Objective Primary liver cancer,predominantly hepatocellular carcinoma(HCC),is a significant global health issue,ranking as the sixth most diagnosed cancer and the third leading cause of cancer-related mortality.Accura...Objective Primary liver cancer,predominantly hepatocellular carcinoma(HCC),is a significant global health issue,ranking as the sixth most diagnosed cancer and the third leading cause of cancer-related mortality.Accurate and early diagnosis of HCC is crucial for effective treatment,as HCC and non-HCC malignancies like intrahepatic cholangiocarcinoma(ICC)exhibit different prognoses and treatment responses.Traditional diagnostic methods,including liver biopsy and contrast-enhanced ultrasound(CEUS),face limitations in applicability and objectivity.The primary objective of this study was to develop an advanced,lightweighted classification network capable of distinguishing HCC from other non-HCC malignancies by leveraging the automatic analysis of brightness changes in CEUS images.The ultimate goal was to create a user-friendly and cost-efficient computer-aided diagnostic tool that could assist radiologists in making more accurate and efficient clinical decisions.Methods This retrospective study encompassed a total of 161 patients,comprising 131 diagnosed with HCC and 30 with non-HCC malignancies.To achieve accurate tumor detection,the YOLOX network was employed to identify the region of interest(ROI)on both B-mode ultrasound and CEUS images.A custom-developed algorithm was then utilized to extract brightness change curves from the tumor and adjacent liver parenchyma regions within the CEUS images.These curves provided critical data for the subsequent analysis and classification process.To analyze the extracted brightness change curves and classify the malignancies,we developed and compared several models.These included one-dimensional convolutional neural networks(1D-ResNet,1D-ConvNeXt,and 1D-CNN),as well as traditional machine-learning methods such as support vector machine(SVM),ensemble learning(EL),k-nearest neighbor(KNN),and decision tree(DT).The diagnostic performance of each method in distinguishing HCC from non-HCC malignancies was rigorously evaluated using four key metrics:area under the receiver operating characteristic(AUC),accuracy(ACC),sensitivity(SE),and specificity(SP).Results The evaluation of the machine-learning methods revealed AUC values of 0.70 for SVM,0.56 for ensemble learning,0.63 for KNN,and 0.72 for the decision tree.These results indicated moderate to fair performance in classifying the malignancies based on the brightness change curves.In contrast,the deep learning models demonstrated significantly higher AUCs,with 1D-ResNet achieving an AUC of 0.72,1D-ConvNeXt reaching 0.82,and 1D-CNN obtaining the highest AUC of 0.84.Moreover,under the five-fold cross-validation scheme,the 1D-CNN model outperformed other models in both accuracy and specificity.Specifically,it achieved accuracy improvements of 3.8%to 10.0%and specificity enhancements of 6.6%to 43.3%over competing approaches.The superior performance of the 1D-CNN model highlighted its potential as a powerful tool for accurate classification.Conclusion The 1D-CNN model proved to be the most effective in differentiating HCC from non-HCC malignancies,surpassing both traditional machine-learning methods and other deep learning models.This study successfully developed a user-friendly and cost-efficient computer-aided diagnostic solution that would significantly enhances radiologists’diagnostic capabilities.By improving the accuracy and efficiency of clinical decision-making,this tool has the potential to positively impact patient care and outcomes.Future work may focus on further refining the model and exploring its integration with multimodal ultrasound data to maximize its accuracy and applicability.展开更多
Objective To explore the value of contrast-enhanced ultrasound(CEUS)for predicting differentiation degree of hepatocellular carcinoma(HCC).Methods Totally 86 HCC patients confirmed by postoperative pathology were retr...Objective To explore the value of contrast-enhanced ultrasound(CEUS)for predicting differentiation degree of hepatocellular carcinoma(HCC).Methods Totally 86 HCC patients confirmed by postoperative pathology were retrospectively enrolled and divided into poorly differentiated,moderately differentiated and highly differentiated groups according to postoperative Edmondson-Steiner grading.Preoperative CEUS parameters were compared among groups,and binary logistic regression was used to analyze CEUS-related independent predictors of HCC with different differentiation.The receiver operating characteristic curves of parameters being significant different among groups were drawn,the areas under the curve(AUC)were calculated,and the efficacy for predicting HCC with different differentiation degree was evaluated.Results There were 29 cases in poorly differentiated group,37 in moderately differentiated group and 20 cases in highly differentiated group.The arrival time of contrast agent in poorly differentiated group was earlier than that in moderately and high differentiated groups(both P<0.05),while in moderately differentiated group was not significantly different with that in highly differentiated group(P>0.05).The washout grade were significantly different between each 2 groups(all P<0.05).The arrival time of contrast agent and washout grade were independent predictors of highly or poorly differentiated,moderately or poorly differentiated,moderate-highly or poorly differentiated HCC,and washout grade also was independent predictor of highly or moderately differentiated HCC(all P<0.05).The AUC of the arrival time of contrast agent for predicting highly or moderately differentiated,highly or poorly differentiated,moderately or poorly differentiated,moderate-highly or poorly differentiated HCC was 0.615,0.787,0.690 and 0.724,respectively,while of washout grade was 0.801,0.927,0.795 and 0.841,respectively.Conclusion CEUS could be used to effectively predict differentiation degree of HCC.展开更多
OBJECTIVE Angiogenesis therapy has attracted interest as a potential treatment for hepatocellular carcinoma(HCC).In this study,we investigated the anti-proliferative activities and antiangiogenesis effects of saikosap...OBJECTIVE Angiogenesis therapy has attracted interest as a potential treatment for hepatocellular carcinoma(HCC).In this study,we investigated the anti-proliferative activities and antiangiogenesis effects of saikosaponins(SS)-b on hepatocellular carcinoma(HCC)and its regulation on VEGF/ERK/HIF-1 αsignal pathway.METHODS H22 hepatoma-bearing mice model and HepG-2 cells were used to study the anti-tumor and anti-angiogenesis effects of SS-b in vivo and in vitro.Pathological change of tumor tissue was observed by HE staining,the microvascular changes were detected by immunohistochemical method.The effects of SS-b on angiogenesis were examined by using the chick embryo chorioallantoic membrane(CAM)model.The effects of SS-b on proliferation,migration and invasion were investigated by MTT assay,scratch wound healing assay and transwell assay inhuman umbilical vein endothelial cell(HUVEC)and HepG2 cells in vitro.Vascular endothelial growth factor(VEGF),matrix metalloproteinase-2/9(MMP-2/9),hypoxia-inducible factor-1α(HIF-1α)expression and the phosphorylation of extracellular regulated kinase(ERK)were analyzed using RT-PCR and Westernblot.RESULTS SS-b effectively inhibited the tumor growth of H22 mice in vivo.The inhibitory rate of tumor was 49.1%,50.7%,66.1%in SS-b 5,10 and 20 mg·kg-1group respectively.HE staining results showed that SS-b induced tumor necrosis and nuclear dissolution in H22 mice.Moreover,SS-b also reduced the number of microvessels of tumor tissue in H22 mice significantly and suppressed the angiogenesis of CAM induced by b-FGF.SS-b had an obvious inhibitory effect on cell proliferation,migration and invasion of HUVEC cells and HepG-2 cells.These effects were associated with downregulation of the expression of MMP2/9 and suppression of VEGF/ERK/HIF-1αsignaling in H22 mice and Hep-G2 cells.CONCLUSION Our findings showed that SS-b exerts anti-tumor effects by inhibiting tumor angiogenesis via regulating VEGF/ERK/HIF-1α signal pathway in vivo and in vitro.展开更多
Objective To study the damage of liver function after transcatheter arterial chemoembolization (TACE) with low-dose versus conventional-dose anticancer drugs in patients with hepatocellular carcinoma (HCC). Methods On...Objective To study the damage of liver function after transcatheter arterial chemoembolization (TACE) with low-dose versus conventional-dose anticancer drugs in patients with hepatocellular carcinoma (HCC). Methods One hundred and twelve patients with unresectable HCC were randomly divided into two groups (A and B) to receive superselective TACE. Low-dose anticancer drugs including mitomycin C (MMC) 2 ～ 8 mg,epirubicin (EPI) 5 ～ 10 mg and carboplatin (CBP) 100 mg were used in group A (n = 52),and conventional-dose of anticancer drugs (MMC 10 mg,EPI 40 mg and CBP 300 mg)for patients in group B(n = 60). Lipiodol-anticancer drugs emulsion was injected into the feeding arteries of tumor and then followed by embolization of gelatin sponge (GS) or polyvinyl alcohol (PVA) particles. Laboratory examination of the liver function including Child-Pugh scores,total bilirubin (TBIL),albumin (ALB) and alanine aminotransferase (ALT) were evaluated respectively before TACE and at third day,one week and four weeks after this procedure. Results In both groups,TBIL,ALT,and Child-Pugh scores increased (P < 0.001 or P < 0.05) and ALB decreased (P < 0.001 or P < 0.01) at three days and one week after TACE. Four weeks after-procedure,all the parameters described above showed no significant difference than those before the procedure in group A (P > 0.05). On the contrary in group B,a significant difference (P < 0.05) was found in the comparison of these parameters (except ALT). Conclusion Superselective TACE with low-dose anticancer drugs may induce transient impairment of liver function in the patients with HCC,but those patients used conventional-dose of anticancer drugs frequently cause lasting and more serious worsening of liver function. (J Intervent Radiol,2006,15: 351-355)展开更多
OBJECTIVE To study the dysregulation of metallothioneins(MT)and circadian genes in achieved human hepatocellular carcinoma(HCC),Peri-HCC tissues as compared to normal human livers,which may open up a new avenue for ta...OBJECTIVE To study the dysregulation of metallothioneins(MT)and circadian genes in achieved human hepatocellular carcinoma(HCC),Peri-HCC tissues as compared to normal human livers,which may open up a new avenue for targeting circadian clock to prevent and treatment of HCC.METHODS Total RNA was extracted,purified,and reverse transcribed.Realtime quantitative polymerase chain reaction(RT-q PCR)was performed to determine the expression of genes of metallothionein-1(MT-1),MT-2,and metal transcription factor-1(MFT-1)and circadian clock genes including core clock genes,circadian locomotor output cycles kaput(Clock)and brain and muscle Arnt-like protein 1(Bmal1),the clock feedback control genes,period(Per1,Per2)and cryptochrome(Cry1,Cry2),and clock target genes,nuclear orphan receptor factor protein(Nr1d1)and D-box-binding protein(Dbp)in human HCC,Peri-HCC and normal livers.RESULTS The expression of MT-1,MT-2,MFT-1 in human HCC was decreased,which were previously shown to have circadian rhythms.Similarly,the expression of the core clock genes(Bmal1,Clock),the clock feedback genes(Per1,Per2,Cry1and Cry2)was decreased in human HCC,as compared to Peri-HCC and normal livers.However,the expression of clock target genes(Nr1d1and Dbp)was increased in human HCC,as compared to Peri-HCC and normal livers.CONCLUSION These data clearly demonstrated the dysregulation of MTs and circadian clock genes in HCC,which could provide new insights into the relationship of circadian clock disruption and loss of MT in hepatocarcinogenesis,and could help a new strategy of targeting MT and circadian clock in the prevention and treatment of HCC.展开更多
OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing 1(PID1,NYGGF4)on promotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown...OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing 1(PID1,NYGGF4)on promotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown of PID1 in HFD induced IR mouse model as well as ob/ob mice.Intraperitoneal glucose and insulin tolerance were performed 4 weeks after lentivirus injection.Hydrodynamics-based transfection was applied to inducethe liver specific overexpression of PID1.Flow cytometry was exerted to detect the proportion and function of immune cells.qR T-PCR and Western blot were used to detect the expression of downstream pathways of PID1.Immunoprecipitation was used to determine the receptor of PID1.Chromatin immunoprecipitation(ChI P)was operated to measure the modification of H3K4me3 of PID1 promoter.RESULTS PID1 restriction improved insulin resistance,hyperglycemia and fatty liver.Conversely,hepatic knockdown of PID1 attenuated liver xenografted tumor growth.Moreover,PID1 liver-specific protooncogenes via hydrodynamics-based transfection established a primary hepatocellular carcinoma mouse model,induced an immunosuppressive environment,with the reduction of CD3^+,CD4^+,CD8^+T cel s,retarded maturation of dendritic cel s(DCs),pronounced differentiation of regulatory T cells(Tregs),and recruitment of MDSC.In addition,PID1 overexpression activated proliferation related genes,promoted anti-inflammatory genes,suppressed pro-inflammatory genes,induced glycolysis and lipid metabolism genes to facilitate tumorigenesis in liver.Importantly,PID1 exerted its tumor-promoting function through binding to epidermal growth factor receptor(EGFR)and activation of downstream MAPK pathway.As such,PID1 exist trimethylation of histone H3 at lysine 4(H3K4me3)modification and IR up-regulated the expression of PID1 by activation the H3K4me3 modification.CONCLUSION PID1 is a new gene that exerts both liver cancer-promoting and insulin resistance inducing function.IR accelerates liver cancer development and progressionpartially dependent on the activation of PID1.展开更多
Aim Oxyresveratrol （trans-2,3 ＇ ,4,5 ＇ -tetrahydroxystilbene, OXY） , a natural polyphenolic phyto- chemical presents in mulberry （Morus alba L. ） , has been reported to have various bioactivities. Though OXY has...Aim Oxyresveratrol （trans-2,3 ＇ ,4,5 ＇ -tetrahydroxystilbene, OXY） , a natural polyphenolic phyto- chemical presents in mulberry （Morus alba L. ） , has been reported to have various bioactivities. Though OXY has high structural similarity with resveratrol, which has been identified as a chemopreventive agent, little is known a- bout OXY＇s effect on cancer. The main objective of our study was to investigate the effect of OXY on metastasis in vivo. To establish an experimental metastasis model, male Kunming mice were challenged with H22 cells by tail vein injection, and were given different doses of OXY （20, 40,80 mg · kg^-1 body weight per day） for 14 days in- traperitoneally. Administration of OXY showed a clear anti-metastatic effect. Compared to control group （u - 10） , the numbers of pulmonary nodules and lung weight were significantly decreased in mice of 40 mg · kg^- 1 group （ n = 10, P 〈 0.05） , which results in 54.5% reduction in the number of metastases. Similar inhibitory effects were ob- served both at 20 and 80 mg · kg^-1 groups（n= 10, 34.2% and 35.7% , respectively）. OXY at the doses used caused an increase in spleen index （P 〈 0.05） but not thymus index. Further we observed animal body weights loss and food intake decrease （P 〈 0.05） , suggesting the toxicity of high dose used. Therefore, we suggest that oxyresveratrol may benefit human as a new preventive agent for cancer metastasis.展开更多
Aim To investigate the antitumor activities and mechanisms of sodium rosmarinate against hepatocellu- lar carcinoma. Methods Antitumor activities of sodium rosmarinate were measured on HepG2, HNE, K562, HCT116, and SW...Aim To investigate the antitumor activities and mechanisms of sodium rosmarinate against hepatocellu- lar carcinoma. Methods Antitumor activities of sodium rosmarinate were measured on HepG2, HNE, K562, HCT116, and SW480 cells by MTT assay in vitro at 5 mg· L^-1, 25 mg · L^-1 , and 50 mg · L^-1. Nude mice and H22 cells were employed to establish a liver tumor-bearing murine model. Sodium rosmarinate were intraperitoneal- ly administered at 25 mg. kg^-1 and 50 mg · kg^-1 for 10 days. Body weights, organ indexes, white blood cells, lymphocytes, and neutrophils of peripheral blood were measured. Murine tumors were histologically stained. TNF- ot and IFN-γ in serum were detected by ELISA. Expressions of Caspase-3, Bcl-2, Bax, Sift1, NF-KB p65, NF-KB pS0, and p-IKB-ot were measured by realtime-PCR and Western blot. Results Sodium rosmarinate showed obvi- ous inhibition on proliferation of HepG-2 cells at 5 mg · L^-1 But no inhibition effects were observed on HNE K562, HCT116, and SW480 cells. Body weights and organ indexes of nude mice with H22 cells were not changed by sodium rosmarinate. But sodium rosmarinate showed significant inhibition rate at 25 mg · kg^-1（45.67% ） and 50 mg · kg ^-l （ 52. 82% ）. Necrosis was aggregated by sodium rosmarinate as shown by H＆E staining. TNF-α and IFN-γ in murine serum were significantly increased by sodium rosmarinate at both doses （P 〈 0.05）. Expressions of caspase-3 were significantly increased （P 〈 0.01 ）. Sodium rosmarinate were shown to increase expressions of Bax, decrease expressions of Bcl-2, and significantly decrease Bacl-2/Bax ratio to induce apoptosis. Expressions ofSirtl, NF-KB p65, NF-KB p50, and p-IKB-αwere all decreased dose-dependently. Discussion Sodium rosmari- hate were demonstrated to inhibit hepatocellular carcinoma in vivo and in vitro through up-regulating TNF-α, IFN- γ , Bcl-2/Bax ratio, and down-regulating Sirtl and NF-KB related genes dose dependently, which may be devel- oped a promising drug for treatment of hepatocellular carcinoma.展开更多
Hypoxia was a prominent feature of hepatocellular carcinoma cells （HCC）, contributing to therapeutic resistance towards a variety chemotherapeutic agents including Topoisomerase I inhibitor SN38, with mechanism not...Hypoxia was a prominent feature of hepatocellular carcinoma cells （HCC）, contributing to therapeutic resistance towards a variety chemotherapeutic agents including Topoisomerase I inhibitor SN38, with mechanism not yet fully understood, thus remaining a major clinical challenge. Herein, we present evidences that the hypoxia-in- duced nuclear translocation and accumulation of Yes-associated protein （YAP） acts as a survival input to promote hypoxic-resistance to SN38 in HCC. YAP induction by hypoxia was not mediated by HIF-lα, since the manipula- tion of HIF-1α either by COC12, exogenous expression nor siRNA of HIF-1α imposed any effect on the phosphoryla- tion or total level of YAP. Instead, mevalonate-HMG-CoA reductase （HMGCR） pathway may modulate the YAP pathway under hypoxia. Combined YAP inhibition by either siRNA or HMGCR inhibitor statins with SN38 achieved improved anti-cancer activities in HCC cells. Moreover, the increased anti-cancer efficacy of statins combined with irinotecan （the prodrug of SN-38 ） was further validated in a human HCC HepG2 xenografl model in nude mice. Taken together, our findings identify YAP as a novel mechanism of hypoxic-resistance to SN38. These results un- veil the combined suppression of YAP （ for instance , statins） and SN38 as a potential promising strategy to enhance treatment response of HCC patients, particularly those with advanced stage suffering from hypoxic resistance.展开更多
The cytochrome P450 2El （ CYP2E1 ） and aldehyde dehydrogenase 2 （ALDH2） have been demonstrated that they were related to the development of hepatocellular carcinoma （HCC）. However, the associations have not been...The cytochrome P450 2El （ CYP2E1 ） and aldehyde dehydrogenase 2 （ALDH2） have been demonstrated that they were related to the development of hepatocellular carcinoma （HCC）. However, the associations have not been explained conclusively, and the combined analysis with the CYP2E1 Rsa I polymorphism and the ALDH2 pol- ymorphism have not been clarifed. In this study, we performed a meta-analysis to interpret the association between CYP2E1 and ALDH2 polymorphisms and HCC risk. Published literatures were retrieved from PubMed and Embase up to July, 2014. The pooled odds ratio （OR） with 95% confidence interval （CI） was calculated by using fixed- effects or random-effects model. A total of twelve case-controlled studies with 1 077 cancer cases and 2 000 controls concerning the CYP2E1 polymorphism were selected for this meta-analysis. The results indicated that there was no significantly associations between CYP2E1 polymorphism and risk of HCC （cl/c2 vs el/el ： OR - 1.11, 95% CI： 0.88-=1.39, P-0.38; c2/c2 vs el/el. OR -0.90, 95% CI. 0.54-=1.50, P-0.69; cl/c2 ＋ c2/c2 vs el/ el ： OR - 1.07, 95% CI： 0.89 -~ 1.30, P -0.47）. Further analysis of subgroup based on the ethnicity also showed no statistically significant associated with risk of HCC between the East Asians and the Europeans. In addi- tion, eight studies including 911 cases and 1 903 controls were included in this meta-analysis about the association between ALDH2 polymorphism and HCC risk. Results Based on our study also showed no significant association between ALDH2 polymorphism and the risk of HCC risk （ ＊ 1/＊ 2 vs ＊ 1/＊ 1： OR -0. 92, 95% CI： 0.65 -＊ 1.32, P-0.66; ,2/,2 vs ＊ 1/＊ 1. OR -0.82, 95% CI. 0.57-=1.18, P-0.28, ＊ 1/,2 ＋ ,2/,2 vs ＊ 1/＊ 1 ： OR -0.90, 95% CI. 0. 63 -- 1.29, P -0. 57）. The present meta-analysis indicated that there was no sig- nificant association between CYP2E1 polymorphism or ALDH2 polymorphism and HCC risk in the East Asians and the Europeans.展开更多
Combretastatin A-1 phosphate （CA1P） is a tubulin polymerization inhibitor that binds to the colchicine- binding site of tubulin and shows potential anti-tumor activity to acute myelocytic leukemia as reported. We de...Combretastatin A-1 phosphate （CA1P） is a tubulin polymerization inhibitor that binds to the colchicine- binding site of tubulin and shows potential anti-tumor activity to acute myelocytic leukemia as reported. We demon- strated that CA1P also showed an outstanding anti-cancer effect on hepatocellular carcinoma （HCC） in vivo and in vitro. As determined by DCFH-DA dye and Western blot, CA1P induced ROS accumulation and apoptosis in HepG2 cells with the down-regulation of Mcl-1. Additonal western blot and immunofluorescence assays further indi- cated that CA1P inhibited Wnt/β-catenin pathway through GSK-3β activition with an increasing of Mcl phosphoryl- ation and subsequent degradation mediated by tubulin-dynactin p l50-AKT signaling pathway axis. Apoptosis of HepG2 cells induced by CA1P was reversed by the GSK-3β inhibitor （ CHIR-99021 ）. Furthermore, determined by immunohistochemistry of an orthotopic HCC tumor model, CA1P showed a significantly effect on tumor associated macrophage （TAM） apoptosis in vitro and eliminated TAM in tumor microenviroment in vivo, while the infiltration of Treg cells and expression of TGF-β were also altered. Adoptive transfer of macrophages reinstated tumor growth treated by CA1P. These results indicated that CA1P presented potent potential on the regulation of hepatocellular carcinoma cells and TAMs, and also revealed a novel anti-HCC mechanism of CA1P, which acted on both cancer cells and tumor microenvironment. The findings would be beneficial for exploring new application of anti-microtubu- lar drugs on oncotherapy.展开更多
This report describes a hepatocellular carcinoma (HCC) with concomitant focal nodular hyperplasia (FNH) in a 56 years old Chinese man. There were two well circumscribed tumours measuring 3×2.5×2 cm and 2...This report describes a hepatocellular carcinoma (HCC) with concomitant focal nodular hyperplasia (FNH) in a 56 years old Chinese man. There were two well circumscribed tumours measuring 3×2.5×2 cm and 2×1.5×1.5 cm. The larger mass was grey and soft with a small area of bleeding and necrosis and an intact capsule. The smaller mass was yellow and had no capsule. Clonal analysis was carried out to clarify the relation between the HCC and the adjacent FNH. The clonal analysis was based on the methylation pattern of the polymorphic X chromosome linked androgen receptor gene (HUMARA). In FNH, after Hpa Ⅱ digestion, the allelic bands showed two well defined peaks. The intensity of the two peaks in the DNA from cirrhotic tissue did not differ significantly, consistent with a random pattern of X chromosome inactivation. However, in HCC, after Hpa Ⅱ digestion, the allelic bands differed significantly in intensity. Therefore, there was a typical polyclonal pattern of inactivation in FNH but the HCC was interpreted as being monoclonal.展开更多
We report the cloning and functional characterization of human cyclin L2, a novel member of the cyclin family. Human cyclin L2 shares significant homology to cyclin L1, K, T1, T2, and C, which are involved in transcri...We report the cloning and functional characterization of human cyclin L2, a novel member of the cyclin family. Human cyclin L2 shares significant homology to cyclin L1, K, T1, T2, and C, which are involved in transcriptional regulation via phosphorylation of the C-terminal domain of RNA polymerase Ⅱ. The cyclin L2 protein contains an N-terminal "cyclin box" and C-terminal dipeptide repeats of alternating arginines and serines, a hallmark of the SR family of splicing factors. A new isoform and the mouse homologue of human cyclin L2 have also been cloned in this study. Human cyclin L2 is expressed ubiquitously in normal human tissues and tumor cells. We show here that cyclin L2 co-localizes with splicing factors SC-35 and 9G8 within nuclear speckles and that it associates with hyperphosphorylated, but not hypophosphorylated, RNA polymerase Ⅱ and CDK p110 PITSLRE kinase via its N-terminal cyclin domains. It can also associate with the SC-35 and 9G8 through its RS repeat region. Recombinant cyclin L2 protein can stimulate in vitro mRNA splicing. Overexpression of human cyclin L2 suppresses the growth of human hepatocellular carcinoma SMMC 7721 cells both in vitro and in vivo, inducing cellular apoptosis. This process involves up-regulation of p53 and Bax and decreased expression of Bcl-2. The data suggest that cyclin L2 represents a new member of the cyclin family, which might regulate the transcription and RNA processing of certain apoptosis-related factors, resulting in tumor cell growth inhibition and apoptosis.展开更多
OBJECTIVE Granulin A(GRN A),a cytokinesis protein,is derived from proteolysis of progranulin.The previous study in our laboratory has shown that GRN A is able to inhibit cancer cell growth significantly.This study aim...OBJECTIVE Granulin A(GRN A),a cytokinesis protein,is derived from proteolysis of progranulin.The previous study in our laboratory has shown that GRN A is able to inhibit cancer cell growth significantly.This study aimed to investigate the effect of combination of GRN A and cisplatin on in vitro and in vivo on the growth of hepatocellular carcinoma.METHODS The in vitro and in vivo antitumor effects of combination of GRN A and Cisplatin were evaluated with MTS assay and subcuta.neous transplantation tumor model.Chou-Talalay method was used to calculate the combination index(CI).Colony formation assay and flow cytometry were used to detect the effects of GRN A on apoptosis.The expression of apoptosis-related proteins were detected by Western blot.RESULTS MTS assay showed that GRN A significantly inhibit hepatocellular carcinoma cells growth with the IC50 of 5.6 μmol·L^(-1),and GRN A combined with cisplatin synergistically inhibit hepatocellular carcinoma proliferation,with the CI<1.The colony-formation assay showed that GRN A significantly enhanced the inhibitory effects of cisplatin on cellular anchorage-independent growth.Flow cytometry showed that GRN A combined with cisplatin synergistically induced apoptosis,with the apoptotic rates of 5.87%,32.74%,35.67% and 67.15% in control,GRN A,Cisplatin,and combination of GRN A and Cisplatin groups,respectively.Western blot confirmed that the two drugs synergistically changed the expressions of proteins related to apoptosis.In vivo experiment indicated that combination of GRN A and cisplatin significantly suppressed tumor growth compared with single drug treatment groups.CONCLUSION The combination of GRN A and cisplatin resulted in synergistic antitumor effects against hepatocellular carcinoma both in vitro and in vivo.展开更多
OBJECTIVE To study the bioactive phytochemicals in the leaves of A.ilicifolius against Hepatocellular carcinoma(HCC) through in silico,in vitro and in vivo studies.METHODS A.ilicifolius leaves were collected from Cudd...OBJECTIVE To study the bioactive phytochemicals in the leaves of A.ilicifolius against Hepatocellular carcinoma(HCC) through in silico,in vitro and in vivo studies.METHODS A.ilicifolius leaves were collected from Cuddalore District,Tamil Nadu,India.Authenticated by the Botanical Survey of India.The fresh leaves of A.ilicifolius were washed and shade dried at room temperature(28 ± 2)℃.The dried leaves were powdered by electrical blender.25 gms of A.ilicifolius leaf powder was used for methanol extraction in the Soxhlet apparatus.The Phytochemical compounds were analyzed by GC-MS and the structure was retrieved from PubChem.Totally,seven HCC target proteins were collected from literature,ligand and proteins were prepared for in silico molecular docking.HepG2 cell lines were used for in vitro(MTT assay).BALB/c mice were used for in vivo studies,the biochemical parameters and histopathological studies were carried out with standard procedure.RESULTS The phytochemical26.27-Di(nor)-cholest-5,7,23-trien-22-ol,3-methoxymethoxy exhibited maximum docking score against the HCC target protein C-Jun N-terminal kinase 1(JNK 1)(-6.839798).MTT assay revealed that the extract at a concentration of 200 μg·mL-1,caused 60% cell death in HepG2 cell lines.Further animal studies using to injecting HCC induced BALB/c mice,restoration of haematological parameters and cells to normal was observed after 15 days of oral administration of the extract.These findings suggest the possibility of using A.ilicifolius leaves in the treatment of HCC.CONCLUSION The in silico,in vitro and in vivo studies indicated that the A.ilicifolius leaves had anticancereous activity against Hepatocellular carcinoma.There can be a possibility of synergistic activity of phytochemicals together against HCC.展开更多
OBJECTIVBE To investigate the intervention of compound Astragalus and Salvia miltiorrhiza extract(CASE) consisted of astragalosides,astragalus polysaccharides and salvianolic acids on the interaction of microRNA-145/m...OBJECTIVBE To investigate the intervention of compound Astragalus and Salvia miltiorrhiza extract(CASE) consisted of astragalosides,astragalus polysaccharides and salvianolic acids on the interaction of microRNA-145/microRNA-21(miR-145/miR-21) and Smad3 C/3 L phosphorylation(pSmad3 C/pSmad3 L) down-stream of transforming growth factor-β(TGF-β)/mitogen activated protein kinase(MAPK) signaling in hepatocellular carcinoma(HCC) progression by in vitro and in vivo experi.ments.METHODS In HepG2 cells and xenografts of nude mice,antagomir/agomir and plasmids of Smad3 C/3 L phosphorylation site mutation(Smad3 3 S-A/Smad3 EPSM) were used to intervene miR-145/miR-21 and pSmad3 C/pSmad3 L expression respectively,then incorporative CASE treatment.Cell proliferation,migration,apoptosis,tumor growth and histopathologic characteristics of xenografts,relevant proteins of TGF-β/Smad pathway and miR-145/miR-21 were evaluated.RESULTS CASE up-regulated miR-145 while down-regulated miR-21,inhibited cell proliferation,migration and tumor growth,accelerated cell apoptosis in HepG2 cells respectively transfected with Smad3 WT,Smad3 EPSM,Smad3 3 S-A plasmids in cultured dishes and xenografts of nude mice,the above effects were more evident in HepG2 cells with increased pSmad3 C.In TGF-β1-stimulated HepG2 cells and xenografts of nude mice,CASE antagonized the facilitating effects of miR-145 antagomir/miR-21 agomir on cell migration,proliferation,tumor growth and inhibiting effects of miR-145 antagomir/miR-21 agomir on cell apoptosis;CASE increased miR-145 down-regulated by miR-145 antagomir and decreased miR-21 up-regulated by miR-21 agomir,reduced protein level of pSmad3 L and their proteins including TβRⅡ,pERK1/2,pJNK1/2 and pp38 while elevated pSmad3 C expression.CONCLUSION These results suggest that pSmad3 C/pSmad3 L maybe interact with miR-145/miR-21 in HCC progression,which may be one of important molecular mechanisms of CASE's anti-HCC effects.展开更多
文摘Objective Primary liver cancer,predominantly hepatocellular carcinoma(HCC),is a significant global health issue,ranking as the sixth most diagnosed cancer and the third leading cause of cancer-related mortality.Accurate and early diagnosis of HCC is crucial for effective treatment,as HCC and non-HCC malignancies like intrahepatic cholangiocarcinoma(ICC)exhibit different prognoses and treatment responses.Traditional diagnostic methods,including liver biopsy and contrast-enhanced ultrasound(CEUS),face limitations in applicability and objectivity.The primary objective of this study was to develop an advanced,lightweighted classification network capable of distinguishing HCC from other non-HCC malignancies by leveraging the automatic analysis of brightness changes in CEUS images.The ultimate goal was to create a user-friendly and cost-efficient computer-aided diagnostic tool that could assist radiologists in making more accurate and efficient clinical decisions.Methods This retrospective study encompassed a total of 161 patients,comprising 131 diagnosed with HCC and 30 with non-HCC malignancies.To achieve accurate tumor detection,the YOLOX network was employed to identify the region of interest(ROI)on both B-mode ultrasound and CEUS images.A custom-developed algorithm was then utilized to extract brightness change curves from the tumor and adjacent liver parenchyma regions within the CEUS images.These curves provided critical data for the subsequent analysis and classification process.To analyze the extracted brightness change curves and classify the malignancies,we developed and compared several models.These included one-dimensional convolutional neural networks(1D-ResNet,1D-ConvNeXt,and 1D-CNN),as well as traditional machine-learning methods such as support vector machine(SVM),ensemble learning(EL),k-nearest neighbor(KNN),and decision tree(DT).The diagnostic performance of each method in distinguishing HCC from non-HCC malignancies was rigorously evaluated using four key metrics:area under the receiver operating characteristic(AUC),accuracy(ACC),sensitivity(SE),and specificity(SP).Results The evaluation of the machine-learning methods revealed AUC values of 0.70 for SVM,0.56 for ensemble learning,0.63 for KNN,and 0.72 for the decision tree.These results indicated moderate to fair performance in classifying the malignancies based on the brightness change curves.In contrast,the deep learning models demonstrated significantly higher AUCs,with 1D-ResNet achieving an AUC of 0.72,1D-ConvNeXt reaching 0.82,and 1D-CNN obtaining the highest AUC of 0.84.Moreover,under the five-fold cross-validation scheme,the 1D-CNN model outperformed other models in both accuracy and specificity.Specifically,it achieved accuracy improvements of 3.8%to 10.0%and specificity enhancements of 6.6%to 43.3%over competing approaches.The superior performance of the 1D-CNN model highlighted its potential as a powerful tool for accurate classification.Conclusion The 1D-CNN model proved to be the most effective in differentiating HCC from non-HCC malignancies,surpassing both traditional machine-learning methods and other deep learning models.This study successfully developed a user-friendly and cost-efficient computer-aided diagnostic solution that would significantly enhances radiologists’diagnostic capabilities.By improving the accuracy and efficiency of clinical decision-making,this tool has the potential to positively impact patient care and outcomes.Future work may focus on further refining the model and exploring its integration with multimodal ultrasound data to maximize its accuracy and applicability.
文摘Objective To explore the value of contrast-enhanced ultrasound(CEUS)for predicting differentiation degree of hepatocellular carcinoma(HCC).Methods Totally 86 HCC patients confirmed by postoperative pathology were retrospectively enrolled and divided into poorly differentiated,moderately differentiated and highly differentiated groups according to postoperative Edmondson-Steiner grading.Preoperative CEUS parameters were compared among groups,and binary logistic regression was used to analyze CEUS-related independent predictors of HCC with different differentiation.The receiver operating characteristic curves of parameters being significant different among groups were drawn,the areas under the curve(AUC)were calculated,and the efficacy for predicting HCC with different differentiation degree was evaluated.Results There were 29 cases in poorly differentiated group,37 in moderately differentiated group and 20 cases in highly differentiated group.The arrival time of contrast agent in poorly differentiated group was earlier than that in moderately and high differentiated groups(both P<0.05),while in moderately differentiated group was not significantly different with that in highly differentiated group(P>0.05).The washout grade were significantly different between each 2 groups(all P<0.05).The arrival time of contrast agent and washout grade were independent predictors of highly or poorly differentiated,moderately or poorly differentiated,moderate-highly or poorly differentiated HCC,and washout grade also was independent predictor of highly or moderately differentiated HCC(all P<0.05).The AUC of the arrival time of contrast agent for predicting highly or moderately differentiated,highly or poorly differentiated,moderately or poorly differentiated,moderate-highly or poorly differentiated HCC was 0.615,0.787,0.690 and 0.724,respectively,while of washout grade was 0.801,0.927,0.795 and 0.841,respectively.Conclusion CEUS could be used to effectively predict differentiation degree of HCC.
基金supported by Scientific and Technology Projects of Henan Province(142102310137)Science and Technology Development Project of Luoyang City(1603001A-3)
文摘OBJECTIVE Angiogenesis therapy has attracted interest as a potential treatment for hepatocellular carcinoma(HCC).In this study,we investigated the anti-proliferative activities and antiangiogenesis effects of saikosaponins(SS)-b on hepatocellular carcinoma(HCC)and its regulation on VEGF/ERK/HIF-1 αsignal pathway.METHODS H22 hepatoma-bearing mice model and HepG-2 cells were used to study the anti-tumor and anti-angiogenesis effects of SS-b in vivo and in vitro.Pathological change of tumor tissue was observed by HE staining,the microvascular changes were detected by immunohistochemical method.The effects of SS-b on angiogenesis were examined by using the chick embryo chorioallantoic membrane(CAM)model.The effects of SS-b on proliferation,migration and invasion were investigated by MTT assay,scratch wound healing assay and transwell assay inhuman umbilical vein endothelial cell(HUVEC)and HepG2 cells in vitro.Vascular endothelial growth factor(VEGF),matrix metalloproteinase-2/9(MMP-2/9),hypoxia-inducible factor-1α(HIF-1α)expression and the phosphorylation of extracellular regulated kinase(ERK)were analyzed using RT-PCR and Westernblot.RESULTS SS-b effectively inhibited the tumor growth of H22 mice in vivo.The inhibitory rate of tumor was 49.1%,50.7%,66.1%in SS-b 5,10 and 20 mg·kg-1group respectively.HE staining results showed that SS-b induced tumor necrosis and nuclear dissolution in H22 mice.Moreover,SS-b also reduced the number of microvessels of tumor tissue in H22 mice significantly and suppressed the angiogenesis of CAM induced by b-FGF.SS-b had an obvious inhibitory effect on cell proliferation,migration and invasion of HUVEC cells and HepG-2 cells.These effects were associated with downregulation of the expression of MMP2/9 and suppression of VEGF/ERK/HIF-1αsignaling in H22 mice and Hep-G2 cells.CONCLUSION Our findings showed that SS-b exerts anti-tumor effects by inhibiting tumor angiogenesis via regulating VEGF/ERK/HIF-1α signal pathway in vivo and in vitro.
文摘Objective To study the damage of liver function after transcatheter arterial chemoembolization (TACE) with low-dose versus conventional-dose anticancer drugs in patients with hepatocellular carcinoma (HCC). Methods One hundred and twelve patients with unresectable HCC were randomly divided into two groups (A and B) to receive superselective TACE. Low-dose anticancer drugs including mitomycin C (MMC) 2 ～ 8 mg,epirubicin (EPI) 5 ～ 10 mg and carboplatin (CBP) 100 mg were used in group A (n = 52),and conventional-dose of anticancer drugs (MMC 10 mg,EPI 40 mg and CBP 300 mg)for patients in group B(n = 60). Lipiodol-anticancer drugs emulsion was injected into the feeding arteries of tumor and then followed by embolization of gelatin sponge (GS) or polyvinyl alcohol (PVA) particles. Laboratory examination of the liver function including Child-Pugh scores,total bilirubin (TBIL),albumin (ALB) and alanine aminotransferase (ALT) were evaluated respectively before TACE and at third day,one week and four weeks after this procedure. Results In both groups,TBIL,ALT,and Child-Pugh scores increased (P < 0.001 or P < 0.05) and ALB decreased (P < 0.001 or P < 0.01) at three days and one week after TACE. Four weeks after-procedure,all the parameters described above showed no significant difference than those before the procedure in group A (P > 0.05). On the contrary in group B,a significant difference (P < 0.05) was found in the comparison of these parameters (except ALT). Conclusion Superselective TACE with low-dose anticancer drugs may induce transient impairment of liver function in the patients with HCC,but those patients used conventional-dose of anticancer drugs frequently cause lasting and more serious worsening of liver function. (J Intervent Radiol,2006,15: 351-355)
文摘OBJECTIVE To study the dysregulation of metallothioneins(MT)and circadian genes in achieved human hepatocellular carcinoma(HCC),Peri-HCC tissues as compared to normal human livers,which may open up a new avenue for targeting circadian clock to prevent and treatment of HCC.METHODS Total RNA was extracted,purified,and reverse transcribed.Realtime quantitative polymerase chain reaction(RT-q PCR)was performed to determine the expression of genes of metallothionein-1(MT-1),MT-2,and metal transcription factor-1(MFT-1)and circadian clock genes including core clock genes,circadian locomotor output cycles kaput(Clock)and brain and muscle Arnt-like protein 1(Bmal1),the clock feedback control genes,period(Per1,Per2)and cryptochrome(Cry1,Cry2),and clock target genes,nuclear orphan receptor factor protein(Nr1d1)and D-box-binding protein(Dbp)in human HCC,Peri-HCC and normal livers.RESULTS The expression of MT-1,MT-2,MFT-1 in human HCC was decreased,which were previously shown to have circadian rhythms.Similarly,the expression of the core clock genes(Bmal1,Clock),the clock feedback genes(Per1,Per2,Cry1and Cry2)was decreased in human HCC,as compared to Peri-HCC and normal livers.However,the expression of clock target genes(Nr1d1and Dbp)was increased in human HCC,as compared to Peri-HCC and normal livers.CONCLUSION These data clearly demonstrated the dysregulation of MTs and circadian clock genes in HCC,which could provide new insights into the relationship of circadian clock disruption and loss of MT in hepatocarcinogenesis,and could help a new strategy of targeting MT and circadian clock in the prevention and treatment of HCC.
基金supported by National Natural Science Foundation of China(81673440,81273521,and 91229114)
文摘OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing 1(PID1,NYGGF4)on promotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown of PID1 in HFD induced IR mouse model as well as ob/ob mice.Intraperitoneal glucose and insulin tolerance were performed 4 weeks after lentivirus injection.Hydrodynamics-based transfection was applied to inducethe liver specific overexpression of PID1.Flow cytometry was exerted to detect the proportion and function of immune cells.qR T-PCR and Western blot were used to detect the expression of downstream pathways of PID1.Immunoprecipitation was used to determine the receptor of PID1.Chromatin immunoprecipitation(ChI P)was operated to measure the modification of H3K4me3 of PID1 promoter.RESULTS PID1 restriction improved insulin resistance,hyperglycemia and fatty liver.Conversely,hepatic knockdown of PID1 attenuated liver xenografted tumor growth.Moreover,PID1 liver-specific protooncogenes via hydrodynamics-based transfection established a primary hepatocellular carcinoma mouse model,induced an immunosuppressive environment,with the reduction of CD3^+,CD4^+,CD8^+T cel s,retarded maturation of dendritic cel s(DCs),pronounced differentiation of regulatory T cells(Tregs),and recruitment of MDSC.In addition,PID1 overexpression activated proliferation related genes,promoted anti-inflammatory genes,suppressed pro-inflammatory genes,induced glycolysis and lipid metabolism genes to facilitate tumorigenesis in liver.Importantly,PID1 exerted its tumor-promoting function through binding to epidermal growth factor receptor(EGFR)and activation of downstream MAPK pathway.As such,PID1 exist trimethylation of histone H3 at lysine 4(H3K4me3)modification and IR up-regulated the expression of PID1 by activation the H3K4me3 modification.CONCLUSION PID1 is a new gene that exerts both liver cancer-promoting and insulin resistance inducing function.IR accelerates liver cancer development and progressionpartially dependent on the activation of PID1.
文摘Aim Oxyresveratrol （trans-2,3 ＇ ,4,5 ＇ -tetrahydroxystilbene, OXY） , a natural polyphenolic phyto- chemical presents in mulberry （Morus alba L. ） , has been reported to have various bioactivities. Though OXY has high structural similarity with resveratrol, which has been identified as a chemopreventive agent, little is known a- bout OXY＇s effect on cancer. The main objective of our study was to investigate the effect of OXY on metastasis in vivo. To establish an experimental metastasis model, male Kunming mice were challenged with H22 cells by tail vein injection, and were given different doses of OXY （20, 40,80 mg · kg^-1 body weight per day） for 14 days in- traperitoneally. Administration of OXY showed a clear anti-metastatic effect. Compared to control group （u - 10） , the numbers of pulmonary nodules and lung weight were significantly decreased in mice of 40 mg · kg^- 1 group （ n = 10, P 〈 0.05） , which results in 54.5% reduction in the number of metastases. Similar inhibitory effects were ob- served both at 20 and 80 mg · kg^-1 groups（n= 10, 34.2% and 35.7% , respectively）. OXY at the doses used caused an increase in spleen index （P 〈 0.05） but not thymus index. Further we observed animal body weights loss and food intake decrease （P 〈 0.05） , suggesting the toxicity of high dose used. Therefore, we suggest that oxyresveratrol may benefit human as a new preventive agent for cancer metastasis.
文摘Aim To investigate the antitumor activities and mechanisms of sodium rosmarinate against hepatocellu- lar carcinoma. Methods Antitumor activities of sodium rosmarinate were measured on HepG2, HNE, K562, HCT116, and SW480 cells by MTT assay in vitro at 5 mg· L^-1, 25 mg · L^-1 , and 50 mg · L^-1. Nude mice and H22 cells were employed to establish a liver tumor-bearing murine model. Sodium rosmarinate were intraperitoneal- ly administered at 25 mg. kg^-1 and 50 mg · kg^-1 for 10 days. Body weights, organ indexes, white blood cells, lymphocytes, and neutrophils of peripheral blood were measured. Murine tumors were histologically stained. TNF- ot and IFN-γ in serum were detected by ELISA. Expressions of Caspase-3, Bcl-2, Bax, Sift1, NF-KB p65, NF-KB pS0, and p-IKB-ot were measured by realtime-PCR and Western blot. Results Sodium rosmarinate showed obvi- ous inhibition on proliferation of HepG-2 cells at 5 mg · L^-1 But no inhibition effects were observed on HNE K562, HCT116, and SW480 cells. Body weights and organ indexes of nude mice with H22 cells were not changed by sodium rosmarinate. But sodium rosmarinate showed significant inhibition rate at 25 mg · kg^-1（45.67% ） and 50 mg · kg ^-l （ 52. 82% ）. Necrosis was aggregated by sodium rosmarinate as shown by H＆E staining. TNF-α and IFN-γ in murine serum were significantly increased by sodium rosmarinate at both doses （P 〈 0.05）. Expressions of caspase-3 were significantly increased （P 〈 0.01 ）. Sodium rosmarinate were shown to increase expressions of Bax, decrease expressions of Bcl-2, and significantly decrease Bacl-2/Bax ratio to induce apoptosis. Expressions ofSirtl, NF-KB p65, NF-KB p50, and p-IKB-αwere all decreased dose-dependently. Discussion Sodium rosmari- hate were demonstrated to inhibit hepatocellular carcinoma in vivo and in vitro through up-regulating TNF-α, IFN- γ , Bcl-2/Bax ratio, and down-regulating Sirtl and NF-KB related genes dose dependently, which may be devel- oped a promising drug for treatment of hepatocellular carcinoma.
文摘Hypoxia was a prominent feature of hepatocellular carcinoma cells （HCC）, contributing to therapeutic resistance towards a variety chemotherapeutic agents including Topoisomerase I inhibitor SN38, with mechanism not yet fully understood, thus remaining a major clinical challenge. Herein, we present evidences that the hypoxia-in- duced nuclear translocation and accumulation of Yes-associated protein （YAP） acts as a survival input to promote hypoxic-resistance to SN38 in HCC. YAP induction by hypoxia was not mediated by HIF-lα, since the manipula- tion of HIF-1α either by COC12, exogenous expression nor siRNA of HIF-1α imposed any effect on the phosphoryla- tion or total level of YAP. Instead, mevalonate-HMG-CoA reductase （HMGCR） pathway may modulate the YAP pathway under hypoxia. Combined YAP inhibition by either siRNA or HMGCR inhibitor statins with SN38 achieved improved anti-cancer activities in HCC cells. Moreover, the increased anti-cancer efficacy of statins combined with irinotecan （the prodrug of SN-38 ） was further validated in a human HCC HepG2 xenografl model in nude mice. Taken together, our findings identify YAP as a novel mechanism of hypoxic-resistance to SN38. These results un- veil the combined suppression of YAP （ for instance , statins） and SN38 as a potential promising strategy to enhance treatment response of HCC patients, particularly those with advanced stage suffering from hypoxic resistance.
文摘The cytochrome P450 2El （ CYP2E1 ） and aldehyde dehydrogenase 2 （ALDH2） have been demonstrated that they were related to the development of hepatocellular carcinoma （HCC）. However, the associations have not been explained conclusively, and the combined analysis with the CYP2E1 Rsa I polymorphism and the ALDH2 pol- ymorphism have not been clarifed. In this study, we performed a meta-analysis to interpret the association between CYP2E1 and ALDH2 polymorphisms and HCC risk. Published literatures were retrieved from PubMed and Embase up to July, 2014. The pooled odds ratio （OR） with 95% confidence interval （CI） was calculated by using fixed- effects or random-effects model. A total of twelve case-controlled studies with 1 077 cancer cases and 2 000 controls concerning the CYP2E1 polymorphism were selected for this meta-analysis. The results indicated that there was no significantly associations between CYP2E1 polymorphism and risk of HCC （cl/c2 vs el/el ： OR - 1.11, 95% CI： 0.88-=1.39, P-0.38; c2/c2 vs el/el. OR -0.90, 95% CI. 0.54-=1.50, P-0.69; cl/c2 ＋ c2/c2 vs el/ el ： OR - 1.07, 95% CI： 0.89 -~ 1.30, P -0.47）. Further analysis of subgroup based on the ethnicity also showed no statistically significant associated with risk of HCC between the East Asians and the Europeans. In addi- tion, eight studies including 911 cases and 1 903 controls were included in this meta-analysis about the association between ALDH2 polymorphism and HCC risk. Results Based on our study also showed no significant association between ALDH2 polymorphism and the risk of HCC risk （ ＊ 1/＊ 2 vs ＊ 1/＊ 1： OR -0. 92, 95% CI： 0.65 -＊ 1.32, P-0.66; ,2/,2 vs ＊ 1/＊ 1. OR -0.82, 95% CI. 0.57-=1.18, P-0.28, ＊ 1/,2 ＋ ,2/,2 vs ＊ 1/＊ 1 ： OR -0.90, 95% CI. 0. 63 -- 1.29, P -0. 57）. The present meta-analysis indicated that there was no sig- nificant association between CYP2E1 polymorphism or ALDH2 polymorphism and HCC risk in the East Asians and the Europeans.
文摘Combretastatin A-1 phosphate （CA1P） is a tubulin polymerization inhibitor that binds to the colchicine- binding site of tubulin and shows potential anti-tumor activity to acute myelocytic leukemia as reported. We demon- strated that CA1P also showed an outstanding anti-cancer effect on hepatocellular carcinoma （HCC） in vivo and in vitro. As determined by DCFH-DA dye and Western blot, CA1P induced ROS accumulation and apoptosis in HepG2 cells with the down-regulation of Mcl-1. Additonal western blot and immunofluorescence assays further indi- cated that CA1P inhibited Wnt/β-catenin pathway through GSK-3β activition with an increasing of Mcl phosphoryl- ation and subsequent degradation mediated by tubulin-dynactin p l50-AKT signaling pathway axis. Apoptosis of HepG2 cells induced by CA1P was reversed by the GSK-3β inhibitor （ CHIR-99021 ）. Furthermore, determined by immunohistochemistry of an orthotopic HCC tumor model, CA1P showed a significantly effect on tumor associated macrophage （TAM） apoptosis in vitro and eliminated TAM in tumor microenviroment in vivo, while the infiltration of Treg cells and expression of TGF-β were also altered. Adoptive transfer of macrophages reinstated tumor growth treated by CA1P. These results indicated that CA1P presented potent potential on the regulation of hepatocellular carcinoma cells and TAMs, and also revealed a novel anti-HCC mechanism of CA1P, which acted on both cancer cells and tumor microenvironment. The findings would be beneficial for exploring new application of anti-microtubu- lar drugs on oncotherapy.
文摘This report describes a hepatocellular carcinoma (HCC) with concomitant focal nodular hyperplasia (FNH) in a 56 years old Chinese man. There were two well circumscribed tumours measuring 3×2.5×2 cm and 2×1.5×1.5 cm. The larger mass was grey and soft with a small area of bleeding and necrosis and an intact capsule. The smaller mass was yellow and had no capsule. Clonal analysis was carried out to clarify the relation between the HCC and the adjacent FNH. The clonal analysis was based on the methylation pattern of the polymorphic X chromosome linked androgen receptor gene (HUMARA). In FNH, after Hpa Ⅱ digestion, the allelic bands showed two well defined peaks. The intensity of the two peaks in the DNA from cirrhotic tissue did not differ significantly, consistent with a random pattern of X chromosome inactivation. However, in HCC, after Hpa Ⅱ digestion, the allelic bands differed significantly in intensity. Therefore, there was a typical polyclonal pattern of inactivation in FNH but the HCC was interpreted as being monoclonal.
文摘We report the cloning and functional characterization of human cyclin L2, a novel member of the cyclin family. Human cyclin L2 shares significant homology to cyclin L1, K, T1, T2, and C, which are involved in transcriptional regulation via phosphorylation of the C-terminal domain of RNA polymerase Ⅱ. The cyclin L2 protein contains an N-terminal "cyclin box" and C-terminal dipeptide repeats of alternating arginines and serines, a hallmark of the SR family of splicing factors. A new isoform and the mouse homologue of human cyclin L2 have also been cloned in this study. Human cyclin L2 is expressed ubiquitously in normal human tissues and tumor cells. We show here that cyclin L2 co-localizes with splicing factors SC-35 and 9G8 within nuclear speckles and that it associates with hyperphosphorylated, but not hypophosphorylated, RNA polymerase Ⅱ and CDK p110 PITSLRE kinase via its N-terminal cyclin domains. It can also associate with the SC-35 and 9G8 through its RS repeat region. Recombinant cyclin L2 protein can stimulate in vitro mRNA splicing. Overexpression of human cyclin L2 suppresses the growth of human hepatocellular carcinoma SMMC 7721 cells both in vitro and in vivo, inducing cellular apoptosis. This process involves up-regulation of p53 and Bax and decreased expression of Bcl-2. The data suggest that cyclin L2 represents a new member of the cyclin family, which might regulate the transcription and RNA processing of certain apoptosis-related factors, resulting in tumor cell growth inhibition and apoptosis.
文摘OBJECTIVE Granulin A(GRN A),a cytokinesis protein,is derived from proteolysis of progranulin.The previous study in our laboratory has shown that GRN A is able to inhibit cancer cell growth significantly.This study aimed to investigate the effect of combination of GRN A and cisplatin on in vitro and in vivo on the growth of hepatocellular carcinoma.METHODS The in vitro and in vivo antitumor effects of combination of GRN A and Cisplatin were evaluated with MTS assay and subcuta.neous transplantation tumor model.Chou-Talalay method was used to calculate the combination index(CI).Colony formation assay and flow cytometry were used to detect the effects of GRN A on apoptosis.The expression of apoptosis-related proteins were detected by Western blot.RESULTS MTS assay showed that GRN A significantly inhibit hepatocellular carcinoma cells growth with the IC50 of 5.6 μmol·L^(-1),and GRN A combined with cisplatin synergistically inhibit hepatocellular carcinoma proliferation,with the CI<1.The colony-formation assay showed that GRN A significantly enhanced the inhibitory effects of cisplatin on cellular anchorage-independent growth.Flow cytometry showed that GRN A combined with cisplatin synergistically induced apoptosis,with the apoptotic rates of 5.87%,32.74%,35.67% and 67.15% in control,GRN A,Cisplatin,and combination of GRN A and Cisplatin groups,respectively.Western blot confirmed that the two drugs synergistically changed the expressions of proteins related to apoptosis.In vivo experiment indicated that combination of GRN A and cisplatin significantly suppressed tumor growth compared with single drug treatment groups.CONCLUSION The combination of GRN A and cisplatin resulted in synergistic antitumor effects against hepatocellular carcinoma both in vitro and in vivo.
基金supported by Key Construction Program of International Cooperation Base in S＆T,Shaanxi Province,China(2015SD0018)
文摘OBJECTIVE To study the bioactive phytochemicals in the leaves of A.ilicifolius against Hepatocellular carcinoma(HCC) through in silico,in vitro and in vivo studies.METHODS A.ilicifolius leaves were collected from Cuddalore District,Tamil Nadu,India.Authenticated by the Botanical Survey of India.The fresh leaves of A.ilicifolius were washed and shade dried at room temperature(28 ± 2)℃.The dried leaves were powdered by electrical blender.25 gms of A.ilicifolius leaf powder was used for methanol extraction in the Soxhlet apparatus.The Phytochemical compounds were analyzed by GC-MS and the structure was retrieved from PubChem.Totally,seven HCC target proteins were collected from literature,ligand and proteins were prepared for in silico molecular docking.HepG2 cell lines were used for in vitro(MTT assay).BALB/c mice were used for in vivo studies,the biochemical parameters and histopathological studies were carried out with standard procedure.RESULTS The phytochemical26.27-Di(nor)-cholest-5,7,23-trien-22-ol,3-methoxymethoxy exhibited maximum docking score against the HCC target protein C-Jun N-terminal kinase 1(JNK 1)(-6.839798).MTT assay revealed that the extract at a concentration of 200 μg·mL-1,caused 60% cell death in HepG2 cell lines.Further animal studies using to injecting HCC induced BALB/c mice,restoration of haematological parameters and cells to normal was observed after 15 days of oral administration of the extract.These findings suggest the possibility of using A.ilicifolius leaves in the treatment of HCC.CONCLUSION The in silico,in vitro and in vivo studies indicated that the A.ilicifolius leaves had anticancereous activity against Hepatocellular carcinoma.There can be a possibility of synergistic activity of phytochemicals together against HCC.
基金supported by National Natural Science Foundation of China(8137401281573652)
文摘OBJECTIVBE To investigate the intervention of compound Astragalus and Salvia miltiorrhiza extract(CASE) consisted of astragalosides,astragalus polysaccharides and salvianolic acids on the interaction of microRNA-145/microRNA-21(miR-145/miR-21) and Smad3 C/3 L phosphorylation(pSmad3 C/pSmad3 L) down-stream of transforming growth factor-β(TGF-β)/mitogen activated protein kinase(MAPK) signaling in hepatocellular carcinoma(HCC) progression by in vitro and in vivo experi.ments.METHODS In HepG2 cells and xenografts of nude mice,antagomir/agomir and plasmids of Smad3 C/3 L phosphorylation site mutation(Smad3 3 S-A/Smad3 EPSM) were used to intervene miR-145/miR-21 and pSmad3 C/pSmad3 L expression respectively,then incorporative CASE treatment.Cell proliferation,migration,apoptosis,tumor growth and histopathologic characteristics of xenografts,relevant proteins of TGF-β/Smad pathway and miR-145/miR-21 were evaluated.RESULTS CASE up-regulated miR-145 while down-regulated miR-21,inhibited cell proliferation,migration and tumor growth,accelerated cell apoptosis in HepG2 cells respectively transfected with Smad3 WT,Smad3 EPSM,Smad3 3 S-A plasmids in cultured dishes and xenografts of nude mice,the above effects were more evident in HepG2 cells with increased pSmad3 C.In TGF-β1-stimulated HepG2 cells and xenografts of nude mice,CASE antagonized the facilitating effects of miR-145 antagomir/miR-21 agomir on cell migration,proliferation,tumor growth and inhibiting effects of miR-145 antagomir/miR-21 agomir on cell apoptosis;CASE increased miR-145 down-regulated by miR-145 antagomir and decreased miR-21 up-regulated by miR-21 agomir,reduced protein level of pSmad3 L and their proteins including TβRⅡ,pERK1/2,pJNK1/2 and pp38 while elevated pSmad3 C expression.CONCLUSION These results suggest that pSmad3 C/pSmad3 L maybe interact with miR-145/miR-21 in HCC progression,which may be one of important molecular mechanisms of CASE's anti-HCC effects.
