CCL14 is a member of CC chemokines and its role in hepatocellular carcinoma (HCC) is still unknown. In this study, CCL14 expression were analyzed by tissue microarray (TMA) including 171 paired tumor ...and peritumor tissues of patients from Zhongshan Hospital of Fudan University. We found for the first time that CCL14 was downregulated in HCC tumor tissues compared with peritumor tissues (P = 0.01). Meanwhile, CCL14 low expression in HCC tumor tissues is associated with a poor prognosis (P = 0.035). CCL14 also displayed its predictive value in high differentiation (P = 0.026), liver cirrhosis (P = 0.003), and no tumor capsule (P = 0.024) subgroups. The underlying mechanisms were further investigated in HCC cell lines by CCL14 overexpression and knock-down in vitro. We found overexpression of CCL14 suppressed proliferation and promoted apoptosis of HCC cells. Finally, the effect was confirmed by animal xenograft tumor models in vivo. The results shown overexpression of CCL14 lead to inhibiting the growth of tumor in nude mice. Interestingly, our data also implied that CCL14 played these effects by inhibiting the activation of Wnt/β-catenin pathway. These findings suggest CCL14 is a novel prognostic factor of HCC and serve as a tumor suppressor.
Sleep disturbance is common in patients with cancer and is associated with poor prognosis. However, the effects of sleep deprivation (SD) on immune surveillance during the development of ...hepatocellular carcinoma (HC) and the underlying mechanisms are not known. This was investigated in the present study using mouse models of SD and tumorigenesis. We determined that acute and chronic sleep deprivation (CSD) altered the relative proportions of various immune cell types in blood and peripheral organs. CSD increased tumor volume and weight, an effect that was enhanced with increasing CSD time. Expression of the cell proliferation marker Ki-67 was elevated in tumor tissues, and tumor cell infiltration into adjacent muscles was enhanced by CSD. Multicolor flow cytometry analysis revealed that CSD significantly reduced the numbers of antitumor CD3
T cells and natural killer (NK) cells and increased that of immunosuppressive CD11b
cells infiltrating into the tumor microenvironment from the spleen
the peripheral blood. These results indicate that CSD impairs immune surveillance mechanisms and promotes immunosuppression in the tumor microenvironment to accelerate tumor growth, underscoring the importance of alleviating sleep disturbance in HC patients in order to prevent HC progression.
NLRC3 (NLR family caspase recruitment domain containing 3) has been reported as a factor of inhibiting inflammatory responses. It's role in HCC (hepatocellular carcinoma) is still unknown. In this ...study we firstly used the GEO (Gene Expression Omnibus) database and mIHC (multiple immunohistochemical analysis) with TMAs (tumor tissue microarrays) of HCC patients to evaluate NLRC3 levels. The tumor-bearing mouse models were also established with NLRC3 over-expressing and knock-down Hepal-6 cells to assess its effect. The data showed high NLRC3 expression was related with favorable overall survival (
=0.0386) and disease-free survival (
=0.0458). In addition, NLRC3 expression showed a positive correlation between CD8
T cells infiltration.
, NLRC3-overexpressing Hepal-6 tumors showed increased CD8
T cell infiltration. NLRC3-knockdown Hepa1-6 tumors displayed decreased CD8
T cell infiltration. At the same time, we also found the positive correlations between NLRC3 and CCL5 (C-C motif chemokine ligand 5,
<0.0001, R
= 0.2372) as well as CXCL9 (C-X-C motif chemokine ligand 9,
<0.0001, R
= 0.2338) expressions. So NLRC3 high expression represents a novel predictor for positive survival outcomes in HCC patients, and NLRC3 is involved in CD8
T cell infiltration, which is correlated with increased CCL5 and CXCL9 in TME (tumor microenvironment). This study implies that boosting NLRC3 is a promising treatment to enhance survival in HCC patients.
Sleep-wake disturbance is prevalent in patients with liver cancer, but there is no direct evidence of its association and related biological mechanisms. Our study was to assess quality of sleep and ...to describe prevalence of sleep disturbances in patients with different etiologies of liver cancer, especially to explore whether sleep quality influences immune factors.
A total of 210 patients with liver cancer from August 2015 to December 2015 were randomly divided into two groups including HBV cirrhosis and non-HBV cirrhosis. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate their sleep quality, and then 202 patients enrolled in this study were divided into two groups according to their PSQI scores: PSQI ≤ 5 and PSQI > 5. The association between sleep disturbances and immune factors was analyzed by logistic regression models.
A total of 56.9% of liver cancer patients experienced poor sleep quality (PSQI > 5). The prevalence of sleep disturbances was significantly higher in patients with liver cancer of non-hepatitis B virus (HBV) cirrhosis than with that evolving from HBV cirrhosis (66.7% vs. 50%,
= 0.018). In non-HBV cirrhosis liver cancer patients, the PSQI > 5 group had a higher percentage of CD3
T cells (71.06 ± 11.07 vs. 63.96 ± 14.18,
= 0.014) and lower natural killer (NK) cells (14.67 ± 9.65 vs. 20.5 ± 10.77,
= 0.014) compared with patients with PSQI ≤ 5. Logistic regression further confirmed that liver cancer patients without HBV cirrhosis are more prone to experience poor sleep with increased CD3
T cells (OR = 1.07, 95% CI = 1.01-1.13,
= 0.030) and decreased NK cells (OR = 0.92, 95% CI = 0.85-0.98,
= 0.014). Our results indicate that increased CD3
T cells and decreased NK cells are both associated with sleep disturbances in patients with liver cancer of non-HBV cirrhosis.
Most liver cancer patients suffer from sleep disturbances, especially evolving from non-HBV cirrhosis. A rise in CD3
T cells and a reduction in NK cells are associated with sleep disturbances in patients with liver cancer of non-HBV cirrhosis.
Abstract
Chromobox protein homolog 4 (CBX4) is a component of the Polycomb group (PcG) multiprotein Polycomb repressive complexes 1 (PRC1), which is participated in several processes including ...growth, senescence, immunity, and tissue repair. CBX4 has been shown to have diverse, even opposite functions in different types of tissue and malignancy in previous studies. In this study, we found that CBX4 deletion promoted lung adenocarcinoma (LUAD) proliferation and progression in Kras
G12D
mutated background. In vitro, over 50%
Cbx4
L/L
, Kras
G12D
mouse embryonic fibroblasts (MEFs) underwent apoptosis in the initial period after Adeno-Cre virus treatment, while a small portion of survival cells got increased proliferation and transformation abilities, which we called selected
Cbx4
−/−
, Kras
G12D
cells. Karyotype analysis and RNA-seq data revealed chromosome instability and genome changes in selected
Cbx4
−/−
, Kras
G12D
cells compared with
Kras
G12D
cells. Further study showed that P15, P16 and other apoptosis-related genes were upregulated in the primary
Cbx4
−/−
, Kras
G12D
cells due to chromosome instability, which led to the large population of cell apoptosis. In addition, multiple pathways including Hippo pathway and basal cell cancer-related signatures were altered in selected
Cbx4
−/−
, Kras
G12D
cells, ultimately leading to cancer. We also found that low expression of CBX4 in LUAD was associated with poorer prognosis under Kras mutation background from the human clinical data. To sum up, CBX4 deletion causes genomic instability to induce tumorigenesis under Kras
G12D
background. Our study demonstrates that CBX4 plays an emerging role in tumorigenesis, which is of great importance in guiding the clinical treatment of lung adenocarcinoma.
•We found that U.S. uncertainty is positively related to the systemic tail risk of Chinese enterprises.•Employing principal component analysis, this study captures the aggregate levels of U.S. ...uncertainty.•This study sheds additional light on the role of investor sentiment and financing constraints as transmission channels.
This study examines the impact of U.S. uncertainties, as indicated by the Macroeconomic Uncertainty Index (MU), Financial Uncertainty Index (FU), and Economic Policy Uncertainty Index (EPU), on the systemic tail risk within Chinese enterprises. Our findings reveal a significant positive relationship between U.S. uncertainties and systemic tail risk of Chinese enterprises. Additionally, this relationship is mediated through two main transmission channels—investor sentiment and financing constraints.
Cetuximab (C225), an anti-Epidermal Growth Factor receptor (EGFR) monoclonal antibody, has been widely used as a routine treatment for patients with metastatic colorectal cancer (mCRC); However, many ...patients who initially respond to cetuximab acquire resistance. The purpose of this study was to characterize new mechanism of acquired Cetuximab resistance. Firstly, tissue microarrays (TMA) comprising 191 CRC patients was constructed to evaluate the expression of chemokine receptor 7 (CCR7) by using immunohistochemistry (IHC). In CRC tumor tissues, CCR7 was significantly over-expressed compared with paired normal tissues (
< 0.001), and correlated with the infiltration depth (
= 0.03) and the regional lymph node metastasis (
= 0.006). Significant differences were also found in forms of overall survival (OS) and disease-free survival (DFS) between normal and tumor tissues (
). More interestingly, EGFR was also highly expressed and co-localized with CCR7 in the tumor tissues from the patients who were insensitive to Cetuximab treatment. Secondly, we further explored the relationship between CCR7 expression and Cetuximab resistance by two CCR7 positive CRC cell lines, Caco-2 with wild-type
(
) and HCT116 with mutated
(
). By the treatment of secondary lymphoid tissue chemokine (SLC, an exogenous high-affinity legend of CCR7), the inhibition rate of Cetuximab significantly decreased in both cells. Furthermore, the activation of SLC/CCR7 axis promoted epithelial mesenchymal transformation (EMT) in CRC tumor cells by increasing the expression of Twist and β-catenin. By using of CCR7 neutralizing antibody and p-AKT inhibitor rescued the above effects. These findings suggested that CCR7 was a key factor in those CRC patients, who have poorer reaction to Cetuximab. So combined inhibition of CCR7 and p-AKT will represent a rational therapeutic strategy for Cetuximab resistance patients.
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