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1.
J Hepatocell Carcinoma ; 8: 1323-1338, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765572

RESUMO

Background: Cytochrome P450 2C8 (CYP2C8) gene is one of the members of the cytochrome P450 enzymes (CYPs) gene family. The aim of this study was to reveal the function of CYP2C8 in hepatocellular carcinoma (HCC) and its effect on the sorafenib resistance. Methods: Differential expression analysis in multiple HCC datasets all suggested that CYP2C8 expression was significantly decreased in HCC tissues, compared with para-carcinoma liver tissues. The expression level of CYP2C8 was subsequently compared between HCC tissues and para-carcinoma liver tissues of 70 patients form Guangxi, China, with the result consistent with the above. Survival analysis and ROC analysis indicated that CYP2C8 was equipped with satisfactory diagnostic and prognostic value in HCC. To examine the effect of CYP2C8 on the malignant phenotype of HCC cells, stable transcriptional cell lines with CYP2C8 over-expression were established, and then Cell Counting Kit-8 (CCK8) assay, colony formation assay, cell cycle assay, cell invasion assay and wound healing assay were performed. Results: The results of aforementioned assays suggested that CYP2C8 over-expression restricted the proliferation, clonality, migration, invasion and cell cycle of HCC cells but had no significant effect on cell apoptosis. The enrichment analysis in terms of sequencing data of HCC cell lines with stable CYP2C8 over-expression suggested that CYP2C8 might be related to PI3K/Akt/p27Kip1 axis. The inhibition of CYP2C8 over-expression on PI3K/Akt/p27Kip1 axis was subsequently demonstrated with Western blot assay. In the rescue experiment, it was observed that both P27 inhibitor and PI3K agonist counteracted the repressed malignant phenotype caused by CYP2C8 over-expression, which further demonstrated that CYP2C8 played a role in HCC cells via PI3K/Akt/p27Kip1 axis. Discussion: The results demonstrated that CYP2C8 enhances the anticancer activity of sorafenib in vitro assays and in tumor xenograft model, with Ki-67 down-regulation and PI3K/Akt/p27Kip1 axis inhibition. In conclusion, these findings hinted that CYP2C8 restricted malignant phenotype and sorafenib resistance in HCC via PI3K/Akt/p27kip1 axis.

2.
J Cancer ; 12(18): 5506-5518, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34405013

RESUMO

Objective: The objective was to identify and validate C-X-C motif chemokine ligand 1(CXCL1) for diagnosis and prognosis in colon adenocarcinoma (COAD). Methods: Our current study had enrolled one The Cancer Genome Atlas (TCGA) cohort and two Guangxi cohorts to identify and verify the diagnostic and prognostic values of CXCL1 in COAD. Functional enrichment was performed by gene set enrichment analysis (GSEA). Results: In TCGA cohort, the expression of CXCL1 was significantly up-regulated in tumor tissues and decreased as the tumor stage developed. The receiver operating characteristic (ROC) curve showed that CXCL1 had a high diagnostic value for COAD. The result of Kaplan-Meier survival analysis showed that CXCL1 gene expression (P=0.045) was significantly correlated with overall survival (OS) of COAD. Results of Guangxi cohort also verified the diagnostic value of CXCL1 in COAD, and sub-group survival analyses also suggested that patients with high CXCL1 expression were related to a favorable OS (Corrected P=0.005). GSEA revealed that CXCL1 high expression phenotype was related to cytokine activity, cell apoptosis, P53 regulation pathway, and regulation of autophagy in COAD. Conclusions: In this study, we found that CXCL1 gene might be a potential diagnostic biomarker for COAD, and might serve as a prognostic biomarker for specific subgroup of COAD.

3.
J Cancer ; 12(12): 3486-3500, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995626

RESUMO

Background: Hepatitis B virus infection is associated with liver disease, including cancers. In this study, we assessed the power of sex-determining region Y (SRY)-related high-mobility group (HMG)-box 4(SOX4) gene to predict the clinical course of hepatocellular carcinoma (HCC). Methods: To evaluate the differential expression of SOX4 and its diagnostic and prognostic potential in HCC, we analyzed the GSE14520 dataset. Stratified analysis and joint-effect analysis were done using SOX4 and clinical factor. We then designed a nomogram for predicting the clinical course of HCC. Differential SOX4 expression and its correlation with tumor stage as well as its diagnostic and prognostic value were analyzed on the oncomine and GEPIA websites. Gene set enrichment analysis was explored as well as candidate gene ontology and metabolic pathways modulated by in SOX4 HCC. Results: Our analysis revealed that the level of SOX4 was significantly upregulated in tumor issue (P <0.001). This observation was validated through oncomine dataset and MERAV analysis (all P <0.05). Diagnostic receiver operating characteristic (ROC) analysis of SOX4 suggested it has diagnostic potential in HCC (GSE14520 dataset: P <0.001, area under curve (AUC) = 0.782; Oncomine: (Wurmbach dataset) P = 0.002, AUC = 0.831 and (Mas dataset) P <0.001, AUC = 0.947). In addition, SOX4 exhibited high correlation with overall survival of HBV-associated HCC (adjusted P = 0.004, hazard ratio (HR) (95% confidence interval (CI)) = 2.055 (1.261-3.349) and recurrence-free survival (adjusted P = 0.008, HR (95% CI) = 1.721 (1.151-2.574). These observations which were verified by GEPIA analysis for overall survival (P = 0.007) and recurrence-free survival (P= 0.096). Gene enrichment analysis revealed that affected processes included lymphocyte differentiation, pancreatic endocrine pathways, and insulin signaling pathway. SOX4 prognostic value was evaluated using nomogram analysis for HCC 1, 3, and 5-year, survival. Conclusion: Differential SOX4 expression presents an avenue of diagnosing and predicting clinical course of HCC. In HCC, SOX4 may affect TP53 metabolic processes, lymphocyte differentiation and the insulin signaling pathway.

4.
BMC Cancer ; 21(1): 462, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902495

RESUMO

BACKGROUD: In our current work, we aimed to investigate the expressions of glypican (GPC) family genes at the mRNA level and assess their prognostic significances in patients with hepatocellular carcinoma (HCC). METHODS: The pathological roles of GPC family genes were examined using bioinformatics analysis. The diagnostic values of GPC genes were explored with the Gene Expression Profiling Interactive Analysis. Moreover, the mRNA expression and prognostic values of GPC genes were assessed via the KM plotter database. RESULTS: Our data showed that the expression of GPC-3 was dramatically increased in the liver tumor tissue. Moreover, the expressions of the other five GPC family members were not significantly different between the tumor and normal liver tissues (P > 0.05). Furthermore, the up-regulation of GPC-1 at the mRNA level was dramatically correlated to the reduced overall survival (OS) for all HCC patients (hazard ratio = 2.03, 95% confidence intervals =1.44-2.87, P = 4.1e-05) compared with its low-expression group. Besides, the prognosis of the Caucasians was related to most GPC family genes, while the prognosis of the Asian race was only related to the expression of GPC-2. Besides, for pathological factors, including stage, grade, AJCC, and vascular invasion, the higher the pathological grade and vascular invasiveness, the lower the expression levels of GPC family genes (P < 0.05). Finally, the expression levels of GPC-1, 2, and 3 in the hepatitis group were related to the poor prognosis of HCC in the risk factor (alcohol consumption and hepatitis) subgroup (P < 0.05). CONCLUSIONS: Our findings indicated that GPC-3 was dysregulated in HCC compared with paracancerous tissues. The expression of GPC-1 could be used as a potent predictive index for the general prognosis of HCC. The pathology, patients, and risk factors might affect the prognostic value of GPC family genes in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Glipicanas/genética , Neoplasias Hepáticas/genética , RNA Mensageiro/metabolismo , Algoritmos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Biologia Computacional , Intervalos de Confiança , Bases de Dados Genéticas , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Glipicanas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Prognóstico
5.
Acta Pharmacol Sin ; 42(1): 160-170, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32541921

RESUMO

Sorafenib is the first-line treatment of advanced hepatocellular carcinoma (HCC). However, there is a lack of validated biomarkers to predict sorafenib sensitivity. In this study we investigated the role of ACSL4, a positive-activating enzyme of ferroptosis, in sorafenib-induced cell death and HCC patient outcome. We showed that ACSL4 protein expression was negatively associated with IC50 values of sorafenib in a panel of HCC cell lines (R = -0.952, P < 0.001). Knockdown of ACSL4 expression by specific siRNA/sgRNA significantly attenuated sorafenib-induced lipid peroxidation and ferroptosis in Huh7 cells, and also rescued sorafenib-induced inhibition of xenograft tumor growth in vivo. We selected 29 HCC patients with surgery as primary treatment and sorafenib as postoperative adjunct therapy from a hospital-based cohort. A high proportion (66.7%) of HCC patients who had complete or partial responses to sorafenib treatment (according to the revised RECIST guideline) had higher ACSL4 expression in the pretreated HCC tissues, compared with those who had stable or progressed tumor growth (23.5%, P = 0.029). Since ACSL4 expression was independent of sorafenib treatment, it could serve as a useful predictive biomarker. Taken together, this study demonstrates that ACSL4 is essential for sorafenib-induced ferroptosis and useful for predicting sorafenib sensitivity in HCC. This study may have important translational impacts in precise treatment of HCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Coenzima A Ligases/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Coenzima A Ligases/genética , Ferroptose/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J BUON ; 25(5): 2147-2153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33277829

RESUMO

Type 2 diabetes mellitus (T2DM) is a pandemic metabolic disease worldwide. Multiple types of cancer, particularly liver cancer, are closely associated with T2DM. As a result, there is growing interest in investigating whether anti-diabetic medications could lower cancer risks in the population and even prolong patient survival among those with concurrent cancer. There are many types of anti-diabetic medications available in the clinic. The present study reviewed how different anti-diabetic drugs affect cancer risk and patient survival. On the one hand, multiple retrospective studies have shown that the different anti-diabetic medications have distinct effects on cancer risks. Insulin-raising drugs, including exogenous insulin, increased cancer risks, while drugs potentiating insulin sensitivity like metformin reduced cancer risks. On the other hand, the effects of anti-diabetic medications on patient survival are relatively less studied, except limited reports in liver cancer and pancreatic cancer. It seems that metformin could extend overall survival in patients of early-stage cancer. In contrast in the advanced cancer with metastasis, metformin has no effect or even worsens cancer mortality. It is yet unknown whether these distinct effects of metformin are attributable to the severity of the cancer staging or to the drug interactions between metformin and other medications. This question warrants reconsideration of the current clinical practice in the control of T2DM. Future large-scale prospective studies are needed to resolve this.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Metformina/uso terapêutico , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Metformina/farmacologia , Fatores de Risco , Análise de Sobrevida
7.
BMC Gastroenterol ; 20(1): 415, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33302876

RESUMO

BACKGROUND: This study explored the prognostic significance of Glypican (GPC) family genes in patients with pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). METHODS: A total of 112 PDAC patients from TCGA and 48 patients from GEO were included in the analysis. The relationship between overall survival and the expression of GPC family genes as well as basic clinical characteristics was analyzed using the Kaplan-Meier method with the log-rank test. Joint effects survival analysis was performed to further examine the relationship between GPC genes and prognosis. A prognosis nomogram was established based on clinical characteristics and prognosis-related genes. Prognosis-related genes were investigated by genome-wide co-expression analysis and gene set enrichment analysis (GSEA) was carried out to identify potential mechanisms of these genes affecting prognosis. RESULTS: In TCGA database, high expression of GPC2, GPC3, and GPC5 was significantly associated with favorable survival (log-rank P = 0.031, 0.021, and 0.028, respectively; adjusted P value = 0.005, 0.022, and 0.020, respectively), and joint effects analysis of these genes was effective for prognosis prediction. The prognosis nomogram was applied to predict the survival probability using the total scores calculated. Genome-wide co-expression and GSEA analysis suggested that the GPC2 may affect prognosis through sequence-specific DNA binding, protein transport, cell differentiation and oncogenic signatures (KRAS, RAF, STK33, and VEGFA). GPC3 may be related to cell adhesion, angiogenesis, inflammatory response, signaling pathways like Ras, Rap1, PI3K-Akt, chemokine, GPCR, and signatures like cyclin D1, p53, PTEN. GPC5 may be involved in transcription factor complex, TFRC1, oncogenic signatures (HOXA9 and BMI1), gene methylation, phospholipid metabolic process, glycerophospholipid metabolism, cell cycle, and EGFR pathway. CONCLUSION: GPC2, GPC3, and GPC5 expression may serve as prognostic indicators in PDAC, and combination of these genes showed a higher efficiency for prognosis prediction.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Biomarcadores Tumorais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , Glipicanas/genética , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Fosfatidilinositol 3-Quinases , Prognóstico
8.
Onco Targets Ther ; 13: 9389-9405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061426

RESUMO

Background: This study was mainly to explore and study the potential application of lipoxygenases (ALOX) family genes in the diagnostic and prognostic values of colon adenocarcinoma (COAD). Methods: Data sets related to the ALOX genes of COAD were obtained from The Cancer Genome Atlas and the University of California, Santa Cruz Xena browser. Then, the relevant biological information was downloaded from the public data platform. Finally, the bioinformatics technologies and clinical verification were employed to comprehensively analyze the potential values of ALOX genes. Results: The Pearson correlation analysis indicated that there were correlations among ALOXE3, ALOX5, ALOX12, and ALOX12B. The diagnostic receiver operating characteristic (ROC) curves suggested that ALOXE3 and ALOX12 had significant diagnosis in COAD: ALOXE3; P<0.001, area under curve (AUC) 95%CI:=0.818 (0.773-0.862) and ALOX12; P<0.001, AUC 95%CI=0.774 (0.682-0.807). Besides, the verification study indicated that ALOX12 had a diagnostic value in COAD. Finally, our multivariate survival analysis and comprehensive prognosis of ALOX genes in COAD suggested that the ALOXE3 and ALOX12 were associated with COAD overall survival: ALOXE3; P=0.025, HR 95%CI=1.765 (1.074-2.901), ALOX12; P=0.046, HR 95%CI=1.680 (1.009-2.796), and the low expression of ALOXE3 and ALOX12 had a favorable prognosis of COAD (all P<0.05); on the contrary, the high regulation of them increased the risk of death. Conclusion: In our study, we observed that the mRNA expressions of ALOX genes were associated with the diagnosis and prognosis of COAD. The results of the diagnostic analysis suggested that ALOX12 might have a diagnosis value in COAD. Besides, our comprehensive prognosis analysis indicated that ALOXE3 combined ALOX12 might serve as potential prognosis biomarkers for COAD.

9.
J Cancer ; 11(19): 5556-5567, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32913451

RESUMO

Objective: Our current study is to explore the prognostic value and molecular mechanisms underlying the role of lncRNA in non-homologous end joining pathway 1 (LINP1) in early stage pancreatic ductal adenocarcinoma (PDAC). Methods: Genome-wide RNA-seq datasets of 112 early stage PDAC patients were got from The Cancer Genome Atlas and analyzed using multiple online tools. Results: Overall survival in high LINP1 expression patients was shorter than those with low expression (high-LINP1 vs. low-LINP1=481 vs. 592 days, log-rank P=0.0432). The multivariate Cox proportional hazard regression model suggested that high-LINP1 patients had a markedly higher risk of death than low-LINP1 patients (adjusted P=0.004, hazard ratio=2.214, 95% confidence interval=1.283-3.820). Analysis of genome-wide co-expressed genes, screening of differentially expressed genes, and gene set enrichment analysis indicated that LINP1 may be involved in the regulation of cell proliferation-, cell adhesion- and cell cycle-related biological processes in PDAC. Six small-molecule compounds including STOCK1N-35874, fenofibrate, exisulind, NU-1025, vinburnine, and doxylamine were identified as potential LINP1-targeted drugs for the treatment of PDAC. Conclusions: Our study indicated that LINP1 may serve as a prognostic biomarker of early stage PDAC. Analysis of genome-wide datasets led to the elucidation of the underlying mechanisms and identified six potential targeted drugs for the treatment of early PDAC.

10.
J Cancer ; 11(20): 6140-6156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922554

RESUMO

Backgrounds: Hepatocellular carcinoma (HCC) is a lethal malignancy worldwide that is difficult to diagnose during the early stages and its tumors are recurrent. Long non-coding RNAs (lncRNAs) have increasingly been associated with tumor biomarkers for diagnosis and prognosis. This study attempts to explore the potential clinical significance of lncRNA DUXAP8 and its co-expression related protein coding genes (PCGs) for HCC. Method: Data from a total of 370 HCC patients from The Cancer Genome Atlas were utilized for the analysis. DUXAP8 and its top 10 PCGs were explored for their diagnostic and prognostic implications for HCC. A risk score model and nomogram were constructed for prognosis prediction using prognosis-related genes and DUXAP8. Molecular mechanisms of DUXAP8 and its PCGs involved in HCC initiation and progression were investigated. Then, potential target drugs were identified using genome-wide DUXAP8-related differentially expressed genes in a Connectivity Map database. Results: The top 10 PCGs were identified as: RNF2, MAGEA1, GABRA3, MKRN3, FAM133A, MAGEA3, CNTNAP4, MAGEA6, MALRD1, and DGKI. Diagnostic analysis indicated that DUXAP8, MEGEA1, MKRN3, and DGKI show diagnostic implications (all area under curves ≥0.7, p≤0.05). Prognostic analysis indicated that DUXAP8 and RNF2 had prognostic implications for HCC (adjusted p=0.014 and 0.008, respectively). The risk score model and nomogram showed an advantage for prognosis prediction. A total of 3 target drugs were determined: cinchonine, bumetanide and amiprilose and they may serve as potential therapeutic targets for HCC. Conclusion: Functioning as an oncogene, DUXAP8 is overexpressed in tumor tissue and may serve as both a diagnostic and prognosis biomarker for HCC. MEGEA1, MKRN3, and DGKI maybe potential diagnostic biomarkers and DGKI may also be potentially prognostic biomarkers for HCC.

11.
J Cancer ; 11(7): 1869-1882, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194798

RESUMO

Background: Hepatocellular carcinoma (HCC) has high morbidity and mortality and lacks effective biomarkers for early diagnosis and survival surveillance. Origin recognition complex (ORC), consisting of ORC1-6 isoforms, was examined to assess the potential significance of ORC isoforms for HCC prognosis. Methods: Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to examine differential isoform expression, stage-specific expression, calculate Pearson correlations and perform survival analysis. A human protein atlas database was utilized to evaluate the protein expression of ORCs in liver tissue. The cBioPortal database was used to assess isoform mutations and the survival significance of ORCs in HCC. Cytoscape software was employed to construct gene ontologies, metabolic pathways and gene-gene interaction networks. Results: Differential expression analysis indicated that ORC1 and ORC3-6 were highly expressed in tumor tissues in the Oncomine and GEPIA databases, while ORC2 was not. All the ORCs were showed positive and statistically significant correlations with each other (all P<0.001). ORC1-2 and ORC4-6 expressions were associated with disease stages I-IV (all P<0.05), but ORC3 was not. Survival analysis found that ORC1 and ORC4-6 expressions were associated with overall survival (OS), and ORC1-3 and ORC5-6 expression were associated with recurrence-free survival (RFS; all P<0.05). In addition, low expression of these ORC genes consistently indicated better prognosis compared with high expression. Protein expression analysis revealed that ORC1 and ORC3-6 were expressed in normal liver tissues, whereas ORC2 was not. Enrichment analysis indicated that ORCs were associated with DNA metabolic process, sequence-specific DNA binding and were involved in DNA replication, cell cycle, E2F-enabled inhibition of pre-replication complex formation and G1/S transition. Conclusions: Differentially expressed ORC1, 5 and 6 are candidate biomarkers for survival prediction and recurrence surveillance in HCC.

12.
J Cell Physiol ; 235(10): 7003-7017, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32037547

RESUMO

Hepatocellular carcinoma (HCC) is a lethal malignancy worldwide. HCC has traits of late diagnosis and high recurrence. This study explored potential diagnosis and prognosis significance of phospholipase C epsilon 1 (PLCE1) in HCC. The messenger RNA (mRNA) levels and diagnostic value of PLCE1 were determined by real-time polymerase chain reaction and online databases GEPIA, oncomine, and GSE14520 data set. Survival analysis used the Kaplan-Meier Plotter website. Cell cycle, proliferation, migration, and invasion assays were performed with downregulated PLCE1 expression in HCC-M and HepG2 cell lines. PLCE1 was differentially expressed and highly expressed in tumors and had low expression in nontumor tissues (all p < .05). The diagnostic value of PLCE1 was validated with the datasets (all p < .01, all areas under curves > 0.7). PLCE1 mRNA expression was associated with the overall and relapse-free survival (both p < .05). Functional experiments indicated that downregulation of PLCE1 expression led to increased G1 stage in cell cycle and decreased cell proliferation, migration, and invasion compared with a negative control group (all p ≤ .05). The oncogene PLCE1 was differentially expressed in HCC and non-HCC tissues. It is a candidate for diagnosis and serves as prognosis biomarker. PLCE1 influenced survival by affecting the cell cycle, proliferation, migration, and invasion ability.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Ciclo Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Hepáticas/genética , Oncogenes/genética , Fosfoinositídeo Fosfolipase C/genética , Adulto , Apoptose/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Recidiva Local de Neoplasia/genética , Prognóstico , RNA Mensageiro/genética
13.
J Cancer ; 11(4): 906-918, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31949494

RESUMO

Objective: The goal of our current study is to assess the immunohistochemical of p53, p21, nm23, and VEGF expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) prognosis after hepatectomy, as well as the prospective molecular mechanisms of prognostic indicator. Methods: There were 419 HBV-related HCC patients who were from southern China of Guangxi province and were used to evaluate the immunohistochemical expression for these biomarkers in prognosis. A genome-wide expression microarray dataset of HBV-related HCC were obtained from GSE14520. Results: In our study, the expression of p53, p21, and nm23 in cancer tissues of patients with hepatitis B-related hepatocellular carcinoma did not affected the clinical outcome of 2 years, 5 years or overall. Patients with high expression of VEGF had a worse overall survival after 2 years of surgery than patients with low expression (adjusted P=0.040, adjusted HR = 1.652, 95% CI = 1.024-2.665). Survival analysis of VEGF in GSE14520 cohort also demonstrated that VEGF mRNA expression also significantly associated with HBV-related HCC OS (adjusted P=0.035, adjusted HR =1.651, 95% CI =1.035-2.634). The prospective molecular mechanisms by co-expression analysis suggested that VEGF might be correlated to regulation of cell proliferation, cell growth and apoptotic process, Rap1 signaling pathway, HIF-1 signaling pathway, PPAR signaling pathway, cell cycle. Whereas the GSEA suggested that VEGF might involve in the regulation of HIF and HIF1A pathway, and TP53 regulation pathway. Conclusion: Our findings suggested that VEGF might be a prognostic indicator of HBV-related HCC, and we also identified the VEGF prospective molecular mechanisms through the whole genome co-expression and GSEA approaches.

14.
Am J Cancer Res ; 10(12): 4178-4197, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33414994

RESUMO

Hepatocellular carcinoma (HCC) is a worldwide malignancy with high morbidity and mortality. In this study, ubiquitin conjugating enzyme E2I (UBE2I), a small ubiquitin-like modifier E2 enzyme reportedly expressed in tumors, was examined for its potential effects in HCC. Bioinformatics analysis was performed based on HCCDB, TIMER, and Kaplan-Meier plotter databases to explore the clinical implications in HCC. An siRNA kit was used to downregulate UBE2I, and in vitro experiments-including migration, invasion and proliferation assays-were performed to examine UBE2I expression in HCC. Western blot (WB) was used to determine whether downregulated UBE2I expression influenced the prognosis of HCC via autophagy pathways. Finally, RNA-sequencing was performed to explore candidate molecular mechanisms underlying the effect of UBE2I. Bioinformatics analysis including stratification by alcohol ingestion and hepatitis status in HCC showed that highly expressed UBE2I was not only correlated with poor prognosis, but was also associated with immune infiltrates. In vitro experiments showed that high expression of UBE2I was associated with increased migration, invasion and proliferation of HCC cells. WB results indicated that downregulated expression of UBE2I was associated with higher levels of autophagy-related proteins including LC3A/B, Beclin-1 and ATG16L1. Moreover, RNA-sequencing results suggested that UBE2I was involved in hepatocarcinogenesis, non-alcohol fatty liver disease, steatohepatitis, liver fibrosis, inflammation, hepatoblastoma, tumor angiogenesis, type 2 mellitus diabetes, biliary tract disease and other diseases. We conclude that oncogene UBE2I is associated with poor prognosis of HCC via autophagy pathways and may be involved in hepatocarcinogenesis, tumor angiogenesis, non-alcohol fatty liver disease and inflammation.

15.
J Cancer ; 10(21): 5173-5190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602270

RESUMO

Background: Hepatitis B virus infection had been identified its relationship with liver diseases, including liver tumors. We aimed to explore diagnostic and prognostic values between the Human Leukocyte Antigen (HLA) complex and hepatocellular carcinoma (HCC). Methods: We used the GSE14520 dataset to explore diagnostic and prognostic significance between HLA complex and HCC. A nomogram was constructed to predict survival probability of HCC prognosis. Gene set enrichment analysis was explored using gene ontologies and metabolic pathways. Validation of prognostic values of the HLA complex was performed in the Kaplan-Meier Plotter website. Results: We found that HLA-C showed the diagnostic value (P <0.0001, area under curve: 0.784, sensitivity: 93.14%, specificity: 62.26%). In addition, HLA-DQA1 and HLA-F showed prognostic values for overall survival, and HLA-A, HLA-C, HLA-DPA1 and HLA-DQA1 showed prognostic values for recurrence-free survival (all P ≤ 0.05, elevated 0.927, 0.992, 1.023, 0.918, 0.937 multiples compared to non-tumor tissues, respectively). Gene set enrichment analysis found that they were involved in antigen processing and toll like receptor signalling pathway, etc. The nomogram was evaluated for survival probability of HCC prognosis. Validation analysis indicated that HLA-C, HLA-DPA1, HLA-E, HLA-F and HLA-G were associated with HCC prognosis of overall survival (all P ≤ 0.05, elevated 0.988 and 0.997 multiples compared to non-tumor tissues, respectively). Conclusion: HLA-C might be a diagnostic and prognostic biomarker for HCC. HLA-DPA1 and HLA-F might be prognostic biomarkers for HCC.

16.
Oncol Rep ; 42(5): 1996-2008, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545503

RESUMO

The diagnostic and prognostic mechanisms of C­X­C motif chemokine ligand 3 (CXCL3) in colon cancer (CC) have not yet been reported. Therefore, the objective of the present study was to use cohorts of patients from Guangxi Medical University and the Gene Expression Omnibus (GEO) database to investigate and validate CXCL3 for the diagnosis and prognosis of CC, and to explore its prospective molecular mechanism. Reverse transcription­quantitative PCR (RT­qPCR) analysis of 38 paired tumor and non­tumor tissues, and immunohistochemistry (IHC) of 212 tumor and 46 non­tumor tissues was conducted to explore the expression of CXCL3 and its diagnostic and prognostic significance in the Guangxi Medical University CC cohort. A GEO dataset, GSE40967, was used to validate the prognostic significance of CXCL3. Gene set enrichment analysis (GSEA) was also conducted to explore the potential molecular mechanisms underlying the effects of CXCL3 in CC. The RT­qPCR results indicated that CXCL3 expression was significantly higher in cancer tissues compared with adjacent normal tissues, suggesting that it may have high diagnostic value for CC. Multivariate Cox analysis based on the IHC results suggested that there was no appreciable association between CXCL3 positivity and the overall survival (OS) time of CC. However, a stratified analysis revealed that high expression of CXCL3 was associated with considerably increased mortality in the subgroup of CC patients with tumor size <5 cm (adjusted P=0.042, adjusted HR=2.298, 95% CI=1.030­5.126) and with tumor thrombus (adjusted P=0.019, adjusted HR=5.096, 95% CI=1.306­19.886). In the GSE40967 dataset, high expression of CXCL3 was closely associated with poor OS in CC (adjusted P=0.049, adjusted HR=1.416, 95% CI=1.002­2.003). Furthermore, GSEA indicated that the high expression of CXCL3 was closely associated with DNA repair, cell cycle process, cell apoptosis process and the P53 regulation pathway. In summary, these result suggest that CXCL3 might serve as a novel biomarker in the diagnosis and prognosis of CC.


Assuntos
Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Neoplasias do Colo/diagnóstico , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Análise de Sobrevida , Carga Tumoral
17.
Med Sci Monit ; 25: 3716-3727, 2019 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-31104065

RESUMO

BACKGROUND The aim of this study was to identify gene signals for lower-grade glioma (LGG) and to assess their potential as recurrence biomarkers. MATERIAL AND METHODS An LGG-related mRNA sequencing dataset was downloaded from The Cancer Genome Atlas (TCGA) Informix. Multiple bioinformatics analysis methods were used to identify key genes and potential molecular mechanisms in recurrence of LGG. RESULTS A total of 326 differentially-expressed genes (DEGs), were identified from 511 primary LGG tumor and 18 recurrent samples. Gene ontology (GO) analysis revealed that the DEGs were implicated in cell differentiation, neuron differentiation, negative regulation of neuron differentiation, and cell proliferation in the forebrain. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database suggests that DEGs are associated with proteoglycans in cancer, the Wnt signaling pathway, ECM-receptor interaction, the PI3K-Akt signaling pathway, transcriptional deregulation in cancer, and the Hippo signaling pathway. The hub DEGs in the protein-protein interaction network are apolipoprotein A2 (APOA2), collagen type III alpha 1 chain (COL3A1), collagen type I alpha 1 chain (COL1A1), tyrosinase (TYR), collagen type I alpha 2 chain (COL1A2), neurotensin (NTS), collagen type V alpha 1 chain (COL5A1), poly(A) polymerase beta (PAPOLB), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and anomalous homeobox (ANHX). GSEA revealed that the following biological processes may associated with LGG recurrence: cell cycle, DNA replication and repair, regulation of apoptosis, neuronal differentiation, and Wnt signaling pathway. CONCLUSIONS Our study demonstrated that hub DEGs may assist in the molecular understanding of LGG recurrence. These findings still need further molecular studies to identify the assignment of DEGs in LGG.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioma/genética , Glioma/metabolismo , Biomarcadores , Neoplasias Encefálicas/patologia , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes , Glioma/patologia , Humanos , Gradação de Tumores , Mapeamento de Interação de Proteínas/métodos , Mapas de Interação de Proteínas , Transcriptoma
18.
PLoS One ; 12(8): e0182208, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28792511

RESUMO

Hepatocellular carcinoma (HCC) is one of the most prevalent and life-threatening malignancies worldwide. There are few diagnostic and prognostic biomarkers and druggable targets for HCC. Aldehyde dehydrogenase 1 (ALDH1) is a marker of stem cells in a variety of cancers, but the mRNA levels and prognostic value of ALDH1 isoforms in HCC patients remain unknown. In the present study, gene ontology annotation of the ALDH1 family was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID), and the gene pathway analsis was performed using GeneMANIA software. The initial prognostic value of ALDH1 expression in 360 HCC patients was assessed using the OncoLnc database. The expression levels of ALDH1 isoforms in normal liver tissues and clinical specimens of cancer vs. normal control datasets were determined using the GTEx and Oncomine databases, respectively. We then analyzed the prognostic value of ALDH1 expression in 212 hepatitis B virus (HBV)-related HCC patients using the GEO database. We found that the ALDH1 isoform showed high aldehyde dehydrogenase activity. The ALDH1A1, ALDH1B1, and ALDH1L1 genes encoded for the ALDH1 enzyme. High ALDH1B1 expression had protective qualities in HCC patients. Moreover, HBV-related HCC patients who showed high ALDH1L1 gene expression had a better clinical outcomes. In addition, high ALDH1A1 expression was associated with a 57-month recurrence-free survival in HBV-related HCC patients. High ALDH1B1 expression was protective for HCCs with multiple nodules and high serum alpha-fetoprotein (AFP) level. Furthermore, high serum AFP levels contributed to lower ALDH1L1. ALDH1A1, ALDH1B1, and ALDH1L1, all of which were considered promising diagnostic and prognostic markers as well as potential drug targets.


Assuntos
Carcinoma Hepatocelular/enzimologia , Isoenzimas/metabolismo , Neoplasias Hepáticas/enzimologia , Retinal Desidrogenase/metabolismo , Família Aldeído Desidrogenase 1 , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/complicações , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica/fisiologia , Hepatite B/complicações , Hepatite B/enzimologia , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/complicações , Modelos Logísticos , Prognóstico , RNA Mensageiro/metabolismo , Recidiva , Software
19.
Cell Physiol Biochem ; 42(4): 1342-1357, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28700999

RESUMO

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a common malignant tumor with a high rate of recurrence. Immunohistochemical analysis of the marker of proliferation Ki-67 (MKI67) is used to assess proliferation activity of HCC The regulation of MKI67 expression remains unclear in HCC This study aims to explore the association between MKI67 expression and gene variants. METHODS: A total of 195 hepatitis B virus (HBV)-related HCC patients were genotyped using Illumina HumanExome BeadChip-12-1_A (242,901 markers). An independent cohort (97 subjects) validated the association of polymorphism determinants and candidate genes with MKI67 expression. The relationships between MKI67 with p53 and variants of candidate genes in the clinical outcomes of HCC patients were analyzed. RESULTS: We found that MKI67 combined with p53 was associated with a 3-year recurrence-free survival and five variants near TTN and CCDC8 were associated with MKI67 expression. TTN harboring rs2288563-TT and rs2562832-AA+CA indicated a favorable outcome for HCC patients. CONCLUSION: Variants near TTN and CCDC8 were associated with MKI67 expression, and rs2288563 and rs2562832 in TTN are potential biomarkers for the prediction of clinical outcomes in HBV-related HCC patients.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Hepatite B Crônica/genética , Antígeno Ki-67/genética , Neoplasias Hepáticas/genética , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , China , Estudos de Coortes , Conectina/genética , Conectina/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Vírus da Hepatite B/crescimento & desenvolvimento , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/mortalidade , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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