Methylation of the UNC5C gene and its protein expression in colorectal cancer.

UNC5C is a member of the UNC5H family of transmembrane receptors and functions as a dependence receptor. The expression of UNC5C is lost or markedly reduced in a large proportion of cancers at the messenger RNA level. However, there is little information available regarding the protein expression of UNC5C, the relationship between UNC5C protein expression and UNC5C methylation, and the correlation between patient clinical features and UNC5C protein expression in colorectal cancer. In this study, the methylation and protein expression of UNC5C were examined in 36 adenomatous polyps, 73 colorectal cancers, and 28 corresponding normal mucosa, and the correlation between the methylation, as well as protein expression status, and the clinicopathologic features was evaluated. Furthermore, the relationship between the methylation and protein expression of UNC5C, and correlation between UNC5C protein expression and overall survival were analyzed. The results showed that aberrant methylation of UNC5C was observed in colorectal cancers (78%) and adenomatous polyps (64%). The methylation-specific polymerase chain reaction results were confirmed by bisulfite sequencing of UNC5C promoter region. UNC5C methylation was significantly higher in early tumor, node, metastasis stage (I + II) of colorectal cancers. Compared with the corresponding normal tissues, protein expression of UNC5C was significantly lower in colorectal cancers (42%) and adenomatous polyps (81%). Protein expression of UNC5C was significantly higher in early tumor, node, metastasis stage (I + II) of colorectal cancers compared with advanced tumor, node, metastasis stage. Furthermore, patients with UNC5C-negative expression had a poorer prognosis than those with UNC5C-positive expression through Kaplan-Meier survival analysis ( p = 0.038), univariate ( p = 0.044) and multivariate analysis ( p = 0.045). According to Spearman rank correlation analysis, UNC5C methylation and protein expression were negatively correlated ( r = -0.461, p < 0.001). Together, these results suggest that UNC5C methylation may be an earlier event in the development of colorectal cancer, which was negatively correlated with protein expression. UNC5C may have a critical role in the pathogenesis of colorectal cancers and be a valuable prognostic factor of colorectal cancers patients. UNC5C may be identified as an attractive therapeutic target for the treatment of colorectal cancers in the further studies.

Prognostic and Therapeutic Values of Tumor Necrosis Factor-Alpha in Hepatocellular Carcinoma.

BACKGROUND Hepatocellular carcinoma (HCC) causes many deaths worldwide every year, especially in Asia. It is characterized by high malignancy, recurrence, and short survival time. Inflammation is closely related to the initiation and development of HCC. Tumor necrosis factor-α (TNF-α), an essential inflammatory mediator, has been studied as a potential therapy target in many cancers. However, its potential role in HCC diagnosis and therapy is still unclear. MATERIAL AND METHODS In our study, we detected the TNF-α expression in both human HCC tumor tissue and HCC cell lines HepG2 and HuH7. Then, we detected the effect of anti-TNF-α treatment and it synergistic function with 5-FU in an HCC xenograft mouse model and in HCC cell lines. RESULTS Survival analysis and Cox regression analysis based on 97 HCC patients indicated that a high level of TNF-α is an independent predictor of poor survival in HCC patients. Anti-TNF-α treatment by infliximab synergizes with Fluorouracil (5-FU) by promoting apoptosis of HCC tumor cells through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) effects. CONCLUSIONS Based on these data, we conclude that anti-TNF-α treatment could be a good way to increase the effect of classic chemotherapy of HCC patients, especially for the patients who have modest response to classic chemotherapy, such as 5-FU. TNF-α could also be used as a biomarker to help in early diagnosis of HCC.

Clinical Value of PLR, MLR, and NWR in Neoadjuvant Chemotherapy for Locally Advanced Gastric Cancer.

Objective: The clinical value of platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-white blood cell ratio (NWR) in predicting the prognosis of patients with locally advanced gastric cancer after neoadjuvant chemotherapy (NACT) was studied. Methods: A total of 131 patients with locally advanced gastric cancer treated with neoadjuvant chemotherapy in our hospital from May 2015 to June 2018 were selected as the study subjects, and all were treated with neoadjuvant chemotherapy. The relationship between the values of PLR, MLR, and NWR and the efficacy of neoadjuvant chemotherapy and clinical staging was analyzed; all patients were followed up for 3 years. Patients were divided into death group and survival group according to the survival of patients. The predictive value of PLR, MLR, and NWR values for patients' prognosis was analyzed, and the survival rates of patients with different PLR, MLR, and NWR values were compared. Results: The effective rate of neoadjuvant chemotherapy in patients with locally advanced gastric cancer was 62.60% (82/131), and the PLR, MLR, and NWR values in the effective group were lower than those in the ineffective group (P < 0.05). The AUC of combined PLR, MLR, and NWR in evaluating the efficacy of neoadjuvant chemotherapy was greater than that of PLR and NWR alone (P < 0.05). The PLR value of patients with stage IIIa, IIIb, and IIIc was greater than that of patients with stage II, the MLR value of patients with stage IIIb and IIIc was greater than that of patients with stage II and IIIa, and the NMR value of patients with stage IIIc was greater than that of patients with stage II, IIIa, and IIIb (P < 0.05). PLR, MLR, and NWR values were positively correlated with clinical stage (P < 0.05). The PLR, MLR, and NWR values in the survival group were lower than those in the death group (P < 0.05). The AUC of combined PLR, MLR, and NWR in predicting the prognosis of patients was greater than that of MLR and NWR alone (P < 0.05). The survival rate of patients with PLR ≥ 162.11 (36.21%) was lower than that of patients with PLR < 162.11 (80.82%), and the survival rate of patients with MLR ≥ 0.31 (42.86%) was lower than that of patients with MLR < 0.31 (74.67%), and the survival rate of patients with NWR ≥ 0.62 (45.00%) was lower than that of patients with NWR < 0.62 (74.65%) (P < 0.05). Conclusions: PLR, MLR, and NWR values are correlated with clinical stage, and the combined detection has value in evaluating the clinical efficacy of neoadjuvant chemotherapy and predicting the prognosis of patients with locally advanced gastric cancer.

Enhancing Natural Killer Cell-Mediated Cancer Immunotherapy by the Biological Macromolecule Nocardia rubra Cell-Wall Skeleton.

The biological macromolecule Nocardia rubra cell-wall skeleton (Nr-CWS) has well-established immune-stimulating and anti-tumor activities. However, the role of Nr-CWS on natural killer (NK) cells remains unclear. Here, we explore the function and related mechanisms of Nr-CWS on NK cells. Using a tumor-bearing model, we show that Nr-CWS has slightly effect on solid tumor. In addition, using a tumor metastasis model, we show that Nr-CWS suppresses the lung metastasis induced by B16F10 melanoma cells in mice, which indicates that Nr-CWS may up-regulate the function of NK cells. Further investigation demonstrated that Nr-CWS can increase the expression of TRAIL and FasL on spleen NK cells from Nr-CWS treated B16F10 tumor metastasis mice. The spleen index and serum levels of TNF-α, IFN-γ, and IL-2 in B16F10 tumor metastasis mice treated with Nr-CWS were significantly increased. In vitro, the studies using purified or sorted NK cells revealed that Nr-CWS increases the expression of CD69, TRAIL, and FasL, decreases the expression of CD27, and enhances NK cell cytotoxicity. The intracellular expression of IFN-γ, TNF-α, perforin (prf), granzyme-B (GrzB), and secreted TNF-α, IFN-γ, IL-6 of the cultured NK cells were significantly increased after treatment with Nr-CWS. Overall, the findings indicate that Nr-CWS could suppress the lung metastasis induced by B16F10 melanoma cells, which may be exerted through its effect on NK cells by promoting NK cell terminal differentiation (CD27lowCD11bhigh), and up-regulating the production of cytokines and cytotoxic molecules.