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Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis.

Hepatocellular carcinoma (HCC) is the third deadliest cancer in the world with high morbidity and poor prognosis. CTCFL (CCCTC-binding factor like) is a member of the cancer testis antigen (CTA) family with oncogenic properties. To demonstrate whether the hypomethylation of CTCFL promoters in plasma could be used as a noninvasive biomarker to predict poor prognosis of HCC, we extracted cell-free DNA from the plasma and detected the methylation status of CTCFL in 43 HCC, 5 liver cirrhosis and 6 benign lesion samples using methylation specific PCR (MSP). Our study indicated that the hypomethylation of CTCFL promoters in HCC plasma samples (60.4%) was significantly different from that in benign lesion plasma samples (16.7%) with a p-value of 0.043. Analysis of clinicopathological data showed that the methylation status of CTCFL promoters was significantly correlated with microvascular involvement (MVI) (p=0.001) and postoperative recurrence (p=0.031). Furthermore, clinical prognosis data of 347 HCC patients from The Cancer Genome Atlas (TCGA) database displayed that the hypomethylated group had worse overall survival than the hypermethylated group (p=0.0056). In conclusion, we provide evidence that the hypomethylation of CTCFL promoters in cell-free DNA is a biomarker for monitoring HCC patients, which can be used as a noninvasive prediction index for tumor recurrence and provide the individualized decision-making for clinicians.

Background Transcatheter arterial chemoembolization (TACE) and TACE in combination with sorafenib (TACE-sorafenib) have shown a significant survival benefit for the treatment of unresectable hepatocellular carcinoma (HCC). Adopting either as a first-line therapy carries major cost and resource implications. The objective of this study was to estimate the relative cost-effectiveness of TACE against TACE-sorafenib for unresectable HCC using a decision analytic model. Methods A Markov cohort model was developed to compare TACE and TACE-sorafenib. Transition probabilities and utilities were obtained from systematic literature reviews, and costs were obtained from West China Hospital, Sichuan University, China. Survival benefits were reported in quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was calculated. Sensitive analysis was performed by varying potentially modifiable parameters of the model. Results The base-case analysis showed that TACE cost $26 951 and yielded survival of 0.71 QALYs, and TACE-sorafenib cost $44 542 and yielded survival of 1.02 QALYs in the entire treatment. The ICER of TACE-sorafenib versus TACE was $56 745 per QALY gained, which was above threshold for cost-effectiveness in China. Sensitivity analysis revealed that the major driver of ICER was the cost post TACE-sorafenib therapy with stable state. Conclusion TACE is a more cost-effective strategy than TACE-sorafenib for the treatment of unresectable HCC.

SOCS3 as an important negative regulator of IL6/JAK/STAT3 signaling pathway may be early critical determinants of carcinogenesis. This study aimed to explore the aberrant promoter methylation of SOCS3 gene in circulating DNA as a noninvasive biomarker for screening hepatocellular carcinoma (HCC) high-risk individuals and for prognosis of HCC patients after partial hepatectomy. We detected its methylation status in 116 liver tissues and 326 plasma specimens of different hepatic diseases and healthy subjects, and its mRNA and protein expression in tissues. Higher methylation rate was remarkably detected in HCC (47.92%), compared with corresponding non-tumor (25.0%), liver cirrhosis (LC) (10.0%), benign liver diseases (0%) and normal liver tissues (0%) (all P

Accumulating evidence has revealed the importance of cancer stem cells (CSCs) in chemoresistance and recurrence. BORIS, a testes-specific CTCF paralog, has been shown to be associated with stemness traits of embryonic cancer cells and epithelial CSCs. We previously reported that BORIS is correlated with the expression of the CSC marker CD90 in hepatocellular carcinoma (HCC). These results encourage us to wonder whether BORIS exerts functions on CSC-like traits of human liver cancer cells. Here, we report that BORIS was enriched in HCC tissues. Exogenous overexpression of BORIS promoted CSC-like properties, including self-renewal, chemoresistance, migration and invasion in Huh7 and HCCLM3 cells. Conversely, BORIS knockdown suppressed CSC-like properties in SMMC-7721 and HepG2 cells and inhibited tumorigenicity in SMMC-7721 cells. Moreover, BORIS alteration did not affect the DNA methylation status of the minimal promoter and exon 1 region of OCT4. However, BORIS overexpression enhanced the amount of BORIS bound on the OCT4 promoter and increased H3K4me2, while reducing H3K27me3; BORIS depletion decreased BORIS and H3K4me2 on the OCT4 promoter, while increasing H3K27me3. These results revealed that BORIS is associated with the CSC-like traits of human liver cancer cells through the epigenetic regulation of OCT4.

Dendritic cells (DCs) are the most potent antigen-presenting cells. A strong interest has been developed in DC vaccines for cancer immunotherapy. Besides, angiogenesis is essential for tumor growth. VE-cadherin has a crucial function in various aspects of vascular biological functions. Here, we produced the full VE-cadherin gene modified DC vaccine (DC-VEC). Its antitumor immunity and chief mechanism driving antitumor effect was evaluated. Analyses were performed including test of antitumor antibody, CTL-mediated cytotoxicity experiment, vascular density, evaluation of the variation of cells and cytokines in immunoregulation. Its damage to the major organs was also evaluated. DC-VEC vaccine resulted in retarded tumor progression and prolonged survival in mice. In DC-VEC group, large amount of immunoglobulin was generated, T cells exhibited greater cytotoxicity against VE-cadherin, and tumor angiogenesis was suppressed. Besides, a decrease of VEGF-A and TGF-β1, and an increase of IL-4 and IFN-γ were observed. CD4+ and CD8+ T cells were higher, with increased IFN-γ secretion. The percentage of myeloid-derived suppressor cells and regulatory T cells decreased mildly. Also, it had no pathologic changes in major organs. DC-VEC vaccine represents a promising antitumor immunotherapy. The main mechanism is associated with its anti-angiogenesis and immunoregulation response.

The epigenetic silencing mechanism of suppressor 3 of cytokine signaling (SOCS3) in cancers has not been fully elucidated. Polycomb repressive complexes 2 (PRC2), an important epigenetic regulatory factors, exerts a critical role in repressing the initial phase of gene transcription. Whether PRC2 participates the down- regulation of SOCS3 in Hepatocellular carcinoma (HCC) remains unclear and how does PRC2 be recruited target gene still needs to explore. In this study, Using TCGA HCC dataset, and detecting HCC tissue specimens and cell lines, we found that SOCS3 expression in HCC was inversely related to that of EZH2, and depended on its promoter methylation status. CTCF, vigilin, EZH2 and H3K27me3 were enriched at CTCF and EZH2 binding sites on the methylated SOCS3 gene promoter. The depletion of CTCF did not affect expression of EZH2 and DNMT1, but decrease recruitment of CTCF, vigilin, EZH2 and H3K27me3. Further, knockdown of CTCF led to a loss of methylation of the methylated SOCS3 promoter, which sequentially increased the expression of SOCS3 and decreased the expression of pSTAT3, the downstream effector. These findings suggest that the CTCF dependent recruitment of EZH2 to the SOCS3 gene promoter is likely to participate in the epigenetic silencing of SOCS3 and in regulating its gene expression.

As a highly malignant tumor, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. In most HCC patients, the development of HCC begins with hepatitis, which is followed by fibrosis and cirrhosis before progressing to HCC. Cancer-associated fibroblasts (CAFs), which are generally believed to be derived from activated hepatic stellate cells (HSCs), are highly involved in the development of HCC through the secretion of cytokines and angiogenic factors. The results of our study showed that a considerable number of CAFs highly expressed CD90 and were enriched in HCC tissues. Bioinformatics analysis of the transcriptome of HCC tissues revealed that placental growth factor (PlGF) is significantly correlated with CD90 expression. The isolated primary CAFs and activated HSCs overexpressed PlGF and CD90. In addition, the results of gene expression profiling interactive analysis based on The Cancer Genome Atlas showed that high levels of both PlGF and CD90 are correlated with tumor angiogenesis markers (CD31, CD34, and CD105) and predict poor HCC patient prognosis. In summary, our results suggest that CAFs can generate PlGF and may provide an effective target for CAFs-regulated neoangiogenesis in HCC.

In the presence of cholecystitis or portal hypertension, hemorrhage is common during laparoscopic cholecystectomy (LC) because the vessels of Calot’s triangle are fragile and tortuous. Bleeding can obstruct surgical field visibility and increase conversion rates and risk of common bile duct injury. The Pringle maneuver is a simple occlusion approach that could limit blood flow from the hepatic pedicle, thus controlling bleeding to provide a clear surgical field to reduce conversion rate. In this study, we aimed to investigate the feasibility, effectiveness and safety of hepatic pedicle occlusion with the Pringle maneuver during difficult LC. From 2011 to 2015, LC with hepatic pedicle occlusion by the Pringle maneuver was performed in 67 patients (Pringle group). Another group of 67 cases with matched clinical parameters where LC was performed without the Pringle maneuver (non-Pringle group) was retrieved from a database to serve as the control group. The Pringle group had a significantly lower conversion rate (1.49% vs. 11.9%; P = 0.038), less blood loss (37.5 ± 24.1 mL vs. 94.5 ± 67.8 mL; P = 0.002), shorter postoperative hospitalization (2.5 ± 1.4 days vs. 3.5 ± 2.5 days; P = 0.005), and lower cost ($1343 ± $751 USD vs. $1674 ± $609 USD; P = 0.024) than non-Pringle group. There was one case each of bile duct injury and readmission within 30 days because of bile leakage in the non-Pringle group, but none in the Pringle group. Hepatic pedicle occlusion could provide a clear surgical field and enable the recognition of structures during LC. The Pringle maneuver offers a feasible and safe approach to lower conversion rates in difficult LC.

Background and aim Colorectal cancer is one of the most common malignant disease worldwide with highly metastatic potential. Identification of effective therapeutic treatment overcoming such disease is an urgent need. Our study focuses on hinokiflavone as an antitumor agent against colorectal cancer. Methods MTT assay, cell colony formation assay, Hoechst staining, flow cytometry, Western blot analysis, real-time polymerase chain reaction, and migration and invasion assay were performed to identify the effects of hinokiflavone on cell proliferation, apoptosis, and metastasis. CT26 tumor-bearing mice model was conducted to explore the antitumor activity of hinokiflavone in vivo. Immunohistochemistry staining was used to detect the protein expression of Ki-67, cleaved caspase-3, and MMP9 in treated tumors. Acute toxicity was evaluated by serological and hematological analyses, and drug side effect on organs was evaluated by hematoxylin and eosin staining. Results Hinokiflavone reduced the proliferation, migration, and invasion and promoted the apoptosis in colorectal tumor cells in vitro. Treatment of hinokiflavone at a tolerable and safe dose (50 mg/kg) significantly suppressed tumor growth in mice bearing CT26 tumors by reducing tumor proliferation and metastasis and inducing apoptosis. Mechanically, treatment of hinokiflavone induced apoptosis by loss of mitochondrial transmembrane potential and increased reactive oxygen species generation. Conclusions Hinokiflavone suppressed colorectal tumor cell proliferation, induced apoptosis via the reactive oxygen species-mitochondria-mediated apoptotic pathway, and inhibited tumor cell migration and invasion. Antitumor activity of hinokiflavone was also validated in mice model without observed toxicity. Our findings suggested that the plant-derived hinokiflavone could be used as an antitumor agent against colorectal cancer.

Background: MicroRNAs (miRNAs) negatively regulate the gene expression and act as tumor suppressors or oncogenes in carcinogenesis. The association between single nucleotide polymorphism (SNP) in miR-196a2 rs11614913 and the susceptibility of digestive system cancers was inconsistent in previous studies. Methods: A standardized search of PubMed, Embase, and Cochrane library databases for publications on miR-196a2 rs11614913 polymorphism and digestive system cancer risk was performed. Then the genotype data were analyzed in a meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the association. Test of heterogeneity, sensitivity analysis and assessment of publication bias were conducted in the present meta-analysis by STATA software 12.0. Results: An updated meta-analysis based on 34 independent case-control studies consisting of 13,013 cases and 16,046 controls was performed to address this association. There was a remarkable association between miR-196a2 rs11614913 polymorphism and overall digestive system cancer risk, especially in Asian populations. Moreover, subgroup analysis revealed that variant C allele increased risk of colorectal carcinoma, gastric cancer and hepatocellular carcinoma (HCC), compared with wild T allele. Conclusions: There was a remarkable association between miR-196a2 rs11614913 polymorphism and overall digestive system cancer risk, especially in Asian populations.

Background: Most hepatocellular carcinoma (HCC) patients have undergone a progression from chronic hepatitis, then liver cirrhosis (LC), and finally to carcinoma. The objective of this study was to elucidate risk factors to predict HCC development for cirrhosis patients. Methods: Multiple methylated specific PCR (MSP) was applied to determine methylation status of heparocarcinogenesis-related genes in 396 tissue and plasma specimens and multivariate cox model was used to analyze the relationship between risk variables and HCC development among cirrhosis patients, followed up in a median period of 30 months. Results: Among 105 LC cases, HCC incidence rate at 30 months was 30.48% (32/105), which were statistically associated with patients' age and aberrant methylation of p16, SFRP, and LINE1 (p

The brother of the regulator of the imprinted site (BORIS), an 11 zinc finger (ZF) protein, is a paralogue of CCCTC-binding factor (CTCF), involves in a few crucial events of chromatin functions, complex transcription regulation during spermatogenesis. As a novel tumor oncogene, abnormal expression of BORIS is observed in human hepatocellular carcinoma, however, the underlying mechanisms remain largely unexplored. In this study, the methylation status of BORIS was tested by methylation specific polymerase chain reaction (MSP) in human HCC cell lines and 43 pairs of tissue specimens. Frequently demethylation of BORIS in HCC was significantly higher than that in the paired adjacent non-tumor tissues (P=0.019), and it was correlated with tumor size (P=0.025) and clinical TNM stage (P=0.035). Patients with hypomethylated BORIS had a shorter disease free survival than those without demethylated BORIS (P=0.006). Further, analyses using Cox regression have indicated that the BORIS demethylation status was an independent risk to the reduced overall survival rate of HCC patients (P=0.035). These findings provide clues to clarify whether the demethylation may lead to activation of the promoter for upregulation expression of BORIS. In conclusions, aberrant BORIS hypomethylation is a promising biomarker for the prognosis of HCC.

Laparoscopic liver resection (LLR) is mostly performed to treat benign lesions at easily accessible locations. With improvements in instruments and accumulation of experience, LLR has evolved to treat malignant tumors with major hepatectomy, even in less accessible locations, without compromising the principles of safety and oncology. The present meta-analysis aimed to compare the outcomes of LLR for lesions located in anterolateral (AL) (II, III, IVb, V, and VI) and posterosuperior (PS) (I, IVa, VII, and VIII) liver segments. A comprehensive search was conducted to identify all eligible studies. This meta-analysis was performed using the STATA 12.0 statistical software. Standardized mean differences (SMDs) and odds ratios (ORs) were calculated for continuous variables and dichotomous variables, respectively, with 95% confidence intervals (CIs). A total of 846 patients from five studies were identified for the final analysis, with 565 patients in the AL group and 281 in the PS group. Although the operation time (SMD −0.60; 95% CI −0.75 to −0.45; P = 0.000) and conversion rate (OR 0.40; 95% CI 0.24–0.67; P = 0.000) were lower and the resection margin was wider (SMD 0.2; 95% CI 0.03–0.37; P = 0.019) in the AL group than in the PS group, no significant differences in blood loss (SMD −0.29; 95% CI −0.68 to 0.09; P = 0.131), complication rate (OR 0.73; 95% CI 0.50–1.07; P = 0.103), hospital stay (SMD −0.53; 95% CI −1.16 to 0.11; P = 0.105), and tumor recurrence (OR 1.23; 95% CI 0.81–1.86; P = 0.334) were noted between the groups. LLR is technically feasible and safe for selected patients with lesions in the PS segments of the liver.

Purpose Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GEM-N) have shown a significant survival benefit for the treatment of metastatic pancreatic cancer. The objective of this study was to assess the cost-effectiveness of FOLFIRINOX versus GEM-N for treating metastatic pancreatic cancer based on the PRODIGE and MPACT trials. Methods A decision model was performed to compare FOLFIRINOX with GEM-N. Primary base case data were identified from PRODIGE and MPACT trials. Costs were estimated and incremental cost-effectiveness ratio (ICER) was calculated at West China Hospital, Sichuan University, China. Survival benefits were reported in quality-adjusted life-years (QALY). Finally, sensitive analysis was performed by varying potentially modifiable parameters in the model. Results The base-case analysis showed that FOLFIRINOX cost $37,203.75 and yielded a survival of 0.67 QALY, and GEM-N cost $32,080.59 and yielded a survival of 0.51 QALY in the entire treatment. Thus, the ICER of FOLFIRINOX versus GEM-N was $32,019.75 per QALY gained. Conclusions The GEM-N regimen was more cost-effective compared with the FOLFIRINOX regimen for the treatment of metastatic pancreatic cancer from a Chinese perspective.

Brother of regulator of imprinted sites (BORIS) is a DNA-binding protein that is normally expressed in the testes. However, aberrant expression of BORIS is observed in various carcinomas, indicating a malignant role for this protein. Furthermore, abolishment or reduction of suppressor of cytokine signaling 3 (SOCS3) expression directed by promoter methylation is considered significant in hepatocellular carcinoma (HCC) carcinogenesis. This study aims to investigate BORIS and SOCS3 expression in HCC specimens and assess the prognostic significance of these proteins. BORIS and SOCS3 expression was examined using immunohistochemistry in HCC tissues, along with corresponding paracarcinomatous, cirrhosis, hepatitis, and normal liver tissues. The expression levels of these 2 proteins in HCC were evaluated for their association with clinicopathological parameters. Survival analysis was performed using Kaplan–Meier curves, the log-rank test, and multivariate Cox regression analysis. BORIS expression was significantly higher in HCC tissues than in normal liver tissues. In contrast, SOCS3 expression was dramatically lower in HCC tissues. BORIS expression was associated with tumor size, differentiation grade, satellite lesions, and recurrence while SOCS3 expression correlated with differentiation grade, vascular invasion, and recurrence. A significant negative correlation between BORIS and SOCS3 was observed. Patients with high BORIS expression and/or low SOCS3 expression had poorer postoperative survival. Patients with both these characteristics had the poorest prognostic outcome. BORIS and SOCS3 are promising as valuable indicators for predicting HCC prognosis.

Cetuximab (Cetux)/Bevacizumab (Bev) treatments have shown considerably survival benefits for patients with metastatic colorectal cancer (mCRC) in the last decade. But they are costly. Currently, no data is available on the health economic implications of testing for extended RAS wild-type (wt) prior to Cetux/Bev treatments of patients with mCRC. This paper aimed to evaluate the cost-effectiveness of predictive testing for extended RAS-wt status in mCRC in the context of targeting the use of Cetux/Bev.Markov model 1 was conducted to provide evidence evaluating the cost-effectiveness of predictive testing for KRAS-wt or extended RAS-wt status based on treatments of chemotherapy plus Cetux/Bev. Markov model 2 assessed the cost-effectiveness of FOLFOX plus Cetux/Bev or FOLFIRI plus Cetux/Bev in extended RAS-wt population. Primary base case data were identified from the CALGB 80405 trial and the literatures. Costs were estimated from West China Hospital, Sichuan University, China. Survival benefits were reported in quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was calculated.In analysis 1, the cost per QALY was $88,394.09 for KRAS-Cetux, $80,797.82 for KRAS-Bev, $82,590.72 for RAS-Cetux, and $75,358.42 for RAS-Bev. The ICER for RAS-Cetux versus RAS-Bev was $420,700.50 per QALY gained. In analysis 2, the cost per QALY was $81,572.61, $80,856.50, $80,592.22, and $66,794.96 for FOLFOX-Cetux, FOLFOX-Bev, FOLFIRI-Cetux, and FOLFIRI-Bev, respectively. The analyses showed that the extended RAS-wt testing was less costly and more effective versus KRAS-wt testing before chemotherapy plus Cetux/Bev. Furthermore, FOLFIRI plus Bev was the most cost-effective strategy compared with others in extended RAS-wt population.It was economically favorable to identify patients with extended RAS-wt status. Furthermore, FOLFIRI plus Bev was the preferred strategy in extended RAS-wt patients.