56+ NK cells) were analyzed by real-time PCR and flow cytometry. Patient age correlated negatively with CD3+ T cells (r=-0.264, P=0.001) and positively with CD56+ NK cells (r=0.272, P=0.001). Pre-treatment plasma EBV DNA correlated negatively with CD19+ B cells (r=-0.223, P=0.009) and CD4/CD8 ratio (r=-0.177, P=0.047). Patients with low CD19+ B cell had poorer 5-year progression-free survival (PFS) (66.6 vs. 81.8%, P=0.036) and 5-year overall survival (OS) (70.5 vs. 81.5%, P=0.097) than patients with high CD19+ B cells. Low CD19+ B cells was identified as a negative prognostic factor for 5-year PFS (hazard ratio [HR] 0.487; P=0.040), but not for 5-year OS (HR 0.550; P=0.102) in multivariate analysis. Post-treatment plasma EBV DNA was the most important prognostic factor for 5-year PFS (HR 2.983; P=0.006) and 5-year OS (HR 3.927; P<0.001). This study demonstrates the clinical value of circulating CD19+ B cell measurements in NPC patients.

Distant metastasis is the major contributor to treatment failure and mortality in patients with nasopharyngeal carcinoma (NPC). The lack of effective treatment strategies for metastatic NPC is the major cause for the low survival rate. Therefore, it is crucial to understand the molecular mechanisms underlying NPC metastasis and to identify potential biomarkers for targeted therapy. MicroRNA (miRNAs or miRs) have been shown to play an important role in tumorigenesis and metastasis. In the present study, we aimed to evaluate the significance of hsa-miR-24 in NPC metastasis. Significantly lower hsa-miR-24 levels were observed in NPC metastatic tumors and higher hsa-miR-24 levels were associated with longer progression-free and metastasis-free survival durations. hsa-miR-24 overexpression inhibited cell proliferation, invasion and migration. Using bioinformatics approaches together with functional luciferase reporter assays, we demonstrated that the c-Myc 3′-UTR was a direct target of hsa-miR-24 in regulating NPC metastasis. Protein profiling analysis revealed that a high c-Myc expression was inversely associated with metastasis-free overall survival and with epithelial-mesenchymal transition (EMT). Furthermore, the overexpression of hsa-miR-24 decreased NPC cell invasive ability induced by the overexpression of c-Myc, associated with EMT epithelial marker (E-cadherin) restoration. Thus, on the whole, the findings of this study demonstrate that hsa-miR-24 suppresses metastasis in NPC by regulating the c-Myc/EMT axis, suggesting that hsa-miR-24 may be used as a prognostic factor and as a novel target for the prevention of NPC metastasis.

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An important challenge in nasopharyngeal carcinoma (NPC) research is to develop effective predictors of tumor recurrence following treatment to determine whether immediate adjuvant therapy is necessary. We retrospectively analyzed archived specimens collected from 45 patients with paired samples of primary NPC (pNPC) and recurrent NPC (rNPC). Clinical samples were collected from the Cancer Center Databases of the First People’s Hospital of Foshan and Shantou Central Hospital (affiliates of Sun Yat-Sen University) between 2001 and 2012. Expression levels of phosphor-Stat3 (p-Stat3), signalosome complex subunit 5 (Jab1/Csn5), Akt1, C/EBP homologous protein (CHOP), Ki-67, and apoptosis were determined by immunohistochemistry in pNPC and rNPC samples from the same patients. Differences in these markers between the short-term interval to recurrence (ITR) group (ITR <18 months) and long-term ITR group (ITR ≥18 months) were further analyzed. In Cox’s regression analysis, the ITR was significantly associated as an independent-negative prognostic factor for overall survival (hazard ratio, 0.211; 95% confidence interval, 0.053–0.841; P=0.027). p-Stat3 was increased in the short-term ITR group (ITR <18 months) and tended to be lower in the long-term ITR group (ITR ≥18 months). In the short-term ITR group, nuclear Akt expression was significantly increased in paired rNPC (P=0.028). In the long-term ITR group, the expression of nuclear Jab1/Csn5 (P=0.047) and assessment of apoptosis measured with TdT-mediated dUTP nick end-labeling (TUNEL) (P=0.003) was significantly increased in paired rNPC. The results suggest that differences between short- and long-term ITR may predict outcome in rNPC. Furthermore, the overexpression of Jab1/Csn5 and Akt may contribute to the carcinogenesis of rNPC, and Akt seems to promote the progression of short-term ITR. Intra-individual changes of Jab1/Csn5, Akt, and TUNEL may help to identify short-term ITR.