Hypoxia inducible factor-1α (HIF-1α) up-regulates the expression of programmed death ligand-1 (PD-L1) in some extracranial malignancies. However, whether it could increase PD-L1 expression in intracranial tumor is still unknown. Here, we explored the relationship between HIF-1α and PD-L1 expression in glioma, and investigated their clinical significance. In glioma patients, HIF-1α and PD-L1 were overexpressed in high grade glioma tissues and were significantly associated with poor survival. In glioma cells, PD-L1 expression was induced under hypoxia condition, and the enhanced PD-L1 expression was abrogated by either HIF-1α knock-down or HIF-1α inhibitor treatment. Furthermore, ChIP-qPCR analysis showed the direct binding of HIF-1α to PD-L1 proximal promoter region, providing evidence that HIF-1α up-regulates PD-L1 in glioma. In glioma murine model, the combination treatment with HIF-1α inhibitor and anti-PD-L1 antibody caused a more pronounced suppressive effect on tumor growth compared to either monotherapy. Immunologically, the combination treatment improved both dendritic cell (DC) and CD8+ T cell activation. Overall, our results demonstrated that positive correlation between PD-L1 and HIF-1α in glioma, and provide an alternative strategy, inhibiting HIF-1α, as combination therapies with immunotherapies to advance glioma treatment.

BackgroundThe contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to primary liver cancer (PLC) and their association with cancer aggressiveness remains uncertain in China, a country with half of global PLC. We aimed to characterize this using data from four representative medical centers.MethodsIn total, 15,801 PLC patients were enrolled from the centers distributed in Easter5n, Southern, Northern, and Western China from 2003 to 2020. Of those, 7585 with curative surgery were involved in survival analysis. A nomogram was constructed using preoperative parameters to predict postoperative survival.ResultsHepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma accounted for 93.0%, 4.3%, and 1.6% in PLC, respectively. The seropositivities of HBV and HCV were 84.4% and 3.2% in HCC, respectively. The seropositivity of anti-HCV antibody was significantly higher in HBV-negative than in HBV-positive HCC patients (13.2% vs. 1.1%). Compared to HCV-positive HCC (HCV-HCC), HBV-positive HCC (HBV-HCC) was associated with 12-year earlier onset, higher proportions of males, high α-fetoprotein, large tumor size, advanced Barcelona Clinic Liver Cancer (BCLC) stage, and vascular tumor thrombus. The proportions of HCC and HBV seropositivity increased, whereas that of anti-HCV decreased, from 2003 to 2020. Postoperative five-year survival rate was 73.5%, 64.1%, 34.9%, and 19.7% in HCC at BCLC stage 0, A, B, and C, respectively. The multivariate Cox regression analysis showed that HBV seropositivity, incomplete tumor capsule, vascular tumor thrombus, tumor diameter (≥3 cm), advanced BCLC stage (B+C), α-fetoprotein (≥20ng/ml), and direct bilirubin (>8µmol/L) contributed independently to shorter overall survival (OS); whereas post-operative radiofrequency ablation and second resection independently improved OS in HCC. HCV-HCC had a more favorable prognosis than did HBV-HCC (Log-rank test, P<0.001). A nomogram composed of age, gender, and the preoperative independent risk factors was accurate in predicting postoperative survival in HCC (C-index: 0.735; 95% confidence interval: 0.727–0.743).ConclusionHBV contributes to 84.4% of HCC in China, and actively promotes hepatocarcinogenesis and HCC progression. A favorable postoperative survival obtained in patients at the early BCLC stage highlights the importance of screening for early HCC in high-risk populations. Our preoperative prognosis prediction model is important in clinical decision-making.

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BackgroundThe NF-κB signaling pathway plays an important role in associating inflammation with tumor development and progression. However, few studies have reported that roles of genetic variants of the NF-κB signaling pathway genes in survival of patients with HBV-related hepatocellular carcinoma (HBV-HCC), especially with regards to potentially functional SNPs.MethodsWe used multivariate Cox proportional hazards regression to evaluate associations between 2,060 single nucleotide polymorphisms (SNPs) in 20 NF-κB signaling pathway genes and survival of 866 HBV-HCC patients, which were randomly split (1:1) into discovery and validation datasets. Expression quantitative trait loci (eQTL) analysis was conducted to identify associations between survival-associated SNPs and mRNA expression of corresponding genes. Furthermore, online database was used to assess mRNA expression of corresponding genes and survival. Finally, receiver operating characteristic (ROC) curves were used to assess the prediction accuracy of models integrating both clinical and genetic variables on HCC survival.ResultsA total of 6 SNPs in MAP3K14 remained significantly associated with OS of HBV-HCC patients (P<0.05, BFDP<0.8). Further eQTL analysis demonstrated that significant correlations between the rs2074292 (G>A) A allele was associated with higher mRNA expression levels of MAP3K14 (P=0.044) in normal liver tissue, which was associated with worse survival of HBV-HCC patients. In the additive model, after adjusting for age, sex, smoking status, drinking status, AFP level, cirrhosis, embolus and BCLC stage, the combined dataset showed that HBV-HCC patients carrying the rs2074292 AA and GA genotypes (HR=1.71, 95%CI= 1.29-2.27, P=0.000) (HR=1.40, 95%CI=1.10-1.77, P=0.005) have worse OS than GG genotype, respectively. The addition of risk genotypes to the prediction models increased the AUC significantly from 71.15% to 73.11% (P=0.012) and from 72.55% to 74.21% (P=0.010) for 1-year and 3-year OS, respectively.ConclusionOur study indicated that MAP3K14 rs2074292 A allele may be a potential predictor of HBV-HCC survival, likely regulating MAP3K14 mRNA expression.

BackgroundAspartate transaminase/alanine transaminase (De Ritis) ratio is a good predictor of liver function damage, but its prognostic value in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy remains unclear. This study aimed to assess the association of the De Ritis ratio with overall survival (OS) among hepatitis B virus (HBV)-related HCC patients undergoing hepatectomy.MethodsA total of 1,147 HCC patients were recruited. Cox regression analysis was used to identify the independent risk factors. Restricted cubic spline (RCS) was used to evaluate the association between the De Ritis ratio and mortality risk. Nomogram was constructed to determine the predictive power of the De Ritis ratio.ResultsMultivariate Cox regression analysis revealed that the tertile of the De Ritis ratio was an independent risk factor for mortality. After adjustment for confounding factors, the adjusted hazard ratios (HRs) with corresponding 95% CIs of mortality for the 2nd tertile and 3rd tertile were 1.175 (0.889–1.554) and 1.567 (1.199–2.046), respectively. RCS confirmed a non-linear association between the natural logarithm of the De Ritis ratio and the risk of mortality (p for non-linearity = 0.0375). The nomogram showed that the natural logarithm of the De Ritis ratio contributed the most to the prediction of prognosis in HBV-related HCC patients, and Harrell’s C-index was 0.680 with a 95% CI of 0.645–0.715.ConclusionThe De Ritis ratio is an independent predictor for OS in HBV-related HCC patients undergoing hepatectomy, which allows for prognostic stratification of patients, hence, individualized treatment and follow-up.

Breast cancer (BC) is a serious threat to women's health worldwide. Non-SMC condensin I complex subunit D2 (NCAPD2) is a regulatory subunit of the coagulin I complex, which is mainly involved in chromosome coagulation and separation. The clinical significance, biological behavior, and potential molecular mechanism of NCAPD2 in BC were investigated in this study. We found that NCAPD2 was frequently overexpressed in BC, and it had clinical significance in predicting the prognosis of BC patients. Moreover, loss-of-function assays demonstrated that NCAPD2 knockdown restrained the progression of BC by inhibiting proliferation and migration and enhancing apoptosis in vitro. It was further confirmed that the downregulation of NCAPD2 inhibited tumor growth in vivo. NCAPD2 promoted the progression of BC through the extracellular signal-regulated kinase 5 (ERK5) signaling pathway. Additionally, NCAPD2 could transcriptionally activate CDK1 by interacting with E2F transcription factor 1 (E2F1) in MDA-MB-231 cells. Overexpression of CDK1 alleviated the inhibitory effects of NCAPD2 knockdown in BC cells. In summary, the NCAPD2/E2F1/ CDK1 axis may play a role in promoting the progression of BC, which may provide a blueprint for molecular therapy.

BackgroundImmunological-related genes (IRGs) play a critical role in the immune microenvironment of tumors. Our study aimed to develop an IRG-based survival prediction model for hepatocellular carcinoma (HCC) patients and to investigate the impact of IRGs on the immune microenvironment.MethodsDifferentially expressed IRGs were obtained from The Genomic Data Commons Data Portal (TCGA) and the immunology database and analysis portal (ImmPort). The univariate Cox regression was used to identify the IRGs linked to overall survival (OS), and a Lasso-regularized Cox proportional hazard model was constructed. The International Cancer Genome Consortium (ICGC) database was used to verify the prediction model. ESTIMATE and CIBERSORT were used to estimate immune cell infiltration in the tumor immune microenvironment (TIME). RNA sequencing was performed on HCC tissue specimens to confirm mRNA expression.ResultsA total of 401 differentially expressed IRGs were identified, and 63 IRGs were found related to OS on the 237 up-regulated IRGs by univariate Cox regression analyses. Finally, five IRGs were selected by the LASSO Cox model, including SPP1, BIRC5, STC2, GLP1R, and RAET1E. This prognostic model demonstrated satisfactory predictive value in the ICGC dataset. The risk score was an independent predictive predictor for OS in HCC patients. Immune-related analysis showed that the immune infiltration level in the high-risk group was higher, suggesting that the 5-IRG signature may play an important role in mediating immune escape and immune resistance in the TIME of HCC. Finally, we confirmed the 5-IRG signature is highly expressed in 65 HCC patients with good predictive power.ConclusionWe established and verified a new prognosis model for HCC patients based on survival-related IRGs, and the signature could provide new insights into the prognosis of HCC.

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