Xiaoaiping injection affects the invasionand metastasis of hepatocellular carcinomaby controlling AFP expression

Objective Xiaoaiping (XAP) is a traditional Chinese medicine that is a commonly used as an anticancerdrug in clinical practice owing to its high efficiency and low toxicity. Specifically, XAP can effectively inhibitthe growth of hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is a key HCC diagnostic marker andis closely related to certain malignant cytological behaviors of HCC. However, whether AFP expression andXAP treatment are related to the invasion and metastasis of HCC remains unclear. In the present study, weaimed to evaluate the effects and underlying mechanism of XAP on the invasion and metastasis of HCC..Methods Using a cell scratch assay, Transwell technology, and western blotting we detected the differentinvasion and metastatic abilities of Hep3B cells in XAP treatment and blank control groups. This allowedcomparison of the invasion and metastatic abilities of Hep3B cells with differing levels of AFP expression.AFP mRNA sequencing technology was used to analyze the mechanism of tumor invasion and metastasisassociated with AFP and XAP treatment.Results Cell invasion and metastasis abilities in the XAP group were significantly lower than those in thecontrol group (P < 0.05). Additionally, compared to the control group, the expression of AFP significantlydecreased after XAP treatment (P < 0.05). The ability of Hep3B cells to invade and metastasize waspromoted when AFP expression was up-regulated, whereas it was inhibited when AFP was silenced. XAPinjection and AFP regulate the invasion and metastatic ability of HCC by affecting matrix metalloproteinases(MMPs).Conclusion XAP injection inhibits the invasion and metastatic ability of HCC by influencing the expressionof AFP;additionally, this inhibition of AFP is achieved by affecting MMPs.

Hypoxia-inducible factor-2αand its missense mutations:potential role in HCC diagnosis,progression,and prognosis and underlying mechanism

Objective This study aims to gain further the potential mechanisms of HIF-2αin tumor progression and tumorigenesis.Methods Mined The Cancer Genome Atlas(TCGA)dataset.In total,421 participants were enrolled in the TCGAHepatocellular Carcinoma(HCC)study,comprising 371 patients with cancer and 50 healthy controls.From the 371 tumor samples,three samples containing the missense mutation of the HIF-2αgene were compared with 368 wild-type samples to identify differentially expressed genes(DEGs).Results After filtering,univariate Cox regression and multivariate Cox regression analyses showed that the differentially expressed genes(DEGs)progestagen-associated endometrial protein(PAEP)PNLIPRP2,MIR147B,and pregnancy zone protein(PZP)were significantly correlated with the survival times of patients with HCC.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses were performed using the Database for Annotation,Visualization,and Integrated Discovery(DAVID)v6.8 database to detect the functional annotation of these four DEGs as well as hub genes obtained from protein-protein interaction(PPI)network analysis using the STRING v10 database.Our analysis focused on the PAEP and PZP genes,whose protein expressions were downregulated in samples with HIF-2αmissense mutation.The hub genes of PAEP and PZP were identified using PPI network analysis.Subsequent Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis revealed that PAEP and its hub genes were highly enriched in the TGF-βpathway,which is consistent with the analysis of PZP.Conclusion Our study proved that the missense mutation of HIF-2αinduces the upregulation of PAEP,which is positively related to the poor prognosis of patients with HCC,as it may upregulate the TGF-βpathway.In contrast,PZP downregulation showed the opposite phenomenon,as it may downregulate the TGF-βpathway.

Effects of sorafenib and regorafenib on the expression of hypoxia-inducible factors in hepatocellular carcinoma-transplanted nude mice

Objective The objective of this study was to investigate the inhibitory effects of sorafenib and regorafenib on the growth of hepatocellular carcinoma(HCC)using a subcutaneous transplantation tumor model in nude mice and exploring the effects of sorafenib and regorafenib on the expression of hypoxia-inducible factor(HIF)-1α,HIF-2α,and HIF-1βin HCC tissues collected from HCC-transplanted nude mice.Methods HepG2 cells were inoculated intradermally into nude mice.The mice were randomly assigned to either sorafenib treatment(100 mg/kg),regorafenib treatment(20 mg/kg),or solvent control group(dimethylsulfoxide)(n=8 per group)and received once-daily treatment for 14 days.The tumor volumes were recorded every 3 days after the initiation of treatment.The expression levels of HIF-1α,HIF-1β,HIF-2α,and SART1 in the HCC tissues were examined via quantitative real-time PCR(qRT-PCR)analysis and Western blotting.Results The tumors in the sorafenib and regorafenib treatment groups grew slower and smaller than did the tumors in the solvent control group.qPCR analysis and western blotting demonstrated that the mRNA and protein expressions of HIF-1αand HIF-1βwere down-regulated.The expression of HIF-2αand SART1 was up-regulated in the sorafenib treatment group(P<0.05);meanwhile,the expression of HIF-1αand HIF-1βwas up-regulated,and that of HIF-2αand SART1 was down-regulated in the regorafenib treatment group(P<0.05).Conclusion The expression of hypoxia-associated factor is up-regulated by sorafenib and down-regulated by regorafenib,which may induce the different effects of sorafenib on the expression of HIFs.

Prognostic role of plasma levels ofγ-glutamyl transpeptidase in patients with advanced gastric cancer treated with anti-PD-1 immunotherapy

Objective Antibodies targeting programmed cell death protein 1(PD-1)have become the mainstay of treatment for chemotherapy-refractory gastric cancer,characterized by high levels of programmed cell death ligand-1(PDL-1)expression.However,the routine clinical implementation of PDL-1 testing is currently limited by the lack of robust detection methods.In this regard,the role of plasmaγ-glutamyl transpeptidase(GGT),an N-terminal nucleophilic hydrolase,as an independent predictor of the efficacy of anti-PD-1 therapy remains unknown.In this study,we aimed to assessed the prognostic role of changes in plasma GGT levels(6 weeks vs.baseline)in patients with advanced gastric cancer treated with anti-PD-1 immunotherapy.Methods We retrospectively analyzed data from 57 patients with gastric cancer treated with anti-PD-1 antibodies(camrelizumab,sintilimab,nivolumab,tislelizumab,and toripalimab)at the Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China,from July 2018 to February 2021.Results We found that after 6 weeks of treatment,there were significant differences between responders and non-responders with respect to plasma GGT levels(P<0.001).Multivariate logistic regression analysis revealed that the continuous value of the 6-week difference in GGT levels(OR=1.437,95%CI=1.116-1.849,P=0.005)and 6-week difference in GGT≥0 or<0(OR=53.675,95%CI=6.379-451.669,P<0.001)were independent predictors of disease control.Survival analysis indicated that a reduction in plasma GGT6 levels during treatment was significantly associated with a favorable progression-free survival(PFS)and overall survival(P<0.001).Consistently,univariate and multivariate Cox regression analyses revealed that a reduction in plasma GGT6 levels during treatment was an independent predictor of PFS(HR=1.033,95%CI=1.013-1.053,P=0.001).Conclusion Alterations in plasma GGT levels during treatment can be used as a predictor of disease progression and survival in patients with advanced gastric cancer undergoing treatment with anti-PD-1 antibodies.