Downregulation of the enhancer of zeste homolog 1 transcriptional factor predicts poor prognosis of triple-negative breast cancer patients.

Background: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer and lacks effective biomarkers. This study seeks to unravel the expression status and the prospective transcriptional mechanisms of EZH1/EZH2 in TNBC tissue samples. Moreover, another objective of this study is to reveal the prognostic molecular signatures for risk stratification in TNBC patients. Methods: To determine the expression status of EZH1/EZH2 in TNBC tissue samples, microarray analysis and immunohistochemistry were performed on in house breast cancer tissue samples. External mRNA expression matrices were used to verify its expression patterns. Furthermore, the prospective transcriptional mechanisms of EZH1/EZH2 in TNBC were explored by performing differential expression analysis, co-expression analysis, and chromatin immunoprecipitation sequencing analysis. Kaplan-Meier survival analysis and univariate Cox regression analysis were utilized to detect the prognostic molecular signatures in TNBC patients. Nomogram and time-dependent receiver operating characteristic curves were plotted to predict the risk stratification ability of the prognostic-signatures-based Cox model. Results: In-house TMAs (66 TNBC vs. 106 non-TNBC) and external gene microarrays, as well as RNA-seq datasets (1,135 TNBC vs. 6,198 non-TNBC) results, confirmed the downregulation of EZH1 at both the protein and mRNA levels (SMD = -0.59 [-0.80, -0.37]), as is opposite to that of EZH2 (SMD = 0.74 [0.40, 1.08]). The upregulated transcriptional target genes of EZH1 were significantly aggregated in the cell cycle pathway, where CCNA2, CCNB1, MAD2L1, and PKMYT1 were determined as key transcriptional targets. Additionally, the downregulated transcriptional targets of EZH2 were enriched in response to the hormone, where ESR1 was identified as the hub gene. The six-signature-based prognostic model produced an impressive performance in this study, with a training AUC of 0.753, 0.981, and 0.977 at 3-, 5-, and 10-year survival probability, respectively. Conclusion: EZH1 downregulation may be a key modulator in the progression of TNBC through negative transcriptional regulation by targeting CCNA2, CCNB1, MAD2L1, and PKMYT1.

Upregulated expression of SAC3D1 is associated with progression in gastric cancer.

SAC3 domain containing 1 (SAC3D1) has been reported to be involved in numerous types of cancer. However, the role of SAC3D1 in GC has not yet been elucidated. In the present study, the mRNA expression level of SAC3D1 between GC and normal tissues were assessed with a continuous variable meta­analysis based on multiple datasets from public databases. The protein expression level of SAC3D1 in GC and normal tissues was assessed by an in­house immunohistochemistry (IHC). The association between SAC3D1 expression and some clinical parameters was assessed based on the TCGA and IHC data. Survival analysis was performed to assess the association between SAC3D1 expression and the survival of GC patients. The co­expressed genes of SAC3D1 were determined by integrating three online tools, and the enrichment analyses were performed to determine SAC3D1­related pathways and hub co­expressed genes. SAC3D1 was significantly upregulated in GC tumor tissues in comparison to normal tissues with the SMD being 0.45 (0.12, 0.79). The IHC results also indicated that SAC3D1 protein expression in GC tissues was markedly higher than in normal tissues. The SMD following the addition of the IHC data was 0.59 (0.11, 1.07). The protein levels of SAC3D1 were positively associated with the histological grade, T stage and N stage of GC (P<0.001). The TCGA data also revealed that the SAC3D1 mRNA level was significantly associated with the N stage (P<0.001). Moreover, prognosis analysis indicated that SAC3D1 was closely associated with the prognosis of patients with GC. Moreover, 410 co­expressed genes of SAC3D1 were determined, and these genes were mainly enriched in the cell cycle. In total, 4 genes (CDK1, CCNB1, CCNB2 and CDC20) were considered key co­expressed genes. On the whole, these findings demonstrate that SAC3D1 is highly expressed in GC and may be associated with the progression of GC.

Profiling of prognostic alternative splicing in melanoma.

Alternative splicing can lead to the coding of proteins that act as promoters of cancer, which is associated with the progression of cancer. However, to the best of our knowledge, no systematic survival analysis of alternative splicing in melanoma has previously been reported. The present study conducted an in-depth analysis of integrated alternative splicing events detected in 96 patients with melanoma using data obtained from The Cancer Genome Atlas. Prognostic models and an alternative splicing correlation network were built for patients with melanoma. A total of 41,446 mRNA splicing events were detected in 9,780 genes and 2,348 alternative splicing events were identified to be significantly associated with overall survival of patients with melanoma. Of all the events used in the prognostic model, the model with alternate terminator alternative splicing events exhibited the highest efficiency for evaluating the outcome of patients with melanoma, with an area under the curve of 0.902. The present study identified prognostic predictors for melanoma and revealed alternative splicing networks in melanoma that could indicate underlying mechanisms.

Differentially expressed gene profile and relevant pathways of the traditional Chinese medicine cinobufotalin on MCF­7 breast cancer cells.

Cinobufotalin is a chemical compound extracted from the skin of dried bufo toads that may have curative potential for certain malignancies through different mechanisms; however, these mechanisms remain unexplored in breast cancer. The aim of the present study was to investigate the antitumor mechanism of cinobufotalin in breast cancer by using microarray data and in silico analysis. The microarray data set GSE85871, in which cinobufotalin exerted influences on the MCF­7 breast cancer cells, was acquired from the Gene Expression Omnibus database, and the differentially expressed genes (DEGs) were analyzed. Subsequently, protein interaction analysis was conducted, which clarified the clinical significance of core genes, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to analyze cinobufotalin­related pathways. The Connectivity Map (CMAP) database was used to select existing compounds that exhibited curative properties similar to those of cinobufotalin. A total of 1,237 DEGs were identified from breast cancer cells that were treated with cinobufotalin. Two core genes, SRC proto­oncogene non­receptor tyrosine kinase and cyclin­dependent kinase inhibitor 2A, were identified as serving a vital role in the onset and development of breast cancer, and their expression levels were markedly reduced following cinobufotalin treatment as detected by the microarray of GSE85871. It also was revealed that the 'neuroactive ligand­receptor interaction' and 'calcium signaling' pathways may be crucial for cinobufotalin to perform its functions in breast cancer. Conducting a matching search in CMAP, miconazole and cinobufotalin were indicated to possessed similar molecular mechanisms. In conclusion, cinobufotalin may serve as an effective compound for the treatment of a subtype of breast cancer that is triple positive for the presence of estrogen, progesterone and human epidermal growth factor receptor­2 receptors, and its mechanism may be related to different pathways. In addition, cinobufotalin is likely to exert its antitumor influences in a similar way as miconazole in MCF­7 cells.

miR­146a­5p targets TCSF and influences cell growth and apoptosis to repress NSCLC progression.

Several studies have indicated that microRNAs (miRs) mediate multiple pathways associated with tumorigenesis and progression. Our preliminary study experimentally verified that miR­146a­5p has a role in the biological behavior of non­small cell lung cancer (NSCLC) cells. To perform further investigation of miR­146a­5p, the present study evaluated miR­146a­5p by targeting its downstream gene tumor collagenase stimulatory factor (TCSF) to influence cell viability, proliferation and apoptosis in NSCLC. Online sequence prediction, a thorough search of the open source database The Cancer Genome Atlas (TCGA), immunohistochemistry (IHC) of TCSF in clinical lung cancer tissues, and a dual­luciferase assay, as well as assays to test viability, proliferation and apoptosis in vitro, were conducted to explain the targeted regulation association between miR­146a­5p and TCSF in NSCLC. The miRanda and TargetScanHuman database revealed that TCSF and miR­146a­5p had target binding sites. A luciferase reporter assay demonstrated that miR­146a­5p and TCSF did have complementary sequences (P<0.05). From the TCGA database, TCSF was highly expressed in lung adenocarcinoma and lung squamous cell carcinoma tissues when compared with normal lung tissues (P<0.05). Furthermore, the protein level of TCSF in cancerous lung tissues was determined by IHC, and it was concluded that TCSF protein was also upregulated in NSCLC tissues (P<0.001). A significant difference was identified following in vitro experiments for the NSCLC cell line A549, which revealed that miR­146a­5p and TCSF regulated cell viability, proliferation and apoptosis. In conclusion, the present study verified the target action association between TCSF and miR­146a­5p with high throughput data analysis and experimental results in NSCLC.

Expression and potential molecular mechanisms of miR­204­5p in breast cancer, based on bioinformatics and a meta­analysis of 2,306 cases.

Breast cancer (BC) is the most common cancer among women worldwide. However, there is insufficient research that focuses on the expression and molecular mechanisms of microRNA (miR)­204­5p in BC. In the current study, data were downloaded from the Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO) and the University of California Santa Cruz (UCSC) Xena databases. They were then used to undertake a meta­analysis that leveraged the standard mean difference (SMD) and summarized receiver operating characteristic (sROC) to evaluate the expression of the precursor miR­204 and mature miR­204­5p in BC. Additionally, an intersection of predicted genes, differentially expressed genes (DEGs) from the TCGA database and the GEO database were plotted to acquire desirable putative genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein­protein interaction (PPI) network analyses were performed to assess the potential pathways and hub genes of miR­204­5p in BC. A decreased trend in precursor miR­204 expression was detected in 1,077 BC tissue samples in comparison to 104 para­carcinoma tissue samples in the TCGA database. Further, the expression of mature miR­204­5p was markedly downregulated in 756 BC tissue samples in comparison to 76 para­carcinoma tissue samples in the UCSC Xena database. The outcome of the SMD from meta­analysis also indicated that the expression of miR­204­5p was markedly reduced in 2,306 BC tissue samples in comparison to 367 para­carcinoma tissue samples. Additionally, the ROC and sROC values indicated that miR­204­5p had a great discriminatory capacity for BC. In GO analysis, 'cell development', 'cell surface activity', and 'receptor agonist activity' were the most enriched terms; in KEGG analysis, 'endocytosis' was significantly enriched. Rac GTPase activating protein 1 (RACGAP1) was considered the hub gene in the PPI network. In conclusion, miR­204­5p may serve a suppressor role in the oncogenesis and advancement of BC, and miR­204­5p may have crucial functions in BC by targeting RACGAP1.

Downregulation of miR­224­5p in prostate cancer and its relevant molecular mechanism via TCGA, GEO database and in silico analyses.

The function of the expression of microRNA (miR)­224­5p in prostate adenocarcinoma (PCa) remains to be elucidated, therefore, the present study aimed to investigate the clinical significance and potential molecular mechanism of miR­224­5p in PCa. Data on the expression of miR­224­5p in PCa were extracted from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), ArrayExpress and previous literature, and meta­analyses with standardized mean difference (SMD) and summary receiver operating characteristic (sROC) methods were performed for statistical analyses. The prospective target genes of miR­224­5p were collected by overlapping the differentially expressed mRNAs in TCGA and GEO, and target genes predicted by miRWalk2.0. Subsequently, in silico analysis was performed to examine the associated pathways of miR­224­5p in PCa. The expression of miR­224­5p was markedly lower in PCa; the overall SMD was ­0.562, and overall sROC area under the curve was 0.80. In addition, Kyoto Encyclopedia of Genes and Genomes analysis revealed that the prospective target genes of miR­224­5p were largely enriched in the amino sugar and nucleotide sugar metabolism signaling pathway, and three genes [UDP­N­acetylglucosamine pyrophosphorylase 1 (UAP1), hexokinase 2 (HK2) and chitinase 1 (CHIT1)] enriched in this pathway showed higher expression (P<0.05). In addition, key genes in the protein­protein interaction network analysis [DNA topoisomerase 2­α (TOP2A), ATP citrate lyase (ACLY) and ribonucleotide reductase regulatory subunit M2 (RRM2)] exhibited significantly increased expression (P<0.05). The results suggested that the downregulated expression of miR­224­5p may be associated with the clinical progression and prognosis of PCa. Furthermore, miR­224­5p likely exerts its effects by targeting genes, including UAP1, HK2, CHIT1, TOP2A, ACLY and RRM2. However, in vivo and in vitro experiments are required to confirm these findings.

Upregulated miR­203a­3p and its potential molecular mechanism in breast cancer: A study based on bioinformatics analyses and a comprehensive meta­analysis.

Breast cancer (BC) has been identified as the leading malignancy in women worldwide. However, the potential molecular mechanism of microRNA (miR)­203a­3p in BC remains to be elucidated. The present study evaluated the expression of miR­203a­3p in BC and adjacent normal tissue in several publically available datasets. The distinguishability of precursor miR­203a and miR­203a­3p in BC tissue and adjacent breast tissue was assessed using receiver operating characteristic (ROC) and summarized ROC (sROC) approaches. In addition, gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes pathway analysis and protein­protein interaction analysis were performed to determine the potential molecular mechanism of miR­203a­3p in BC. It was identified that the expression of precursor miR­203a was markedly upregulated in 1,077 BC tissue samples compared to 104 adjacent breast tissue samples from The Cancer Genome Atlas. Additionally, an increasing trend in miR­203a­3p expression was observed in 756 BC tissue samples compared with 76 adjacent breast tissue samples from the University of California Santa Cruz Xena project. In addition, a comprehensive meta­analysis suggested that the expression of miR­203a­3p was markedly increased in 2,444 BC tissue samples compared with 559 adjacent breast tissue samples. The area under the curve of the ROC and sROC revealed that miR­203a­3p expression was able to distinguish between BC tissue and adjacent breast tissue. However, miR­203a­3p exhibited no prognostic value in BC. The results of GO enrichment demonstrated that the miR­203a target genes were associated with 'plasma membrane integrity', 'cell surface receptor linked signal and transduction' and '3',5'­cyclic nucleotide phosphodiesterase activity'. 'Purine metabolism' was identified as the pathway with the most enrichment of miR­203a­3p target genes in BC. The present study also identified insulin­like growth factor receptor (IGF1) as a hub gene associated with miR­203a in BC. In summary, miR­203a­3p may enhance the development and oncogenesis of BC, and IGF1 was defined as a hub gene of miR­203a­3p in BC.

Inflammatory myofibroblastic tumor of the prostate after transurethral resection of the prostate with negative expression of anaplastic lymphoma kinase: a case report

ABSTRACT CONTEXT: Inflammatory myofibroblastic tumors are a rare type of soft-tissue tumor. Inflammatory myofibroblastic tumors are characterized by rearrangements involving the anaplastic lymphoma kinase gene locus on 2p23. Case Report: We report the case of a 67-year-old Chinese male who presented with dysuria and fever. Magnetic resonance imaging showed an irregular prostatic mass with an isointense signal and obscure boundary. Histopathological evaluation showed that the mass consisted mainly of spindle-shaped cells. Immunohistochemical evaluation showed that the tumor cells were negative for anaplastic lymphoma kinase. CONCLUSIONS: Inflammatory myofibroblastic prostate tumors are rare lesions with unclear etiology. The pathological diagnosis is very important.

Inflammatory myofibroblastic tumor of the prostate after transurethral resection of the prostate with negative expression of anaplastic lymphoma kinase: a case report.

CONTEXT: Inflammatory myofibroblastic tumors are a rare type of soft-tissue tumor. Inflammatory myofibroblastic tumors are characterized by rearrangements involving the anaplastic lymphoma kinase gene locus on 2p23. CASE REPORT: We report the case of a 67-year-old Chinese male who presented with dysuria and fever. Magnetic resonance imaging showed an irregular prostatic mass with an isointense signal and obscure boundary. Histopathological evaluation showed that the mass consisted mainly of spindle-shaped cells. Immunohistochemical evaluation showed that the tumor cells were negative for anaplastic lymphoma kinase. CONCLUSIONS: Inflammatory myofibroblastic prostate tumors are rare lesions with unclear etiology. The pathological diagnosis is very important.

MicroRNA-671-3p inhibits the development of breast cancer: A study based on in vitro experiments, in-house quantitative polymerase chain reaction and bioinformatics analysis.

MicroRNAs (miRNAs or miRs) are highly conserved small noncoding RNA molecules involved in gene regulation. An increasing number of studies have demonstrated that miRNAs act as oncogenes or antioncogenes in various types of cancer, including breast cancer (BC). However, the exact role of miR­671­3p in BC has not yet been reported. In the present study, in vitro experiments were implemented to explore the effects of miR­671­3p on the proliferation and apoptosis of BC cells, and reverse transcription­quantitative polymerase chain reaction was conducted using in­house clinical BC samples to address the expression level and clinical value of miR­671­3p in BC. Simultaneously, miR­671­3p target genes were collected, and subsequent bioinformatics analyses were executed to probe the potential signaling pathway through which miR­671­3p influenced the occurrence and progression of BC. According to the results, the expression level of miR­671­3p was lower in BC tissues compared with that in adjacent non­tumorous tissues (P=0.048), and the area under the curve was 0.697 (95% confidence interval=0.538­0.856), with a sensitivity and specificity of 0.818 and 0.579, respectively. Forced miR­671­3p expression in the BC cell line MDA­MB­231 evidently arrested cell proliferation and induced cell apoptosis. Furthermore, in silico enrichment analyses suggested that miR­671­3p may be involved in the initiation and progression of BC through the targeting of genes associated with the Wnt signaling pathway. In conclusion, the present study findings suggested that miR­671­3p may function as a tumor suppressor in BC by influencing the Wnt signaling cascade, which provides a prospective molecular target for the therapy of BC.

Caspase-3 over-expression is associated with poor overall survival and clinicopathological parameters in breast cancer: a meta-analysis of 3091 cases.

Caspase-3 is a vital executioner molecule during the apoptotic process. Numerous studies have revealed the close association of caspase-3 expression and breast cancer. Nevertheless, the prognostic value of caspase-3 expression for patients with breast cancer remains uncertain. To thoroughly analyze the prognostic effect of caspase-3 expression on the clinicopathological features and survival of breast cancer, we conducted this meta-analysis. With various search strategies, electronic databases were comprehensively searched. A total of 3091 patients from 21 studies were ultimately obtained. The analysis results indicated that increased expression of caspase-3 had a negative influence on the overall survival (OS) of breast cancer (HR = 1.73, 95%CI 1.12-2.67, P = 0.014). Subgroup analyses based on race revealed that the value of caspase-3 for evaluating patients' OS was more useful in Asian patients (HR = 3.16, 95%CI 1.20-8.15, P = 0.020), and subgroup analyses based on study analytical methods revealed that caspase-3 was a risk factor for breast cancer patients in multivariate overall survival analyses (HR = 1.67, 95%CI 1.02-2.75, P = 0.044). As for the relationship between caspase-3 expression and breast cancer subtype as well as progression, caspase-3 might serve as a risk factor for the progestogen receptor (PR) and human epidermal growth factor receptor-2 (HER-2) subtypes (OR = 1.44, 95%CI 1.09-1.89, P = 0.010; OR = 1.76, 95%CI 1.18-2.62, P = 0.050, respectively) of breast cancer. However, no evidence showed that increased expression of caspase-3 was statistically correlated with tumor differentiation state (low/moderate or high), tumor TNM stage (I-II/III-IV) or lymph node metastasis (-/+). In conclusion, this meta-analysis revealed that increased caspase-3 expression was significantly associated with worse prognosis and two subtypes of breast cancer. More prospective studies are urgently needed to define the prognostic value of caspase-3 expression in patients with breast cancer.

Integrative analysis of BSG expression in NPC through immunohistochemistry and public high-throughput gene expression data.

BACKGROUND: Though basigin (BSG) was reported to be overexpressed in nasopharyngeal carcinoma (NPC) and correlate with the development of NPC, the molecular basis of BSG in NPC remained elusive. The aim of the research was to investigate BSG expression in NPC and the potential molecular mechanism underlying it. MATERIALS AND METHODS: BSG expression in NPC tissues was detected with immunohistochemistry. Chi-square test, Kruskal-Wallis test and Spearman correlation test were performed to examine the relationship between BSG expression and the clinico-pathological features as well as EGFR and P-53 expression in NPC. In addition, data from the Human Protein Atlas (HPA) database and oncomine were collected to validate BSG expression in NPC. Meta-analysis was conducted to investigate the association between BSG expression and the clinico-pathological variables of NPC. The prognostic value and the alteration of BSG gene status were also analyzed with data from The Cancer Genome Atlas (TCGA). RESULTS: BSG presented notably higher expression in NPC tissues than in non-cancer tissues. Moreover, IHC results showed that BSG expression was significantly correlated with tumor progression. A positive correlation was also found between BSG expression and EGFR, P53 expression. Meta-analysis confirmed that BSG was indicative of lymph node metastasis and TNM stage in NPC. Additionally, data from cBioPortal indicated that alteration of BSG gene existed in 5% of NPC cases and BSG correlative genes were obtained from the Co-expression Analysis in TCGA. CONCLUSION: BSG was overexpressed in NPC and might have an oncogenic effect on the tumorigenesis and progression of NPC.

Progression-free survival of up to 8 months of an advanced intrahepatic cholangiocarcinoma patient treated with apatinib: a case report.

Intrahepatic cholangiocarcinoma (ICC) arises from the biliary epithelium and is a relatively rare and highly fatal neoplasm. The prognosis is poor, and survival is limited to a few months. Here, we report a case of advanced ICC that was successfully treated with apatinib, a new oral tyrosine kinase inhibitor that targets the intracellular domain of vascular endothelial growth factor receptor-2. To the best of our knowledge, this is the first case report of the successful use of apatinib for advanced ICC; this treatment has demonstrated fewer toxic effects than traditional cytotoxic chemotherapy. The progression-free survival time was 8 months. The only toxicity observed was mild hand-foot syndrome. Therefore, apatinib may be an additional option for the treatment of advanced ICC, but further prospective studies are needed to optimize the treatment.