Potential Role of the Anammoxosome in the Adaptation of Anammox Bacteria to Salinity Stress.

The underlying adaptative mechanisms of anammox bacteria to salt stress are still unclear. The potential role of the anammoxosome in modulating material and energy metabolism in response to salinity stress was investigated in this study. The results showed that anammox bacteria increased membrane fluidity and decreased mechanical properties by shortening the ladderane fatty acid chain length of anammoxosome in response to salinity shock, which led to the breakdown of the proton motive force driving ATP synthesis and retarded energy metabolism activity. Afterward, the fatty acid chain length and membrane properties were recovered to enhance the energy metabolic activity. The relative transmission electron microscopy (TEM) area proportion of anammoxosome decreased from 55.9 to 38.9% under salinity stress. The 3D imaging of the anammox bacteria based on Synchrotron soft X-ray tomography showed that the reduction in the relative volume proportion of the anammoxosome and the concave surfaces was induced by salinity stress, which led to the lower energy expenditure of the material transportation and provided more binding sites for enzymes. Therefore, anammox bacteria can modulate nitrogen and energy metabolism by changing the membrane properties and morphology of the anammoxosome in response to salinity stress. This study broadens the response mechanism of anammox bacteria to salinity stress.

Investigating the prognostic and predictive value of the type II cystatin genes in gastric cancer.

BACKGROUND: Accumulating evidence indicates that type II cystatin (CST) genes play a pivotal role in several tumor pathological processes, thereby affecting all stages of tumorigenesis and tumor development. However, the prognostic and predictive value of type II CST genes in GC has not yet been investigated. METHODS: The present study evaluated the expression and prognostic value of type II CST genes in GC by using The Cancer Genome Atlas (TCGA) database and the Kaplan-Meier plotter (KM plotter) online database. The type II CST genes related to the prognosis of GC were then screened out. We then validated the expression and prognostic value of these genes by immunohistochemistry. We also used Database for Annotation, Visualization, and Integrated Discovery (DAVID), Gene Multiple Association Network Integration Algorithm (GeneMANIA), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), nomogram, genome-wide co-expression analysis, and other bioinformatics tools to analyze the value of type II CST genes in GC and the underlying mechanism. RESULTS: The data from the TCGA database and the KM plotter online database showed that high expression of CST2 and CST4 was associated with the overall survival (OS) of patients with GC. The immunohistochemical expression analysis showed that patients with high expression of CST4 in GC tissues have a shorter OS than those with low expression of CST4 (HR = 1.85,95%CI: 1.13-3.03, P = 0.015). Multivariate Cox regression analysis confirmed that the high expression level of CST4 was an independent prognostic risk factor for OS. CONCLUSIONS: Our findings suggest that CST4 could serve as a tumor marker that affects the prognosis of GC and could be considered as a potential therapeutic target for GC.

A radiomics model based on magnetic resonance imaging to predict cytokeratin 7/19 expression and liver fluke infection of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC with liver fluke infection could harbor unique biological behaviors. This study was aimed at investigating radiomics features of HCC with liver fluke infection and establishing a model to predict the expression of cytokeratin 7 (CK7) and cytokeratin 19 (CK19) as well as prognosis at the same time. A total of 134 HCC patients were included. Gadoxetic acid-enhanced magnetic resonance imaging (MRI) images of all patients were acquired. Radiomics features of the tumor were extracted and then data dimensionality was reduced. The radiomics model was established to predict liver fluke infection and the radiomics score (Radscore) was calculated. There were 11 features in the four-phase combined model. The efficiency of the combined model increased significantly compared to each single-phase MRI model. Radscore was an independent predictor of liver fluke infection. It was also significantly different between different expression of CK7/ CK19. Meanwhile, liver fluke infection was associated with CK7/CK19 expression. A cut-off value was set up and all patients were divided into high risk and low risk groups of CK7/CK19 positive expression. Radscore was also an independent predictor of these two biomarkers. Overall survival (OS) and recurrence free survival (RFS) of negative liver fluke infection group were significantly better than the positive group. OS and RFS of negative CK7 and CK19 expression were also better, though not significantly. Positive liver fluke infection and CK19 expression prediction groups harbored significantly worse OS and RFS, survival of positive CK7 expression prediction was unsatisfying as well. A radiomics model was established to predict liver fluke infection among HCC patients. This model could also predict CK7 and CK19 expression. OS and RFS could be foreseen by this model at the same time.

Case Report: A case of hepatocellular carcinoma with aberrant right hepatic artery treated with transarterial chemoembolization and infusion chemotherapy separately to bilobar lesion combining with systemic therapies and sequential hepatectomy.

Background: Hepatocellular carcinoma (HCC) with a dismal prognosis is the second most deadly malignancy globally. Surgery is believed to be a curative approach. Nevertheless, there is still a considerable probability of postoperative recurrence. Most patients present in advanced stages with a surgically and oncologically unresectable disease. Systemic medicines are increasingly important to downstage the disease and further improve survival. Case summary: A 67-year-old Chinese man with uncontrolled hepatitis B was discovered to have liver masses with abnormal serum vitamin K absence or antagonist-II (PIVKA-II) level during checkup for upper abdominal discomfort. Abdominal multiphase computerized tomography (CT) and gadoxetate disodium-enhanced magnetic resonance imaging (MRI) showed the bulky bilobar HCCs of Barcelona Clinic Liver Cancer stage B and China Liver Cancer Staging stage IIa. Furthermore, the aberrant right hepatic artery (RHA) originates from the superior mesenteric artery. Due to the location being adjacent to important vasculatures and massive size of the right-sided lesion, curative resection appears to be challenging. To achieve a favorable surgical margin, repeated hepatic arterial infusion chemotherapy (HAIC) was adopted through the variant RHA, while transarterial chemoembolization (TACE) was delivered to the left lobe to arrest tumor growth. Furthermore, sintilimab plus lenvatinib served as the sequential systemic therapy. After 5 months of conversion treatment, the partial response with a decreased serum PIVKA-II level was attained. The R0 hepatectomy was then performed without postoperative complications. The immunohistochemistry and next-generation sequencing results suggested that the two-side HCCs existing tumor heterogeneity were not completely consistent. The patient continues to be without evidence of disease. Conclusion: Our case highlights a favorable outcome in a man with bilobar bulky HCC after undergoing the comprehensive therapeutic schedule that includes personalized intervention and systemic drug therapy. In terms of conversion therapy, our case provides a secure and practical reference for managing unresectable bilobar HCC coexisting with the aberrant hepatic artery.

Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy.

Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.

Advances in postoperative adjuvant therapy for primary liver cancer.

Hepatocellular carcinoma (HCC) is a highly heterogeneous, invasive, and conventional chemotherapy-insensitive tumor with unique biological characteristics. The main methods for the radical treatment of HCC are surgical resection or liver transplantation. However, recurrence rates are as high as 50% and 70% at 3 and 5 years after liver resection, respectively, and even in Milan-eligible recipients, the recurrence rate is approximately 20% at 5 years after liver transplantation. Therefore, reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer. This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization), adjuvant systemic therapy (e.g., molecular targeted agents and immunotherapy), and other adjuvant therapies (e.g., antiviral and herbal therapy). Finally, potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.

Clinical Significance and Potential Mechanisms of ATP Binding Cassette Subfamily C Genes in Hepatocellular Carcinoma.

The purpose of this investigation was to assess the diagnostic and prognostic significance of ATP binding cassette subfamily C (ABCC) genes in hepatocellular carcinoma (HCC). The Student t-test was used to compare the expression level of ABCCs between HCC and paraneoplastic tissues. Receiver operating characteristic curve (ROC) analysis was applied for diagnostic efficiency assessment. The Kaplan-Meier method and Cox proportional hazards model were respectively applied for survival analysis. Genes with prognostic significance were subsequently used to construct prognostic models. From the perspective of genome-wide enrichment analysis, the mechanisms of prognosis-related ABCC genes were attempted to be elaborated by gene set enrichment analysis (GSEA). It was observed in the TCGA database that ABCC1, ABCC4, ABCC5, and ABCC10 were significantly upregulated in tumor tissues, while ABCC6 and ABCC7 were downregulated in HCC tissues. Receiver operating characteristic analysis revealed that ABCC7 might be a potential diagnostic biomarker in HCC. ABCC1, ABCC4, ABCC5, and ABCC6 were significantly related to the prognosis of HCC in the TCGA database. The prognostic significance of ABCC1, ABCC4, ABCC5, and ABCC6 was also observed in the Guangxi cohort. In the Guangxi cohort, both polymerase chain reaction and IHC (immunohistochemical) assays demonstrated higher expression of ABCC1, ABCC4, and ABCC5 in HCC compared to liver tissues, while the opposite was true for ABCC6. GSEA analysis indicated that ABCC1 was associated with tumor differentiation, nod-like receptor signal pathway, and so forth. It also revealed that ABCC4 might play a role in HCC by regulating epithelial-mesenchymal transition, cytidine analog pathway, met pathway, and so forth. ABCC5 might be associated with the fatty acid metabolism and KRT19 in HCC. ABCC6 might impact the cell cycle in HCC by regulating E2F1 and myc. The relationship between ABCC genes and immune infiltration was explored, and ABCC1,4,5 were found to be positively associated with infiltration of multiple immune cells, while ABCC6 was found to be the opposite. In conclusion, ABCC1, ABCC4, ABCC5, and ABCC6 might be prognostic biomarkers in HCC. The prognostic models constructed with ABCC1, ABCC4, ABCC5, and ABCC6 had satisfactory efficacy.

Protein Phosphatase 1 Regulatory Subunit 3: A Prognostic Biomarker in Stomach Adenocarcinoma.

PURPOSE: This study aimed to determine the potential application of the protein phosphatase 1 regulatory subunit 3 (PPP1R3B) gene as a prognostic marker in stomach adenocarcinoma (STAD), as well as its potential mediating biological processes and pathways. MATERIALS AND METHODS: Differential expression analyses were performed using the TIMER2.0 and UALCAN databases. Complete RNA-seq data and other relevant clinical and survival data were acquired from The Cancer Genome Atlas (TCGA). Univariate survival analyses, Cox regression modelling, and Kaplan-Meier curves were implemented to investigate the associations between PPP1R3B gene expression and clinical pathologic features. A genome wide gene set enrichment analysis (GSEA) was conducted to define the underlying molecular mechanisms mediating the observed associations between the PPP1R3B gene and STAD development. RESULTS: We found that PPP1R3B was overexpressed in STAD tissues, and that higher PPP1R3B expression correlated with worse prognoses in patients with STAD. Comprehensive survival analyses suggested that PPP1R3B might be an independent predictive factor for survival time in patients with STAD. The prognostic relationship between PPP1R3B and STAD was also verified using Kaplan-Meier curves. Patients with higher PPP1R3B levels had a shorter clinical survival time on average. Additionally, a GSEA demonstrated that PPP1R3B might be involved in multiple biological processes and pathways. CONCLUSION: Our findings demonstrate that the PPP1R3B gene has utility as a potential molecular marker for STAD prognoses.

Clinical implications and molecular mechanisms of Cyclin-dependent kinases 4 for patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) was frequently considered as a kind of malignant tumor with a poor prognosis. Cyclin-dependent kinases (CDK) 4 was considered to be cell-cycle-related CDK gene. In this study, we explored the clinical significance of CDK4 in HCC patients. METHODS: Data of HCC patients were obtained from The Cancer Genome Atlas database (TCGA) and the Gene Expression Omnibus (GEO) database. Kaplan-Meier analysis and Cox regression model were performed to calculate median survival time (MST) and the hazard ration (HR), respectively. The joint-effect analysis and prognostic risk score model were constructed to demonstrate significance of prognosis-related genes. The differential expression of prognostic genes was further validated using reverse transcription-quantitative PCR (RT-qPCR) of 58 pairs of HCC samples. RESULTS: CDK1 and CDK4 were considered prognostic genes in TCGA and GSE14520 cohort. The result of joint-effect model indicated patients in CDK1 and CDK4 low expression groups had a better prognosis in TCGA (adjusted HR = 0.491; adjusted P = 0.003) and GSE14520 cohort (adjusted HR = 0.431; adjusted P = 0.002). Regarding Kaplan-Meier analysis, high expression of CDK1 and CDK4 was related to poor prognosis in both the TCGA (P < 0.001 and = 0.001 for CDK1 and CDK4, respectively) and the GSE14520 cohort (P = 0.006 and = 0.033 for CDK1 and CDK4, respectively). However, only CDK4 (P = 0.042) was validated in RT-qPCR experiment, while CDK1 (P = 0.075) was not. CONCLUSION: HCC patients with high CDK4 expression have poor prognosis, and CDK4 could be a potential candidate diagnostic biomarker for HCC.

High-Mobility Group AT-Hook 1 Served as a Prognosis Biomarker and Associated with Immune Infiltrate in Hepatocellular Carcinoma.

BACKGROUND: The protein high-mobility group AT-hook 1 (HMGA1) has been demonstrated that modulated cellular proliferation, invasion, and apoptosis with a poor prognosis in miscellaneous carcinomas. However, the mechanism of circumstantial carcinogenesis and association with the immune microenvironment of HMGA1 in hepatocellular carcinoma (HCC) had not been extensively explored. METHODS: The gene expression, clinicopathological correlation, and prognosis analysis were performed in the data obtained from TCGA. The results were further validated by ICGC and GEO database and external validation cohort from Guangxi. The HMGA1 protein expression was further examined in the HPA database. Biological function analyses were conducted by GSEA, STRING database, and Coexpedia online tool. Using TIMER and CIBERSORT method, the relationship between immune infiltrate and HMGA1 was investigated. RESULTS: In HCC, HMGA1 had much higher transcriptional and proteomic expression than in corresponding paraneoplastic tissue. Patients with high HMGA1 expression had a poor prognosis and unpromising clinicopathological features. High HMGA1 expression was closely related to the cell cycle, tumorigenesis, substance metabolism, and immune processes by regulating complex signaling pathways. Notably, HMGA1 may be associated with TP53 mutational carcinogenesis. Moreover, increased HMGA1 expression may lead to an increase in immune infiltration and a decrease in tumor purity in HCC. CIBERSORT analysis elucidated that the amount of B cell naive, B cell memory, T cells gamma delta, macrophages M2, and mast cell resting decreased when HMGA1 expression was high, whereas T cells follicular helper, macrophages M0, and Dendritic cells resting increased. CONCLUSION: In conclusions, HMGA1 is a potent prognostic biomarker and a sign of immune infiltration in HCC, which may be a potential immunotherapy target for HCC.

CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27kip1 Axis.

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.

Diagnosis and prognostic value of C-X-C motif chemokine ligand 1 in colon adenocarcinoma based on The Cancer Genome Atlas and Guangxi cohort.

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.

SOX4 as biomarker in hepatitis B virus-associated hepatocellular carcinoma.

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.

Identified a disintegrin and metalloproteinase with thrombospondin motifs 6 serve as a novel gastric cancer prognostic biomarker by bioinformatics analysis.

OBJECTIVE: We aimed to explore the prognostic value of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) genes in gastric cancer (GC). METHODS: The RNA-sequencing (RNA-seq) expression data for 351 GC patients and other relevant clinical data were acquired from The Cancer Genome Atlas (TCGA). Survival analysis and a genome-wide gene set enrichment analysis (GSEA) were performed to define the underlying molecular value of the ADAMTS genes in GC development. Besides, qRT-PCR and immunohistochemistry were all employed to validate the relationship between the expression of these genes and GC patient prognosis. RESULTS: The Log rank test with both Cox regression and Kaplan-Meier survival analyses showed that ADAMTS6 expression profile correlated with the GC patients clinical outcome. Patients with a high expression of ADAMTS6 were associated with poor overall survival (OS). Comprehensive survival analysis of the ADAMTS genes suggests that ADAMTS6 might be an independent predictive factor for the OS in patients with GC. Besides, GSEA demonstrated that ADAMTS6 might be involved in multiple biological processes and pathways, such as the vascular endothelial growth factor A (VEGFA), kirsten rat sarcoma viral oncogene (KRAS), tumor protein P53, c-Jun N-terminal kinase (JNK), cadherin (CDH1) or tumor necrosis factor (TNF) pathways. It was also confirmed by immunohistochemistry and qRT-PCR that ADAMTS6 is highly expressed in GC, which may be related to the prognosis of GC patients. CONCLUSION: In summary, our study demonstrated that ADAMTS6 gene could be used as a potential molecular marker for GC prognosis.

Investigation and verification of the clinical significance and perspective of natural killer group 2 member D ligands in colon adenocarcinoma.

This study investigated and verified the diagnostic and prognostic values of natural killer group 2 member D ligand (NKG2DL) genes in colon adenocarcinoma (COAD). We downloaded NKG2DLs expression data and corresponding clinical parameters from The Cancer Genome Atlas (TCGA) and used bioinformatics techniques to investigate the values of NKG2DLs in COAD. Then, we used the GSE40967 cohort to verify the prognostic value of NKG2DLs. Finally, we verified the ULBP2 expression level in tissues, and also investigated the diagnostic and prognostic values of ULBP2 in COAD. The diagnostic receiver operating characteristic curves showed that ULBP1, ULBP2, ULBP3, and RAET1L had high diagnostic values in COAD [Area Under Curve (AUC) > 0.9]. In TCGA cohort, the univariate and multivariate survival analyses suggested that ULBP2 was correlated with the prognosis of COAD recurrence-free survival (RFS) and overall survival (OS). In GSE40967 cohort, ULBP2 was associated with CC RFS and OS. Reverse transcription-quantitative polymerase chain reaction and immunohistochemistry results showed that ULBP2 was highly expressed in COAD tumor tissues (P < 0.05) and both had diagnostic values (AUC > 0.7). Validated survival analysis showed that the high expression of ULBP2 had a worse prognosis in COAD OS and RFS. Thus, ULBP2 might be an independent diagnostic and prognostic biomarker of COAD.

Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms.

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.

The Perspective of Diagnostic and Prognostic Values of Lipoxygenases mRNA Expression in Colon Adenocarcinoma.

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.

Clinical significance of long non-coding RNA DUXAP8 and its protein coding genes in hepatocellular carcinoma.

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.

Genome-wide RNA-sequencing dataset reveals the prognostic value and potential molecular mechanisms of lncRNA in non-homologous end joining pathway 1 in early stage Pancreatic Ductal Adenocarcinoma.

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.

Distinct diagnostic and prognostic values of γ-aminobutyric acid type A receptor family genes in patients with colon adenocarcinoma.

In the present study, the significance of GABAA genes in colon adenocarcinoma (COAD) were investigated from the view of diagnosis and prognosis. All data were achieved from The Cancer Genome Atlas. Overall survival was analyzed by the Kaplan-Meier analyses and Cox regression model and the hazard ratios and 95% confidence interval were calculated for computation. The Database for Annotation, Visualization and Integrated Discovery, and the Biological Networks Gene Ontology (BiNGO) softwares were applied to assess the biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway analysis to predict the biological function of GABAA genes. The associated Gene Ontology and KEGG pathways were conducted by Gene Set Enrichment Analysis (GSEA). From receiver operating characteristics curves analysis, it was found that the expression of GABR, γ-aminobutyric acid type A receptor GABRA2, GABRA3, GABRB2, GABRB3, GABRG2, GABRG3, GABRD, GABRE were correlated with COAD occurrence [P<0.0001, area under the curve (AUC)>0.7]. The low expression of the GABRB1, GABRD, GABRP and GABRQ in genes after tumor staging adjustment were positively correlated with the overall survival rate [P=0.049, hazard ratio (HR)=1.517, 95% confidence interval (CI)=1.001-2.297; P=0.006, HR=1.807, 95% CI=1.180-2.765; P=0.005, HR=1.833, 95% CI=1.196-2.810; P=0.034, HR=1.578, 95% CI=1.036-2.405). GSEA showed enrichment of cell matrix adhesion, integrin binding, angiogenesis, endothelial growth factor and endothelial migration regulation in patients with COAD with GABRD overexpression. GABRB1, GABRD, GABRP and GABRQ were associated with the prognostic factors of COAD. The expression levels of GABRA2, GABRA3, GABRB2, GABRB3, GABRG2, GABRD and GABRE may allow differentiation between tumor tissues and adjacent normal tissues.