Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MCM7 (cancer-related)
Esophageal squamous cell carcinoma (ESCC) is a malignancy that severely threatens human health and carries a high incidence rate and a low 5-year survival rate. MicroRNAs (miRNAs) are commonly accepted as a key regulatory function in human cancer, but the potential regulatory mechanisms of miRNA-mRNA related to ESCC remain poorly understood.The GSE55857, GSE43732, and GSE6188 miRNA microarray datasets and the gene expression microarray datasets GSE70409, GSE29001, and GSE20347 were downloaded from Gene Expression Omnibus databases. The differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were obtained using GEO2R. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). A protein-protein interaction (PPI) network and functional modules were established using the STRING database and were visualized by Cytoscape. Kaplan-Meier analysis was constructed based on The Cancer Genome Atlas (TCGA) database.In total, 26 DEMs and 280 DEGs that consisted of 96 upregulated and 184 downregulated genes were screened out. A functional enrichment analysis showed that the DEGs were mainly enriched in the ECM-receptor interaction and cytochrome P450 metabolic pathways. In addition, MMP9, PCNA, TOP2A, MMP1, AURKA, MCM2, IVL, CYP2E1, SPRR3, FOS, FLG, TGM1, and CYP2C9 were considered to be hub genes owing to high degrees in the PPI network. MiR-183-5p was with the highest connectivity target genes in hub genes. FOS was predicted to be a common target gene of the significant DEMs. Hsa-miR-9-3p, hsa-miR-34c-3p and FOS were related to patient prognosis and higher expression of the transcripts were associated with a poor OS in patients with ESCC.Our study revealed the miRNA-mediated hub genes regulatory network as a model for predicting the molecular mechanism of ESCC. This may provide novel insights for unraveling the pathogenesis of ESCC.
BACKGROUND: Lung adenocarcinoma is the most common type of lung cancer, with high mortality worldwide. Its occurrence and development were thoroughly studied by high-throughput expression microarray, which produced abundant data on gene expression, DNA methylation, and miRNA quantification. However, the hub genes, which can be served as bio-markers for discriminating cancer and healthy individuals, are not well screened.
RESULT: Here we present a new method for extracting gene predictors, aiming to obtain the least predictors without losing the efficiency. We firstly analyzed three different expression microarrays and constructed multi-interaction network, since the individual expression dataset is not enough for describing biological behaviors dynamically and systematically. Then, we transformed the undirected interaction network to directed network by employing Granger causality test, followed by the predictors screened with the use of the stepwise character selection algorithm. Six predictors, including TOP2A, GRK5, SIRT7, MCM7, EGFR, and COL1A2, were ultimately identified. All the predictors are the cancer-related, and the number is very small fascinating diagnosis. Finally, the validation of this approach was verified by robustness analyses applied to six independent datasets; the precision is up to 95.3% ∼ 100%.
CONCLUSION: Although there are complicated differences between cancer and normal cells in gene functions, cancer cells could be differentiated in case that a group of special genes expresses abnormally. Here we presented a new, robust, and effective method for extracting gene predictors. We identified as low as 6 genes which can be taken as predictors for diagnosing lung adenocarcinoma.
Ahmed MY, Salah MM, Kassim SK, et al.Evaluation of the diagnostic and therapeutic roles of non-coding RNA and cell proliferation related gene association in hepatocellular carcinoma.
Gene. 2019; 706:97-105 [PubMed
] Related Publications
Micro RNA-34a-5p (miR-34a-5p) is an important molecule that can act as a modulator of tumor growth. It controls expression of a plenty of proteins controlling cell cycle, differentiation and apoptosis and opposing processes that favor viability of cancer cells, their metastasis and resistance to chemotherapy. Bioinformatics analysis indicated that minichromosome maintenance protein 2 (MCM2) is a target gene of miR-34a-p. In this study, RT-qPCR was employed to detect the expression of miR-34a-5p and MCM2 in 10 hepatocellular carcinoma (HCC) tissues. The functional role of miR-34a-5p in HCC was investigated and the interaction between miR-34a-5p and MCM2 was explored. Results showed miR-34a-5p expression in HCC tissues was significantly lower than in non HCC liver tissues (P < 0.05), but MCM2 expression in HCC tissues was markedly higher than in non HCC liver tissues (P < 0.05). In addition, miR-34a-5p expression was negatively related to MCM2 expression. To confirm effect of miR-34a-5p on tumor growth and its possible effect on MCM2, miR-34a-5p mimic and inhibitor was transfected into HCC cell lines (HepG2). MTS assay, showed miR-34a-5p over-expression could inhibit the proliferation of HCC cells. RT-qPCR was done to detect the expression of miR-34a-5p and MCM2 in HepG2 cells before and after transfection. Results showed that MCM2 expression in HCC tissues was markedly lower in mimic transfected group than in inhibitor transfected group and control group (P < 0.05) while miR-34a-5p expression in HepG2 cells was significantly higher in mimic transfected group than in inhibitor transfected group and control group (P < 0.05). Thus, miR-34a-5p may inhibit the proliferation of HCC cells via regulating MCM2 expression. These findings provide an evidence for the emerging role of microRNAs as diagnostic markers and therapeutic targets in HCC.
BACKGROUND: Cellular senescence is a recognized barrier for progression of chronic liver diseases to hepatocellular carcinoma (HCC). The expression of a cluster of genes is altered in response to environmental factors during senescence. However, it is questionable whether these genes could serve as biomarkers for HCC patients.
AIM: To develop a signature of senescence-associated genes (SAGs) that predicts patients' overall survival (OS) to improve prognosis prediction of HCC.
METHODS: SAGs were identified using two senescent cell models. Univariate COX regression analysis was performed to screen the candidate genes significantly associated with OS of HCC in a discovery cohort (GSE14520) for the least absolute shrinkage and selection operator modelling. Prognostic value of this seven-gene signature was evaluated using two independent cohorts retrieved from the GEO (GSE14520) and the Cancer Genome Atlas datasets, respectively. Time-dependent receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive accuracy of the seven-SAG signature and serum α-fetoprotein (AFP).
RESULTS: A total of 42 SAGs were screened and seven of them, including
CONCLUSION: We developed a seven-SAG signature, which could predict OS of Asian HCC patients. This risk model provides new clinical evidence for the accurate diagnosis and targeted treatment of HCC.
Yang WD, Wang LMCM10 facilitates the invaded/migrated potentials of breast cancer cells via Wnt/β-catenin signaling and is positively interlinked with poor prognosis in breast carcinoma.
J Biochem Mol Toxicol. 2019; 33(7):e22330 [PubMed
] Related Publications
The minichromosome maintenance protein 10 (MCM10) is one of the MCM proteins that initiate DNA replication by interacting with CDC45-MCM2-7. It has been reported that MCM10 has a role in breast cancer progression. However, MCM10 in breast cancer is still not comprehensively studied and further research is needed. This study was aimed at investigating the potential effects of MCM10 on metastasis, the prognosis of breast carcinoma, and its underlying mechanisms. Using the ONCOMINE database and the Kaplan-Meier Plotter, MCM10 was significantly overexpressed in cancers, and high expression of MCM10 was involved in the poor prognosis of breast carcinoma. MCM10 can promote the proliferation, migration, and invasion of MDA-MB-231 cells. MCM10 knockdown brought about a radical reversal in cell behaviors. Meanwhile, decreased expression of β-catenin and cyclin Dl was detected in MCM10 short hairpin RNA cells, implying that MCM10 might induce breast cancer metastasis via the Wnt/β-catenin pathway.MCM10 can be defined as a potential diagnostic tool and a promising target for breast carcinoma.
Butyrate is a short-chain fatty acid decomposed from dietary fiber and has been shown to have effects on inhibition of proliferation but induction of apoptosis in colorectal cancer cells. However, clinical trials have yielded ambiguous outcomes with regard to its antitumor activities. In this study, we aimed to explore the molecular mechanisms underlying the sensitivity of colorectal cancer cells to sodium butyrate (NaB). RNA sequencing was used to establish the whole-transcriptome profile in NaB-treated versus untreated colorectal cancer cells. Differentially expressed genes were bioinformatically analyzed to predict their possible involvement in NaB-triggered cell death, and the expression of eight dysregulated genes was validated by quantitative real-time PCR. We found that there were a total of 7192 genes (5720 upregulated and 1472 downregulated, fold-change ≥ 2 or ≤ 0.5 for upregulation or downregulation, q-value < 0.05) differentially expressed in NaB-treated cells as compared with the untreated controls. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that the differentially expressed genes were enriched in DNA replication, cell cycle, homologous recombination, pyrimidine metabolism, mismatch repair, and other signaling pathways and may take part in NaB-induced cell death. Among the identified factors, the MCM2-7 complex might be a target of NaB. Our findings provide an important basis for further studies of the complicate network that might regulate sensitivity of colorectal cancer cells to NaB.
Recently published structural and functional analyses of the CMG complex have provided insight into the mechanism of its DNA helicase function and into the distinct roles of its central six component proteins MCM2-MCM7 (MCM2-7). To activate CMG helicase, the two protein kinases CDK and DDK, as well as MCM10, are required. In addition to the initiation of DNA replication, MCM function must be regulated at the DNA replication steps of elongation and termination. Polyubiquitylation of MCM7 is involved in terminating MCM function. Reinitiation of DNA replication in a single cell cycle, which is prevented mainly by CDK, is understood at the molecular level. MCM2-7 gene expression is regulated during cellular aging and the cell cycle, and the expression depends on oxygen concentration. These regulatory processes have been described recently. Genomic structural alteration, which is an essential element in cancer progression, is mainly generated by disruptions of DNA replication fork structures. A point mutation in MCM4 that disturbs MCM2-7 function results in genomic instability, leading to the generation of cancer cells. In this review, I focus on the following points: 1) function of the MCM2-7 complex, 2) activation of MCM2-7 helicase, 3) regulation of MCM2-7 function, 4) MCM2-7 expression, and 5) the role of MCM mutation in cancer progression.
BACKGROUND Liposarcoma is the most common type of soft tissue sarcoma, but its molecular mechanism is poorly defined. This study aimed to identify genes crucial to the pathogenesis of liposarcoma and to explore their functions, related pathways, and prognostic value. MATERIAL AND METHODS Differentially expressed genes (DEGs) in the GSE59568 dataset were screened. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to investigate the DEGs at the functional level. Protein-protein interaction (PPI) networks and module analysis were applied to identify hub genes from among the DEGs. The GSE30929 dataset was used to validate the relationship between hub genes and the distant recurrence-free survival (DRFS) of liposarcoma patients using Cox model analysis. RESULTS A total of 1111 DEGs were identified. GO and KEGG pathway analysis indicated that the DEGs were mainly associated with lipopolysaccharides and pathways in cancer. The PPI network and module analysis identified 10 hub genes from the DEG network. The Cox model identified 3 genes (NIP7, RPL10L, and MCM2) significantly associated with DRFS. The risk score calculated by the Cox model of the NIP7-RPL10L-MCM2 signature could largely predict the 1-, 3-, and 5-year DRFS of liposarcoma patients, and the prognostic value was even higher for subtypes of liposarcoma. CONCLUSIONS This study identified genes that might play critical roles in liposarcoma pathogenesis as well as a 3-gene-based signature that could be used as a candidate prognostic biomarker for patients with liposarcoma.
Mehlich D, Garbicz F, Włodarski PKThe emerging roles of the polycistronic miR-106b∼25 cluster in cancer - A comprehensive review.
Biomed Pharmacother. 2018; 107:1183-1195 [PubMed
] Related Publications
MicroRNAs (miRNAs) are short, non-coding RNA molecules that regulate gene expression at the post-transcriptional level by inhibiting translation and decreasing the stability of the targeted transcripts. Over the last two decades, miRNAs have been recognized as important regulators of cancer cell biology, acting either as oncogenes or tumor suppressors. The polycistronic miR-106b∼25 cluster, located within an intron of MCM7 gene, consists of three highly conserved miRNAs: miR-25, miR-93 and miR-106b. A constantly growing body of evidence indicates that these miRNAs are overexpressed in numerous human malignancies and regulate multiple cellular processes associated with cancer development and progression, including: cell proliferation and survival, invasion, metastasis, angiogenesis and immune evasion. Furthermore, recent studies revealed that miR-106b∼25 cluster miRNAs modulate cancer stem cells characteristics and might promote resistance to anticancer therapies. In light of these novel discoveries, miRNAs belonging to the miR-106b∼25 cluster have emerged as key oncogenic drivers as well as potential biomarkers and plausible therapeutic targets in different tumor types. Herein, we comprehensively review novel findings on the roles of miR-106b∼25 cluster in human cancer, and provide a broad insight into the molecular mechanisms underlying its oncogenic properties.
BACKGROUND: Uncontrolled replication is a process common to all cancers facilitated by the summation of changes accumulated as tumors progress. The aim of this study was to examine small groups of genes with known biology in replication and repair at the transcriptional and genomic levels, correlating alterations with survival in uveal melanoma tumor progression. Selected components of Pre-Replication, Pre-Initiation, and Replisome Complexes, DNA Damage Response and Mismatch Repair have been observed.
METHODS: Two groups have been generated for selected genes above and below the average alteration level and compared for expression and survival across The Cancer Genome Atlas uveal melanoma subtypes. Significant differences in expression between subtypes monosomic or disomic for chromosome 3 have been identified by Fisher's exact test. Kaplan Meier survival distribution based on disease specific survival has been compared by Log-rank test.
RESULTS: Genes with significant alteration include MCM2, MCM4, MCM5, CDC45, MCM10, CIZ1, PCNA, FEN1, LIG1, POLD1, POLE, HUS1, CHECK1, ATRIP, MLH3, and MSH6. Exon 4 skipping in CIZ1 previously identified as a cancer variant, and reportedly used as an early serum biomarker in lung cancer was found. Mismatch Repair protein MLH3 was found to have splicing variations with deletions to both Exon 5 and Exon 7 simultaneously. PCNA, FEN1, and LIG1 had increased relative expression levels not due to mutation or to copy number variation.
CONCLUSION: The current study proposes changes in relative and differential expression to replication and repair genes that support the concept their products are causally involved in uveal melanoma. Specific avenues for early biomarker identification and therapeutic approach are suggested.
Yoshimaru S, Shizu R, Tsuruta S, et al.Acceleration of murine hepatocyte proliferation by imazalil through the activation of nuclear receptor PXR.
J Toxicol Sci. 2018; 43(7):443-450 [PubMed
] Related Publications
The nuclear receptor pregnane X receptor (PXR) plays a major role in the xenobiotic-induced expression of drug-metabolizing enzymes. PXR activation is also associated with several adverse events in the liver. Especially, the receptor enhances hepatocyte proliferation mediated by chemical liver tumor promoters, suggesting that exposure to PXR activators increases the risk of liver cancer. In this study, we have investigated the influences of food additives on PXR to understand their potential adverse effects when they are taken in combination with other chemical compounds. We first screened 25 food additives and related compounds for their PXR-activating ability using reporter assays in HepG2 cells expressing mouse PXR, and found that imazalil dose-dependently activated mouse PXR. Next, to investigate whether imazalil could activate mouse PXR in vivo, mice were treated with imazalil and we found that imazalil treatment increased hepatic mRNA levels of Cyp3a11, a PXR target gene. Finally, to investigate the influence of imazalil exposure on the hepatocyte proliferation induced by nuclear receptor constitutive active/androstane receptor (CAR), mice were treated with imazalil with or without mouse CAR activator TCPOBOP. Although imazalil alone did not induce hepatocyte proliferation, co-treatment with imazalil facilitated the TCPOBOP-dependent proliferation, indicated by the increases in cell proliferation marker levels, Ki-67-positive nuclei and Mcm2 mRNA levels. These results suggest that in mice imazalil activates PXR to enhance hepatocyte proliferation mediated by CAR-activating liver tumor promoters.
AIM: To discover methylated-differentially expressed genes (MDEGs) in hepatocellular carcinoma (HCC) and to explore relevant hub genes and potential pathways.
METHODS: The data of expression profiling GSE25097 and methylation profiling GSE57956 were gained from GEO Datasets. We analyzed the differentially methylated genes and differentially expressed genes online using GEO2R. Functional and enrichment analyses of MDEGs were conducted using the DAVID database. A protein-protein interaction (PPI) network was performed by STRING and then visualized in Cytoscape. Hub genes were ranked by cytoHubba, and a module analysis of the PPI network was conducted by MCODE in Cytoscape software.
RESULTS: In total, we categorized 266 genes as hypermethylated, lowly expressed genes (Hyper-LGs) referring to endogenous and hormone stimulus, cell surface receptor linked signal transduction and behavior. In addition, 161 genes were labelled as hypomethylated, highly expressed genes (Hypo-HGs) referring to DNA replication and metabolic process, cell cycle and division. Pathway analysis illustrated that Hyper-LGs were enriched in cancer, Wnt, and chemokine signalling pathways, while Hypo-HGs were related to cell cycle and steroid hormone biosynthesis pathways. Based on PPI networks,
CONCLUSION: In the study, we disclose numerous novel genetic and epigenetic regulations and offer a vital molecular groundwork to understand the pathogenesis of HCC. Hub genes, including
Fujii K, Miyata Y, Takahashi I, et al.Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer.
Proteomics Clin Appl. 2018; 12(6):e1800015 [PubMed
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PURPOSE: The molecular underpinnings that may prognosticate survival and increase our understanding of tumor development and progression are still poorly understood. This study aimed to define the molecular signatures for malignancy in small cell lung carcinoma (SCLC), which is known for its highly aggressive clinical features and poor prognosis.
EXPERIMENTAL DESIGN: Using clinical specimens, the authors perform a comparative proteomic analysis of high-grade SCLCs and low-grade pulmonary carcinoid tumors (PCTs), both of which are types of neuroendocrine tumors. A label-free LC-MS-based quantitative proteomic analysis is applied to tumor cells laser-microdissected from their formalin-fixed paraffin-embedded (FFPE) tissues obtained from six patients each.
RESULTS: Overall, 1991 proteins are identified from tumor cells in the FFPE tissues. Through the protein-protein interaction network analysis of 201 proteins significantly, the authors find that SCLC is functionally characterized by activation of molecular pathways for spliceosome, RNA transport, and DNA replication and cell cycle. Particularly, 11 proteins involved in tumor proliferation (MCM2, 4, 6, 7, and MSH2), metastasis (RCC2, CORO1C, CHD4, and IPO9), and cancer metabolism (PHGDH and TYMP) are identified as SCLC-specific proteins. Furthermore, their prognostic significances are demonstrated by online Kaplan-Meier survival analysis.
CONCLUSIONS AND CLINICAL RELEVANCE: These clinical tissue proteomic approach for SCLC reveals the proteins associated with aggressiveness and poor prognosis. The identified SCLC-specific proteins represent potential therapeutic targets. Moreover, MCMs and PHGDH can be poor prognostic factors for lung cancer.
Small cell lung cancer (SCLC) is one of the highly malignant tumors and a serious threat to human health. The aim of the present study was to explore the underlying molecular mechanisms of SCLC. mRNA microarray datasets GSE6044 and GSE11969 were downloaded from Gene Expression Omnibus database, and the differentially expressed genes (DEGs) between normal lung and SCLC samples were screened using GEO2R tool. Functional and pathway enrichment analyses were performed for common DEGs using the DAVID database, and the protein‑protein interaction (PPI) network of common DEGs was constructed by the STRING database and visualized with Cytoscape software. In addition, the hub genes in the network and module analysis of the PPI network were performed using CentiScaPe and plugin Molecular Complex Detection. Finally, the mRNA expression levels of hub genes were validated in the Oncomine database. A total of 150 common DEGs with absolute fold‑change >0.5, including 66 significantly downregulated DEGs and 84 upregulated DEGs were obtained. The Gene Ontology term enrichment analysis suggested that common upregulated DEGs were primarily enriched in biological processes (BPs), including 'cell cycle', 'cell cycle phase', 'M phase', 'cell cycle process' and 'DNA metabolic process'. The common downregulated genes were signiﬁcantly enriched in BPs, including 'response to wounding', 'positive regulation of immune system process', 'immune response', 'acute inflammatory response' and 'inflammatory response'. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified that the common downregulated DEGs were primarily enriched in the 'complement and coagulation cascades' signaling pathway; the common upregulated DEGs were mainly enriched in 'cell cycle', 'DNA replication', 'oocyte meiosis' and the 'mismatch repair' signaling pathways. From the PPI network, the top 10 hub genes in SCLC were selected, including topoisomerase IIα, proliferating cell nuclear antigen, replication factor C subunit 4, checkpoint kinase 1, thymidylate synthase, minichromosome maintenance protein (MCM) 2, cell division cycle (CDC) 20, cyclin dependent kinase inhibitor 3, MCM3 and CDC6, the mRNA levels of which are upregulated in Oncomine SCLC datasets with the exception of MCM2. Furthermore, the genes in the significant module were enriched in 'cell cycle', 'DNA replication' and 'oocyte meiosis' signaling pathways. Therefore, the present study can shed new light on the understanding of molecular mechanisms of SCLC and may provide molecular targets and diagnostic biomarkers for the treatment and early diagnosis of SCLC.
This study aimed to explore the underlying mechanism of relapsed acute lymphoblastic leukemia (ALL).Datasets of GSE28460 and GSE18497 were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between diagnostic and relapsed ALL samples were identified using Limma package in R, and a Venn diagram was drawn. Next, functional enrichment analyses of co-regulated DEGs were performed. Based on the String database, protein-protein interaction network and module analyses were also conducted. Moreover, transcription factors and miRNAs targeting co-regulated DEGs were predicted using the WebGestalt online tool.A total of 71 co-regulated DEGs were identified, including 56 co-upregulated genes and 15 co-downregulated genes. Functional enrichment analyses showed that upregulated DEGs were significantly enriched in the cell cycle, and DNA replication, and repair related pathways. POLD1, MCM2, and PLK4 were hub proteins in both protein-protein interaction network and module, and might be potential targets of E2F. Additionally, POLD1 and MCM2 were found to be regulated by miR-520H via E2F1.High expression of POLD1, MCM2, and PLK4 might play positive roles in the recurrence of ALL, and could serve as potential therapeutic targets for the treatment of relapsed ALL.
Gynecological malignancies are a leading cause of mortality in the female population. The present study intended to identify the association between three severe types of gynecological cancer, specifically ovarian cancer, cervical cancer and endometrial cancer, and to identify the connective driver genes, microRNAs (miRNAs) and biological processes associated with these types of gynecological cancer. In the present study, individual driver genes for each type of cancer were identified using integrated analysis of multiple microarray data. Gene Ontology (GO) has been used widely in functional annotation and enrichment analysis. In the present study, GO enrichment analysis revealed a number of common biological processes involved in gynecological cancer, including 'cell cycle' and 'regulation of macromolecule metabolism'. Kyoto Encyclopedia of Genes and Genomes pathway analysis is a resource for understanding the high‑level functions and utilities of a biological system from molecular‑level information. In the present study, the most common pathway was 'cell cycle'. A protein‑protein interaction network was constructed to identify a hub of connective genes, including minichromosome maintenance complex component 2 (MCM2), matrix metalloproteinase 2 (MMP2), collagen type I α1 chain (COL1A1) and Jun proto‑oncogene AP‑1 transcription factor subunit (JUN). Survival analysis revealed that the expression of MCM2, MMP2, COL1A1 and JUN was associated with the prognosis of the aforementioned gynecological cancer types. By constructing an miRNA‑driver gene network, let‑7 targeted the majority of the driver genes. In conclusion, the present study demonstrated a connection model across three types of gynecological cancer, which was useful in identifying potential diagnostic markers and novel therapeutic targets, in addition to in aiding the prediction of the development of cancer as it progresses.
Colorectal cancer is a malignant tumor which harmed human beings' health. The aim of this study was to explore common biomarkers associated with colorectal carcinogenesis in paired cancer and noncancer samples. At first, fifty-nine pairs of colorectal cancer and noncancer samples from three gene expression datasets were collected and analyzed. Then, 181 upregulation and 282 downregulation common differential expression genes (DEGs) were found. Next, functional annotation was performed in the DAVID database with the DEGs. Finally, real-time polymerase chain reaction (PCR) assay was conducted to verify the analyses in sixteen colorectal cancer and individual-matched adjacent mucosa samples. Real-time PCR showed that
BACKGROUND: Tumor differentiation is an important process in the development of cancer. It is valuable to identify key differentiation related genes in the prognosis and therapy of pancreatic adenocarcinoma.
METHODS: The mRNA expression data were downloaded from the Cancer Genome Atlas database. Then, differentially expressed tumor differentiation related genes were identified. Additionally, Gene Ontology functional categories and Kyoto Encyclopedia of Genes and Genomes biochemical pathway was used to explore the function. In addition, receiver operating characteristic and survival analysis were carried out to assess the diagnosis and prognosis value. Finally, the electronic validation of selected tumor differentiation related genes was performed.
RESULTS: A total of 932 genes were identified. Among which, 8 genes including JUB, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, TCTA and SSTR1 were differentially expressed in all different tumor differentiation grades. Functional analysis revealed those genes between highly differentiated and other differentiation were remarkably enriched in pancreatic adenocarcinoma and cell cycle pathway. Finally, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, BCL2L1, E2F1 and RAC1 were associated with the survival time of pancreatic adenocarcinoma patient. Among these genes, JUB, ERLIN1, FAM110B, MCM2 and BCL2L1 also had a diagnosis value for pancreatic adenocarcinoma. Additionally, the expression trend of JUB, HMGA2 and MCM2 was increased along with the tumor differentiation grades. And the expression trend of FAM110B was decreased along with the tumor differentiation grades. The electronic validation result was consistent with the bioinformatics analysis.
CONCLUSIONS: 12 tumor differentiation related genes including JUB, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, TCTA, SSTR1, BCL2L1, E2F1, RAC1 and STAT1 played crucial roles in the differentiation of pancreatic adenocarcinoma.
Lv B, Zhang L, Miao R, et al.Comprehensive analysis and experimental verification of LINC01314 as a tumor suppressor in hepatoblastoma.
Biomed Pharmacother. 2018; 98:783-792 [PubMed
] Related Publications
Hepatoblastoma (HB), as a common pediatric liver malignancy, is composed of a variety of subgroups with different clinical outcomes. Long-noncoding RNA (lncRNA) has crucial roles in cancer biology. However, the association between lncRNA and HB has not been fully investigated. In this study, we screened lncRNA expression profiles that were annotated from the GSE75271 dataset. A total of 225 differentially expressed lncRNAs (DELs) were identified based on comparison between three prognostic subgroups, and seven of them (XR_241302, XR_923061, NR_038322, XR_951687, XR_934593, NR_120317 and XR_93406) that exhibited highly predictive accuracies were selected for functional analysis. Weighted gene correlation network analysis (WGCNA) was employed to predict the biological functions of the seven DELs. The Hippo-YAP signaling pathway was predicted to be the most statistically significant predicted pathway associated with the seven DELs. Furthermore, we performed in vitro experiments to validate the biological function of one DEL, NR_120317 (LINC01314). Our results showed decreased proliferation and migration activities of HB cells overexpressing LINC01314. Moreover, mechanistic investigations revealed that LINC01314 overexpression inhibited nuclear translocation of YAP, by inducing MST1 expression and promoting phosphorylation of LATS1 and YAP, consequently downregulating the expression of cell cycle regulatory proteins (MCM7 and cyclin D1). Taken together, our findings provide evidence for LINC01314 as a potential biomarker and anti-cancer therapeutic target in patients with HB.
BACKGROUND: Minichromosome Maintenance family (MCMs), as replication licensing factors, is involved in the pathogenesis of tumors. Here, we investigated the expression of MCMs and their values in hepatocellular carcinoma (HCC).
METHODS: MCMs were analyzed in 105 samples including normal livers (n = 15), cirrhotic livers (n = 40), HCC (n = 50) using quantitative polymerase chain reaction (qPCR) (Cohort 1). Significantly up-regulated MCMs were verified in 102 HCC and matched peritumoral livers using PCR (Cohort 2), and the correlations with clinical features and outcomes were determined. In addition, the focused MCMs were analyzed in parallel immunohistochemistry of 345 samples on spectrum of hepatocarcinogenesis (Cohort 3) and queried for the potential specific role in cell cycle.
RESULTS: MCM2-7, MCM8 and MCM10 was significantly up-regulated in HCC in Cohort 1. In Cohort 2, overexpression of MCM2-7, MCM8 and MCM10 was verified and significantly correlated with each other. Elevated MCM2, MCM6 and MCM7 were associated with adverse tumor features and poorer outcomes. In Cohort 3, MCM6 exhibited superior HCC diagnostic performance compared with MCM2 and MCM7 (AUC: 0.896 vs. 0.675 and 0.771, P < 0.01). Additionally, MCM6 other than MCM2 and MCM7 independently predicted poorer survival in 175 HCC patients. Furthermore, knockdown of MCM6 caused a delay in S/G2-phase progression as evidenced by down-regulation of CDK2, CDK4, CyclinA, CyclinB1, CyclinD1, and CyclinE in HCC cells.
CONCLUSIONS: We analyze MCMs mRNA and protein levels in tissue samples during hepatocarcinogenesis. MCM6 is identified as a driver of S/G2 cell cycle progression and a potential diagnostic and prognostic marker in HCC.
Yu Z, Wang R, Chen F, et al.Five Novel Oncogenic Signatures Could Be Utilized as AFP-Related Diagnostic Biomarkers for Hepatocellular Carcinoma Based on Next-Generation Sequencing.
Dig Dis Sci. 2018; 63(4):945-957 [PubMed
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BACKGROUND: Alpha-fetal protein (AFP) is an important conventional clinical diagnostic indicator of hepatocellular carcinoma (HCC). However, the utilization of AFP alone might yield deceptive results due to its limited sensitivity and accuracy.
AIMS: Our study was designed to investigate latent diagnostic biomarkers that could function as auxiliary clinical indicators of HCC and enhance the accuracy of joint diagnosis with AFP.
METHODS: We analyzed gene expression profiles and clinical data from HCC patients in The Cancer Genome Atlas database. Differentially expressed genes were identified, and a gene set enrichment analysis was conducted to uncover their biological functions and molecular processes. A weighted correlation network analysis and a protein-protein interaction analysis were performed to detect AFP-related biomarkers. The diagnostic performance of these biomarkers was verified using datasets from the GEO database. A diagnostic nomogram was established using the expression levels of potential biomarkers. Quantitative real-time PCR was performed using tissues from 16 HCC patients to validate the results.
RESULTS: Five AFP-related diagnostic biomarkers, CDT1, MCM7, NUDT1, CENPM, and HDAC11, were discovered. The diagnostic performance of these biomarkers and the nomogram were demonstrated to be excellent according to receiver operating characteristic curves. CDT1, MCM7, and NUDT1 were shown to be up-regulated in HCC tissues through quantitative real-time PCR.
CONCLUSIONS: We discovered five diagnostic biomarkers and established a nomogram as a complement to AFP in the diagnosis of HCC. Our results provide a more accurate diagnostic plan for HCC patients based on next-generation sequencing compared with AFP alone.
Nie Y, Lang TThe interaction between ATRIP and MCM complex is essential for ATRIP chromatin loading and its phosphorylation in mantle cell lymphoma cells.
Pharmazie. 2017; 72(11):670-673 [PubMed
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AIM: The ATR-interacting protein (ATRIP) is responsible for the recognition of DNA damage-induced structure and regulation of cellular responses to DNA damage and replication stress. The purpose of our study was to identify the underlying mechanism with respect to chromatin loading and phosphorylation of ATRIP in mantle cell lymphoma (MCL).
METHODS: JeKo cells were used in our study. Differently tagged ATRIP (Myc-, hemaglutinin (HA) or Flag) and minichromosome maintenance (MCM) complex (MCM2, MCM3, MCM5, and MCM6) were transfected into 293T cells. After 48 h, ATRIP-interacting protein was identified by mass spectrometry (MS). Cell fractionation was done to localize proteins inside the cells. Immunoprecipitation (IP) and immunoblot (IB) analysis were used to identify immunoreactive species, and Glutathione S-transferase (GST) pull-down assays were performed to detect protein-protein interaction between ATRIP and MCM complex. After silencing the expression of MCM2 and MCM6 by short hairpin RNA (shRNA), chromatin fraction were analyzed. The expression of ATRIP phosphorylation (pS224-ATRIP) was determined after application of different doses of MCM2 shRNA (0.5 μg, 1 μg, and 2.5 μg).
RESULTS: ATRIP directly interacts with MCM2, MCM3, MCM6, and MCM7 in JeKo cells. Downregulation of MCM2 and MCM6 significantly reduced ATRIP chromatin fraction. Downregulation of MCM2 statistically decreased the expression of ATRIP phosphorylation. The expression levels of pS224-ATRIP were regulated by MCM2 shRNA in a dose-dependent manner.
CONCLUSION: Our results suggest that interaction between ATRIP and MCM complex is required for ATRIP chromatin loading and ATRIP phosphorylation.
Zhong A, Zhang H, Xie S, et al.Inhibition of MUS81 improves the chemical sensitivity of olaparib by regulating MCM2 in epithelial ovarian cancer.
Oncol Rep. 2018; 39(4):1747-1756 [PubMed
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Dysfunction of the DNA repair pathway contributes to tumorigenesis and drug resistance. Methyl methanesulfonate and ultraviolet sensitive gene clone 81 (MUS81), a key endonuclease in DNA repair, is generally considered a tumor suppressor; however, recent studies have revealed its tumor-promoting effect in epithelial ovarian cancer (EOC) and have shown that its overexpression is associated with cisplatin sensitization. However, the exact functional role of MUS81 and its regulation in relation to chemotherapy sensitivity remains unknown. Our previous study using protein interaction chip revealed that minichromosome maintenance complex component 2 (MCM2) is closely correlated with MUS81. This study aimed to investigate the biological effects and mechanisms of MUS81 on cellular responses to chemotherapeutic drugs. To accomplish this, we downregulated MUS81 and MCM2 in A2780 and SKOV3 ovarian cancer cells using lentivirus-mediated RNAi. Using a qPCR-based HR assay kit to detect HR efficiency. The sensitivity of MUS81 to olaparib was investigated by cell proliferation, colony formation assays and flow cytometry. The results showed that MUS81 modulates MCM2 levels as well as homologous recombination (HR) activity. Moreover, downregulation of MUS81 increased the sensitivity of EOC cells to olaparib by inducing S phase arrest and promoting apoptosis through activation of MCM2. MUS81 may be a potential novel therapeutic target for EOC.
Shi SQ, Ke JJ, Xu QS, et al.Integrated network analysis to identify the key genes, transcription factors, and microRNAs involved in hepatocellular carcinoma.
Neoplasma. 2018; 65(1):66-74 [PubMed
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HCC (hepatocellular carcinoma), which can be induced by cirrhosis and viral hepatitis infection, is the most frequent form of liver cancer. This study is performed to investigate the mechanisms of HCC. GSE57957 was obtained from Gene Expression Omnibus database, including 39 HCC samples and 39 adjacent non-tumorous samples. The DEGs (differentially expressed genes) were screened using the limma package in R, and then were conducted with enrichment analysis using "BioCloud" platform. Using STRING database, WebGestalt tool, as well as ITFP and TRANSFAC databases, PPI (protein-protein interaction) pairs, miRNA (microRNA)-target pairs, and TF (transcription factor)-target pairs separately were predicted. Followed by integrated network was constructed by Cytoscape software and module analysis was performed using the MCODE plugin of Cytoscape software. There were 518 DEGs identified from the HCC samples, among which 17 up-regulated genes (including MCM2, MCM6, and CDC20) and 5 down-regulated genes could also function as TFs. In the integrated network for the down-regulated genes, FOS and ESR1 had higher degrees, and both of them were targeted by miR-221 and miR-222. Additionally, MCM2 had interaction with MCM6 in the up-regulated module with the highest score. MCM2, MCM6, CDC20, FOS, ESR1, miR-221 and miR-222 might affect the pathogenesis of HCC.
Shi G, Wang Y, Zhang C, et al.Identification of genes involved in the four stages of colorectal cancer: Gene expression profiling.
Mol Cell Probes. 2018; 37:39-47 [PubMed
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BACKGROUND: Colorectal cancer (CRC) is a common cancer with high morbidity and mortality. However, its molecular mechanism is not clear, nor the genes related to CRC stages.
METHODS: Gene expression data in CRC and healthy colorectal tissues were obtained from gene expression omnibus. Limma package was used to identify the differentially expressed genes (DEGs) between control and CRC (stage I, II, III, and IV), obtaining 4 DEG sets. VennPlex was utilized to find all DEGs and intersection DEGs. Functional interactions between all DEGs and protein-protein interactions (PPIs) between intersection DEGs were analyzed using ReactomeFIViz and STRING, respectively, and networks were visualized. Known CRC-related genes were down-loaded from Comparative Toxicogenomics Database and mapped to PPI network.
RESULTS: Totally, 851, 760, 729, and 878 DEGs were found between control and CRC stage I, II, III, and IV, respectively. Taken together, 1235 DEGs were found, as well as 128 up-regulated intersection DEGs, 365 down-regulated intersection DEGs, and 0 contra-regulated DEG. A functional interaction network of all DEGs and a PPI network of intersection DEGs were constructed, in which CDC20, PTTG1, and MAD2L1 interacted with BUB1B; UGT2B17 interacted with ADH1B; MCM7 interacted with MCM2. BUB1B, ADH1B, and MCM2 were known CRC-related genes. Gradually upregulated expressions of CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 in stage I, II, III, and IV CRC were confirmed by using quantitative PCR. Besides, up-regulated intersection DEGs enriched in pathways about Cell cycle, DNA replication, and p53 signaling.
CONCLUSION: CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 might be CRC stage-related genes.
Yang X, Qu K, Tao J, et al.Inhibition of CIP2A attenuates tumor progression by inducing cell cycle arrest and promoting cellular senescence in hepatocellular carcinoma.
Biochem Biophys Res Commun. 2018; 495(2):1807-1814 [PubMed
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CIP2A is a recent identified oncogene that inhibits protein phosphatase 2A (PP2A) and stabilizes c-Myc in cancer cells. To investigate the potential oncogenic role and prognostic value of CIP2A, we comprehensively analyzed the CIP2A expression levels in pan-cancer and observed high expression level of CIP2A in majority cancer types, including hepatocellular carcinoma (HCC). Based on a validation cohort including 60 HCC and 20 non-tumorous tissue samples, we further confirmed the high mRNA and protein expression levels of CIP2A in HCC, and found high CIP2A mRNA expression level was associated with unfavorable overall and recurrence-free survival in patients with HCC. Mechanistic investigations revealed that inhibition of CIP2A significantly attenuated cellular proliferation in vitro and tumourigenicity in vivo. Bioinformatic analysis suggested that CIP2A might be involved in regulating cell cycle. Our experimental data further confirmed CIP2A knockdown induced cell cycle arrest at G1 phase. We found accumulated cellular senescence in HCC cells with CIP2A knockdown, companying expression changes of senescence associated proteins (p21, CDK2, CDK4, cyclin D1, MCM7 and FoxM1). Mechanistically, CIP2A knockdown repressed FoxM1 expression and induced FoxM1 dephosphorylation. Moreover, inhibition of PP2A by phosphatase inhibitor rescued the repression of FoxM1. Taken together, our results showed that CIP2A was highly expressed in HCC. Inhibition of CIP2A induced cell cycle arrest and promoted cellular senescence via repressing FoxM1 transcriptional activity, suggesting a potential anti-cancer target for patients with HCC.
Wu DM, Shi J, Liu T, et al.Integrated analysis reveals down-regulation of SPARCL1 is correlated with cervical cancer development and progression.
Cancer Biomark. 2018; 21(2):355-365 [PubMed
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Cervical cancer is the fourth most common malignancy among women worldwide, and continued research to discover biomarkers or therapeutic targets will aid early diagnosis and treatment of this cancer. Here, we investigated novel cervical cancer biomarkers using integrated analysis of high-throughput sequencing data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. We have identified nine genes of interest that appear to be involved in cervical cancer development: SPARCL1, SYCP2, KIF4A, PRC1, TOP2A, LAMP3, KIF20A, MCM2, and APOBEC3B. Furthermore, gene ontology (GO) and co-expression analysis of these differentially expressed genes indicated that SPARCL1 may play a core role in cervical cancer development. Further, we analyzed the expression of these nine genes during the progression of cervical cancer, and found that SPARCL1 is also related to precancerous lesions and migration processes during cervical cancer pathogenesis. Finally, we validated these observations by investigating SPARCL1 expression in cervical cancer tissue and serum samples. The diagnostic specificity of serum SPARCL1 in cervical cancer occurrence was also compared with other high incidence diseases. All of these data indicate that SPARCL1 may be a novel cancer predictive marker and a potential therapeutic target for tumor development and progression in cervical cancer.
DNA replication control is vital for maintaining genome stability and the cell cycle, perhaps most notably during cell division. Malignancies often exhibit defective minichromosome maintenance protein 2 (MCM2), a cancer proliferation biomarker that serves as a licensing factor in the initiation of DNA replication. MCM2 is also known to be one of the ATPase active sites that facilitates conformational changes and drives DNA unwinding at the origin of DNA replication. However, the biological networks of MCM2 in lung cancer cells via protein phosphorylation remain unmapped. The RNA-seq datasets from The Cancer Genome Atlas (TCGA) revealed that MCM2 overexpression is correlated with poor survival rate in lung cancer patients. To uncover MCM2-regulated functional networks in lung cancer, we performed multi-dimensional proteomic approach by integrating analysis of the phosphoproteome and proteome, and identified a total of 2361 phosphorylation sites on 753 phosphoproteins, and 4672 proteins. We found that the deregulation of MCM2 is involved in lung cancer cell proliferation, the cell cycle, and migration. Furthermore, HMGA1
Li X, Ding R, Han Z, et al.Targeting of cell cycle and let-7a/STAT3 pathway by niclosamide inhibits proliferation, migration and invasion in oral squamous cell carcinoma cells.
Biomed Pharmacother. 2017; 96:434-442 [PubMed
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The low median survival rate of oral squamous cell carcinoma (OSCC) is associated with chemotherapeutic resistance. Niclosamide is an oral anti-helminthic drug, its anti-cancer effect has been reported in recent years. However, the effect of niclosamide on OSCC remains largely unknown. In this study, we, for the first time, investigated the underlying mechanisms from cell cycle arrest and let-7a/STAT3 axis through CCK-8, cell cycle, apoptosis, wound healing, Transwell invasion, generation of stable cell line, real-time PCR, and western blot assays using two OSCC cell lines WSU-HN6 and Tca83. We showed that niclosamide could inhibit OSCC cells proliferation through causing cell cycle arrest in G1 phase and promoting apoptosis, while the cell cycle-related proteins MCM2, MCM7, CDK2 and CDK4 were downregulated and the apoptosis-related proteins p53 and cleaved caspase-3 were upregulated. Furthermore, niclosamide could inhibit migration and invasion of OSCC through upregulation of let-7a expression and downregulation of p-STAT3 expression. What is more, we established the stably expressing let-7a cell line (HN6-let-7a). Like niclosamide, HN6-let-7a could decrease the ability of the cell migration, invasion as well as the expression of p-STAT3. Collectively, our study finds the new mechanisms that niclosamide inhibits OSCC proliferation through causing cell cycle arrest in G1 phase via downregulation of the above cell cycle-related genes; promotes OSCC apoptosis through upregulation of pro-apoptotic genes; decreases migration and invasion of OSCC by let-7a/STAT3 axis, thus providing a preferred therapeutic candidate for OSCC in future.
Wang Y, Wang Y, Duan X, et al.Interleukin-1 receptor-associated kinase 1 correlates with metastasis and invasion in endometrial carcinoma.
J Cell Biochem. 2018; 119(3):2545-2555 [PubMed
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Endometrial carcinoma (EC) is one of the most common malignancies in the world. Previous studies have investigated the altered expression of interleukin-1 receptor-associated kinase 1 (IRAK1) in various cancers. We aimed at exploring the biological function and the underlying molecular mechanism of IRAK1 in EC. In this study, IRAK1 was found elevated in EC compared with normal tissues. Further, high IRAK1 expression level was correlated with higher tumor stage, lymph node metastasis, myometrial invasion, and lower survival rate. Knockdown of IRAK1 in two EC cell lines, HEC-1-B and JEC, significantly inhibited cell proliferation in vitro and in vivo. We also found that down-regulation of IRAK1 in EC cells notably induced cell cycle arrest and apoptois, and also inhibited cell migration and invasion. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that Kyoto Encyclopedia of Genes and Genomes (KEGG) mitotic cell cycle and cell division pathways were correlative with the IRAK1 expression, which was further confirmed in EC cells by Western blot. The expression of mitotic cell cycle (CDK1 and Cdc45) and cell division pathway (Cdc7 and MCM2) related factors was significantly suppressed by IRAK1 knockdown. These collective data indicated that IRAK1 overexpression promotes EC tumorigenesis by activating mitotic cell cycle and cell division pathways, and IRAK1 may serve as a promising therapeutic strategy for EC.