Aim:This study aims to explore the role of soluble programmed cell death protein 1 (sPD-1) in individuals with hepatocellular carcinoma (HCC) undergoing treatment with drug-eluting beads transarterial chemoembolization (D-TACE). Additionally, we aim to assess the potential utility of sPD-1 for determining the optimal timing for combining D-TACE with immune checkpoint inhibitors (ICIs).Materials and Methods:A total of 44 HCC patients eligible for D-TACE and 55 healthy volunteers were enrolled in this study. Three milliliters of peripheral venous blood from the patients were collected on the day before D-TACE and 3, 7, and 30 days after D-TACE, respectively, for the assay of sPD-1. The relationships between sPD-1 levels, clinical features, outcomes, and the fluctuation of sPD-1 during treatment were analyzed.Results:The initial sPD-1 levels in patients were found to be significantly higher than those in the control group. Although the initial sPD-1 levels displayed a decreasing trend with an increase in BCLC stage, no significant differences were observed among patients at different BCLC stages. The sPD-1 level on day 3 after D-TACE was similar to that on day 7 after D-TACE and significantly lower than the initial level. The sPD-1 level on day 30 after D-TACE was significantly higher than that on day 3 and day 7 after D-TACE and nearly returned to the initial level before D-TACE.Conclusion:The level of sPD-1 was found to be significantly elevated in patients with HCC. However, further research is deemed necessary to fully understand the role of sPD-1 as a potential biomarker in the initiation, progression, and prognosis of HCC. The decrease in sPD-1 following D-TACE suggests that immune effector cells might potentially be reduced, as well as immune function weakened, highlighting the need to avoid the prompt administration of ICIs after D-TACE.

Purpose: To examine the relationship between lactate dehydrogenase (LDH) levels and soluble programmed cell death-ligand 1 (sPD-L1) levels in hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE). Methods: A total of 83 hCC patients participated in this study. Patients were categorized into subgroups based on their alpha-fetoprotein (AFP) levels, presence or absence of extrahepatic metastasis, vascular invasion, Barcelona Clinic Liver Cancer (BCLC) stage, tumor response, tumor size, and number LDH and sPD-L1 levels were compared before and after TACE (3, 7, and 30 days post Results: LDH and sPD-L1 levels were significantly higher at 3 and 7 days post-TACE than at baseline. Positive correlations were observed between changes in LDH levels and sPD-L1 levels at 3 and 7 days post-TACE. LDH levels were higher in patients with elevated AFP compared to those in the normal AFP group at 3 and 7 days post-TACE, in the stable disease (SD) group compared to complete response (CR) and partial response (PR) groups at 7 days post-TACE, and in those with tumor > 5 cm compared with those with tumor <= 5 cm at 3 and 7 days after TACE (all P < 0.05). sPD-L1 levels were higher in patients with vascular invasion than those without vascular invasion at 3 and 7 days post-TACE, in the SD group compared to CR and PR groups at 3 and 7 days post-TACE, and in those with tumor > 5 cm compared to those with tumor < 5 cm at 3 and 7 days after TACE (all P < 0.05). Conclusion: A positive correlation was found between LDH expression and sPD-L1 levels, suggesting LDH as a potential biomarker for assessing immune status in HCC patients following TACE.

To investigate the impact of alkyl linkers of different lengths between dihydroartemisinin and isatin moieties on the anti-breast cancer activity, a series of twenty dihydroartemisinin-isatin hybrids with three- and four-carbon alkyl linkers were synthesized and screened against drug-sensitive MCF-7 and MDA-MB-231 breast cancer cell lines, as well as their multidrug-resistant counterparts MCF-7/ADR and MDA-MB-231/ADR cell lines. The results showed that the length of the carbon spacer had a significant effect on the anti-breast cancer activity, with hybrids tethered through a four-carbon linker exhibiting greater potency than their three-carbon analogs. Additionally, substituents at C-3 and C-5 positions of isatin moiety also greatly influenced the activity, with fluoro at C-3 position and methoxime/ethoxime at C-5 position being favorable for activity. These enriched structure–activity relationships may facilitate the rational design of future compounds.

AIMS:To investigate the implications of soluble programmed cell death-ligand 1 (sPD-L1) in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) and to evaluate the potential value of sPD-L1 to guide selection of the optimal time to begin combination therapy with TACE and immune checkpoint inhibitors (ICIs).MATERIALS AND METHODS:Thirty-one HCC patients suitable for TACE and 55 healthy volunteers were enrolled in this study. Three milliliters of peripheral venous blood of patients were collected on 1 day before TACE and 3, 7, and 30 days after TACE respectively for assay of sPD-L1 using enzyme-linked immunosorbent assay. The associations of the sPD-L1 level with the clinical features, outcomes, and the fluctuation of sPD-L1 during the treatment were analyzed.RESULTS:The initial sPD-L1 level of patients was significantly higher than that of the control group. And it was significantly associated with BCLC stage, portal venous invasion, tumor size, and number of foci. The sPD-L1 levels of 3 and 7 days after TACE were both significantly higher than the initial level. And that of 30 days after TACE was lower than the initial level, but the difference was not statistically significant. There was no significant difference of sPD-L1 level after embolization with embolic beads of different size. The level of sPD-L1 of CR patients was lower than that of PR, SD patients, but the differences were not significant.CONCLUSION:The level of sPD-L1 was associated with tumor aggressiveness and outcomes, suggesting its role as a possible predictive biomarker. The increases in sPD-L1 after TACE suggests that combined treatment with TACE and ICIs may be a promising therapeutic strategy in HCC. One week after TACE might be a suitable time to begin the administration of immunotherapy.

Abstract Background: Long noncoding RNA secretory carrier membrane protein 1 (SCAMP1) has been recently reported to be an oncogene in glioma and ovarian cancer. However, little is known about the clinical significance and functional role of SCAMP1 in hepatocellular carcinoma (HCC).Methods: The expression of SCAMP1 was determined in tissue samples and cell lines using quantitative reverse transcription PCR (qRT-PCR). The clinical significance of SCAMP1 in HCC was evaluated using chi-squared test, Kaplan-Meier survival, as well as univariate and multivariate analysis. Cell proliferation, cell cycle distribution and apoptosis were evaluated using CCK-8 assay, colony formation assay, Flow cytometry analysis. Related protein expression levels were measured by western blot analysis.Results: We found SCAMP1 expression levels were remarkably up-regulated in HCC tissues compared to that in matched adjacent tissues. Increased SCAMP1 expression was significantly correlated with large tumor size, advanced TNM stage and poor survival prognosis in HCC. Knockdown of SCAMP1 significantly inhibited cell proliferation, induced G0/G1 phase arrest and apoptosis in HepG2 and SNU-182 cells. More importantly, knockdown of SCAMP1 downregulated the protein levels of CDK4, Cyclin D1 and Bcl-2, while upregulated the protein levels of p21, p53 and Bax.Conclusions: In summary, our study clarified a positive correlation of the SCAMP1 levels with the HCC cell proliferation.

Abstract Background: Long noncoding RNA secretory carrier membrane protein 1 (SCAMP1) has been recently reported to be an oncogene in several cancers, including glioma and ovarian cancer. However, its clinical significance and functional role in hepatocellular carcinoma (HCC) remain unknown.Methods: The expression of SCAMP1 was determined in tissue samples and cell lines using quantitative reverse transcription PCR. The clinical significance of SCAMP1 in HCC was evaluated using chi-squared test, Kaplan-Meier survival, as well as univariate and multivariate analysis. Cell proliferation, cell cycle distribution and apoptosis were evaluated using CCK-8 assay, colony formation assay, Flow cytometry analysis. Related protein expression levels were measured by western blot analysis.Results: We found SCAMP1 expression levels were remarkably up-regulated in HCC tissues compared with that in matched adjacent tissues. Increased SCAMP1 expression was significantly correlated with large tumor size, advanced TNM stage and poor survival prognosis in HCC. Knockdown of SCAMP1 significantly inhibited cell proliferation, induced G0/G1 phase arrest and apoptosis in HepG2 and SNU-182 cells. More importantly, knockdown of SCAMP1 downregulated the expression levels of CDK4, Cyclin D1 and Bcl-2, while upregulated the expression levels of p21, p53 and Bax.Conclusions: In summary, our study clarified the oncogenic role of SCAMP1 in HCC, and provided a potential therapeutic target for HCC treatment.

In recent decades, the chemokine receptor CXCR4 and its ligand CXCL12 have been extensively reported to be associated with tumorigenesis. In addition, Twist signaling induces the epithelial-mesenchymal transition (EMT) process in glioblastoma development. In the present study, in vitro assays were used to investigate the role of CXCR4 and Twist in human glioblastoma. We explored the impact of CXCR4 and Twist on human glioblastoma using in vitro protein and gene assays. We found the administration of CXCL12 upregulated the expression of p-ERK, p-AKT, Twist, N-cadherin, and MMP9 in U87 cells, whereas the increase of E-cadherin protein was affected. Subsequently, Twist activity and EMT signaling were directly influenced by PD98059 and LY294002. Most importantly, the genetic silencing of Twist inhibited CXCL12-induced EMT occurrence, including proliferation, migration, and tumor formation of U87 cells. In conclusion, CXCL12/CXCR4 pathway activates ERK and PI3K/AKT signaling to upregulate Twist pathway, leading to the progression of EMT in human glioblastoma. Our study creates a new stage for molecule-targeted therapy of human glioblastoma.

The chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1 (SDF-1) plays an important role in tumor progression and are associated with angiogenesis. Meanwhile, the implications of C23 in multiple signaling pathways have been also investigated. However, the effects of C23 on CXCR4 pathway in glioblastoma are not fully characterized. In the present study, C23 and CXCR4 of U87 cell line were inhibited by anti-C23 and anti-CXCR4 antibodies, respectively; and then C23 and CXCR4 siRNAs were used to knock down endogenous C23 and CXCR4, respectively. In addition, MTT assay was also introduced. Our data showed that either anti-C23 or anti-CXCR4 antibodies efficaciously repressed the phosphorylation levels of ERK (p < 0.000) and AKT (p < 0.000) compared with SDF-1 alone and control. As expected, either C23 or CXCR4 siRNAs indeed resulted in C23 and CXCR4 knockdown and further suppressed the expression of p-ERK and p-AKT. Most importantly, immunoprecipitation revealed C23 interacted with CXCR4 once U87 was exposed to SDF-1 treatment. In addition, MTT assay identified that C23 or CXCR4 siRNAs could obviously decreased cell proliferation capacity (p = 0.002). In conclusion, our results suggest that C23 plays a crucial role in activation of SDF-1-induced ERK and PI3K/AKT pathways via interacting with CXCR4. Furthermore, C23 could be recommended as an important element in glioblastoma development and a new target for glioblastoma treatment.

In recent decades, the chemokine receptor CXCR4 and its ligand CXCL12 have been extensively reported to be associated with tumorigenesis. In addition, Twist signaling induces the epithelial-mesenchymal transition (EMT) process in glioblastoma development. In the present study, in vitro assays were used to investigate the role of CXCR4 and Twist in human glioblastoma. We explored the impact of CXCR4 and Twist on human glioblastoma using in vitro protein and gene assays. We found the administration of CXCL12 upregulated the expression of p-ERK, p-AKT, Twist, N-cadherin, and MMP9 in U87 cells, whereas the increase of E-cadherin protein was affected. Subsequently, Twist activity and EMT signaling were directly influenced by PD98059 and LY294002. Most importantly, the genetic silencing of Twist inhibited CXCL12-induced EMT occurrence, including proliferation, migration, and tumor formation of U87 cells. In conclusion, CXCL12/CXCR4 pathway activates ERK and PI3K/AKT signaling to upregulate Twist pathway, leading to the progression of EMT in human glioblastoma. Our study creates a new stage for molecule-targeted therapy of human glioblastoma.

Chemokine receptor CXCR4 has been identified to affect glioma progression by dominating cancer cell survival, proliferation, and migration in vitro recently. However, the implications and utilities of CXCR4 in clinical grade and prognosis were rarely reported. Thus, it is essential to carry out a meta-analysis to draw a convincing conclusion. The relevant articles were included through careful assessment, and then, odds ratios (ORs), standard mean differences (SMDs), and hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) were estimated. Heterogeneity and funnel plots evaluation were conducted. In this meta-analysis, all 13 eligible studies involving 785 patients were included and conducted in China. Ten studies revealed altered CXCR4 expression in glioma tissues was closely associated with high WHO grade (III + IV) (n = 10, OR 5.46, 95 % CI 3.81-7.84; p = 0.000); besides, six studies also demonstrated CXCR4 expression intensity extremely correlated to high grade (n = 6, SMD -2.45, 95 % CI -2.78, -2.12; p = 0.000). Most importantly, three articles identified that CXCR4 expression significantly correlated to 3-year overall survival (OS) (HR 7.32, 95 % CI 4.16-12.90; p = 0.000) in glioma patients. No heterogeneity and publication bias were observed across all studies. Taken together, this meta-analysis suggests CXCR4 expression in gliomas can be recommended as evidence of WHO grade and indeed predict 3-year overall survival. We also provided a scientific rationale for clinically pathological detection of CXCR4 that is required for treatment of glioma patients.

Stromal cell-derived factor 1 (SDF-1) and its receptor, CXCR4, play an important role in tumor progression. Epithelial-mesenchymal transition (EMT) process is linked to disease pathophysiology. This study aimed to investigate the roles and underlying mechanisms of SDF-1/CXCR4 axis in EMT process of glioblastoma. In the present study, CXCR4 activation and inhibition in U87 were induced with exogenous SDF-1 and with CXCR4 small interfering RNA (siRNA), respectively. CXCR4 downstream signal molecules AKT, ERK, and EMT biomarkers (vementin, snail, N-cadherin, and E-cadherin) were tested using the Western blot. Our results showed that SDF-1 can induce AKT and ERK phosphorylation in a dose-dependent manner, and endogenous CXCR4 can be blocked thoroughly by CXCR4 siRNA in U87. Notably SDF-1 alone treatment can induce the upregulation of vementin, snail, and N-cadherin of U87; besides, the downregulation of E-cadherin also occurred. On the contrary, CXCR4 siRNA significantly prohibited SDF-1-induced AKT and ERK phosphorylation, at the same time, EMT biomarker changes were not observed. Function analysis revealed that CXCR4 siRNA obviously interfered with U87 cell migration and proliferation, according to wound healing assay. In conclusion, this study suggested that EMT process can be triggered by the SDF-1/CXCR4 axis in glioblastoma, and then involved in the tumor cell invasion and proliferation via activation of PI3K/AKT and ERK pathway. Our study lays a new foundation for the treatment of glioblastoma through antagonizing CXCR4.