CPNE1 is a potential prognostic biomarker, associated with immune infiltrates and promotes progression of hepatocellular carcinoma.

BACKGROUND: Copine1 (CPNE1), the first discovered CPNE1 family member, participates in the process of carcinogenesis and development of diverse tumors. Our study aimed to investigate the expression and prognostic value of CPNE1 gene in hepatocellular carcinoma (HCC), to explore its functional network in HCC and its effects on biological behaviors. METHODS: HCCDB, CCLE, HPA and LinkedOmics online databases were used to explore the expression of CPNE1 gene and analyze the co-expression network of CPNE1 in hepatocellular carcinoma. Gene set enrichment analysis (GSEA) was used for GO functional annotation, KEGG pathway enrichment analysis and regulators of CPNE1 networks in LIHC. HepG2 and MHCC-97H cells were selected to construct CPNE1 knockdown cell lines by transfection with siRNA, and Hep3B cell was selected to construct CPNE1 overexpression cell line by transfection with plasmid. The effect of CPNE1 on the proliferation of hepatocellular carcinoma cells was examined by CCK8 assay and clone formation assay; the effect of CPNE1 on the migration ability of hepatocellular carcinoma cells was assessed by cell scratch assay and Transwell cell migration assay; finally, the expression of related signaling pathway proteins was examined by Western Blot. The correlation of CPNE1 expression with immune infiltration and immune checkpoint molecules in HCC tissues was analyzed using TIMER online database and GSEA. RESULTS: CPNE1 was highly expressed in HCC tissues and significantly correlated with sex, age, cancer stage and tumor grade. Overall survival (OS) was significantly lower in patients with high CPNE1 expression than in patients with low CPNE1 expression, and CPNE1 could be used as an independent prognostic indicator for HCC. Knockdown of CPNE1 gene inhibited the AKT/P53 pathway, resulting in decreased proliferation, migration and invasion of HCC cells. Overexpression of CPNE1 gene showed the opposite results. The level of CPNE1 expression in HCC was significantly and positively correlated with the level of infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (P < 0.001). GSEA results also showed that CPNE1 of LIHC was involved in some immune response regulating signaling pathways. CONCLUSIONS: Our study firstly found the expression of CPNE1 was significantly higher in LIHC tissues than in normal liver tissues, and high CPNE1 expression was associated with poor prognosis. In addition, we identified the possible mechanism by which CPNE1 functioned in LIHC. CPNE1 influenced AKT/P53 pathway activation and LIHC cell proliferation and migration. There was a significant correlation between CPNE1 expression and tumor immune infiltration in LIHC.

PARP inhibitors in gastric cancer: beacon of hope.

Defects in the DNA damage response (DDR) can lead to genome instability, producing mutations or aberrations that promote the development and progression of cancer. But it also confers such cells vulnerable to cell death when they inhibit DNA damage repair. Poly (ADP-ribose) polymerase (PARP) plays a central role in many cellular processes, including DNA repair, replication, and transcription. PARP induces the occurrence of poly (ADP-ribosylation) (PARylation) when DNA single strand breaks (SSB) occur. PARP and various proteins can interact directly or indirectly through PARylation to regulate DNA repair. Inhibitors that directly target PARP have been found to block the SSB repair pathway, triggering homologous recombination deficiency (HRD) cancers to form synthetic lethal concepts that represent an anticancer strategy. It has therefore been investigated in many cancer types for more effective anti-cancer strategies, including gastric cancer (GC). This review describes the antitumor mechanisms of PARP inhibitors (PARPis), and the preclinical and clinical progress of PARPis as monotherapy and combination therapy in GC.

Novel Pt(IV) complexes to overcome multidrug resistance in gastric cancer by targeting P-glycoprotein.

Systematic toxicity and drug resistance significantly limited FDA-approved platinum drugs for further clinical applications. In order to reverse the resistance (MDR) and enhance their anticancer efficiency, four Pt(IV) complexes (12-15) conjugating with P-glycoprotein (P-gp) inhibitors were designed and synthesized. Among them, complex 14 (IC50 = 3.37 µM) efficiently reversed cisplatin resistance in SGC-7901/CDDP cell line and increased selectivity index (6.9) against normal HL-7702 cell line. Detailed mechanisms in SGC-7901/CDDP cells assays revealed that complex 14 efficiently induced apoptosis via down-regulating expression of P-gp for enhanced intracellular uptake of platinum, arrested cells at G2/M phase, induced DNA damage and initiated mitochondrial apoptosis pathway. Further in vivo studies demonstrated that the enhanced accumulation of complex 14 contributed to tumor inhibition of 75.6% in SGC-7901/CDDP xenografts, which was much higher than cisplatin (25.9%) and oxaliplatin (43%). Moreover, the low systematic toxicity made 14 a potential novel P-gp-mediated MDR modulator.

PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer.

Despite recent improvements in treatment modalities, pancreatic cancer remains a highly lethal tumor with mortality rate increasing every year. Poly (ADP-ribose) polymerase (PARP) inhibitors are now used in pancreatic cancer as a breakthrough in targeted therapy. This study focused on whether PARP inhibitors (PARPis) can affect programmed death ligand-1 (PD-L1) expression in pancreatic cancer and whether immune checkpoint inhibitors of PD-L1/programmed death 1 (PD-1) can enhance the anti-tumor effects of PARPis. Here we found that PARPi, pamiparib, up-regulated PD-L1 expression on the surface of pancreatic cancer cells in vitro and in vivo. Mechanistically, pamiparib induced PD-L1 expression via JAK2/STAT3 pathway, at least partially, in pancreatic cancer. Importantly, pamiparib attenuated tumor growth; while co-administration of pamiparib with PD-L1 blockers significantly improved the therapeutic efficacy in vivo compared with monotherapy. Combination therapy resulted in an altered tumor immune microenvironment with a significant increase in windiness of CD8+ T cells, suggesting a potential role of CD8+ T cells in the combination therapy. Together, this study provides evidence for the clinical application of PARPis with anti-PD-L1/PD-1 drugs in the treatment of pancreatic cancer.

Maximum cadmium limits establishment strategy based on the dietary exposure estimation: an example from Chinese populations and subgroups.

Dietary exposure to cadmium (Cd) in the Chinese population is currently a public health concern. China's national standard for maximum limits (MLs) of Cd in foods needs to be assessed. The objective of this research is to estimate the impacts of different Cd MLs intakes from selected foods and food groups and to provide scientific evidence for ML establishment. Food consumption data were taken from the Chinese National Diet and Nutrition Survey. Cd contamination data were obtained from the National Food Contamination Monitoring Program. A beta binomial normal (BBN) model was applied in the probabilistic assessment. Different possible ML scenarios for rice were selected to assess the impact of different MLs on Cd concentration and intake. More than 70% of children aged 2-6 years and over 30% of the general population have a dietary daily Cd intake above provisional tolerable daily intake (PTMId). Cd intake changed greatly relative to baseline when different possible MLs were used, but the changes were not as large when compared among the different possible MLs. Cd exposure in China, especially for children, is a public health concern. It is recommended that the ML for rice be held at 0.2 mg/kg.