Research IndicatorsGraph generated 01 September 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: THBS2 (cancer-related)
BACKGROUND: Glioma, characterized by its undesirable prognosis and poor survival rate, is a serious threat to human health and lives. MicroRNA-9 (miR-9) is implicated in the regulation of multiple tumors, while the mechanisms underlying its aberrant expression and functional alterations in human glioma are still controversial.
METHODS: Expressions of miR-9 were measured in GEO database, patient specimens and glioma cell lines. Gain- and loss-of-function assays were applied to identify the effects of miR-9 on glioma cells and HUVECs in vitro and in vivo. Potential targets of miR-9 were predicted by bioinformatics and further verified via in vitro experiments. Transcriptional regulation of miR-9 by MYC and OCT4 was determined in glioma cells.
RESULTS: MiR-9 was frequently up-regulated in glioma specimens and cells, and could significantly enhance proliferation, migration and invasion of glioma cells. In addition, miR-9 could be secreted from glioma cells via exosomes and was then absorbed by vascular endothelial cells, leading to an increase in angiogenesis. COL18A1, THBS2, PTCH1 and PHD3 were verified as the direct targets of miR-9, which could elucidate the miR-9-induced malignant phenotypes in glioma cells. MYC and OCT4 were able to bind to the promoter region of miR-9 to trigger its transcription.
CONCLUSIONS: Our results highlight that miR-9 is pivotal for glioma pathogenesis and can be treated as a potential therapeutic target for glioma.
Background: Bladder cancer was a malignant disease in patients, our research aimed at discovering the possible biomarkers for the diseases.
Results: The gene chip GSE31684, including 93samples, was downloaded from the GEO datasets and co-expression network was constructed by the data. Molecular complex detection(MCODE) was used to identify hub genes. The most significant cluster including 16 genes:
Shi S, Tian BIdentification of biomarkers associated with progression and prognosis in bladder cancer via co-expression analysis.
Cancer Biomark. 2019; 24(2):183-193 [PubMed
] Related Publications
BACKGROUND: Bladder cancer is one of the most common genitourinary malignancies, with a high rate of recurrence and progression. The prognosis for patients with bladder cancer, especially muscle-invasive bladder cancer, remains poor despite systemic therapy.
OBJECTIVE: To explore the underlying disease mechanisms and identify more effective biomarkers for bladder cancer.
METHODS: Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis were applied to identify hub genes correlated with the bladder cancer progression. Survival analyses were then conducted to identify potential biomarkers correlated with the prognosis of bladder cancer. Finally, validation and analysis of these potential biomarkers were conducted by a series of bioinformatics analyses.
RESULTS: Based on the results of weighted gene co-expression network analysis and protein-protein interaction network analysis, ten hub genes closely correlated with bladder cancer progression were identified in the relevant module. Survival analyses of these genes indicated that elevated expressions of six potential biomarkers (COL3A1, FN1, COL5A1, FBN1, COL6A1 and THBS2) were significantly associated with a worse overall survival. Furthermore, these 6 potential biomarkers were validated in association with the progression of bladder cancer. Bladder cancer samples with higher expression of these genes were most significantly enriched in gene set associated with ECM-receptor interaction.
CONCLUSIONS: This study identified several biomarkers associated with bladder cancer progression and prognosis. As novel findings, these may have important clinical implications for diagnosis, treatment and prognosis prediction.
Xie B, Zhao Z, Liu Q, et al.CircRNA has_circ_0078710 acts as the sponge of microRNA-31 involved in hepatocellular carcinoma progression.
Gene. 2019; 683:253-261 [PubMed
] Related Publications
Circular RNAs (circRNAs) as new types of endogenous non-coding RNAs have been recently identified important roles in certain types of pathological responses, and in the occurrence and progression of a variety of human malignancies. In the present study, we aimed to evaluate the role of has_circ_0078710, which is back spliced by THBS2 gene in hepatocellular carcinoma (HCC). Expression levels of has_circ_0078710 were tested in both HCC tissue samples and cells using real-time qRT-PCR. Has_circ_0078710 was significantly unregulated in HCC tissues and cells. Moreover, HCC patients with high level of has_circ_0078710 had the advance stage (TNM III-IV). Finally, we constructed an interaction network among circRNA-miRNA-mRNA and we identified miR-31 as the has_circ_0078710-associatedmiRNA. Furthermore, overexpression of has_circ_0078710 in HCC could up-regulate HDAC and CDK2 levels by sponging miR-31, simultaneously mediating the expression of cell cycle components (cyclin A, cyclin D1, CDK4) and negative cell cycle regulator p21. In vitro and in vivo functional studies showed that overexpression of has_circ_0078710 in HepG2, SMMC-7721 cell lines significantly promoted cell proliferation, migration, invasion and tumor growth by inducing the cell cycle progression. In summary, we identified Has_circ_0078710 as a potential HCC biomarker.
Schultz S, Bartsch H, Sotlar K, et al.Progression-specific genes identified in microdissected formalin-fixed and paraffin-embedded tissue containing matched ductal carcinoma in situ and invasive ductal breast cancers.
BMC Med Genomics. 2018; 11(1):80 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The transition from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) is an important step during breast carcinogenesis. Understanding its molecular changes may help to identify high-risk DCIS that progress to IBC. Here, we describe a transcriptomic profiling analysis of matched formalin-fixed and paraffin-embedded (FFPE) DCIS and IBC components of individual breast tumours, containing both tumour compartments. The study was performed to validate progression-associated transcripts detected in an earlier gene profiling project using fresh frozen breast cancer tissue. In addition, FFPE tissues from patients with pure DCIS (pDCIS) were analysed to identify candidate transcripts characterizing DCIS with a high or low risk of progressing to IBC.
METHODS: Fifteen laser microdissected pairs of DCIS and IBC were profiled by Illumina DASL technology and used for expression validation by qPCR. Differential expression was independently validated using further 25 laser microdissected DCIS/IBC sample pairs. Additionally, laser microdissected epithelial cells from 31 pDCIS were investigated for expression of candidate transcripts using qPCR.
RESULTS: Multiple statistical calculation methods revealed 1784 mRNAs which are differentially expressed between DCIS and IBC (P < 0.05), of which 124 have also been identified in the gene profiling project using fresh frozen breast cancer tissue. Nine mRNAs that had been selected from the gene list obtained using fresh frozen tissues by applying pathway and network analysis (MMP11, GREM1, PLEKHC1, SULF1, THBS2, CSPG2, COL10A1, COL11A1, KRT14) were investigated in tissues from the same 15 microdissected specimens and the 25 independent tissue samples by qPCR. All selected transcripts were also detected in tumour cells from pDCIS. Expression of MMP11 and COL10A1 increased significantly from pDCIS to DCIS of DCIS/IBC mixed tumours.
CONCLUSION: We confirm differential expression of progression-associated transcripts in FFPE breast cancer samples which might mediate the transition from DCIS to IBC. MMP11 and COL10A1 may characterize pure DCIS with a high risk developing IDC.
BACKGROUND: Gastric cancer (GC) is a prevalent malignant cancer of digestive system. To identify key genes in GC, mRNA microarray GSE27342, GSE29272, and GSE33335 were downloaded from GEO database.
METHODS: Differentially expressed genes (DEGs) were obtained using GEO2R. DAVID database was used to analyze function and pathways enrichment of DEGs. Protein-protein interaction (PPI) network was established by STRING and visualized by Cytoscape software. Then, the influence of hub genes on overall survival (OS) was performed by the Kaplan-Meier plotter online tool. Module analysis of the PPI network was performed using MCODE. Additionally, potential stem loop miRNAs of hub genes were predicted by miRecords and screened by TCGA dataset. Transcription factors (TFs) of hub genes were detected by NetworkAnalyst.
RESULTS: In total, 67 DEGs were identified; upregulated DEGs were mainly enriched in biological process (BP) related to angiogenesis and extracellular matrix organization and the downregulated DEGs were mainly enriched in BP related to ion transport and response to bacterium. KEGG pathways analysis showed that the upregulated DEGs were enriched in ECM-receptor interaction and the downregulated DEGs were enriched in gastric acid secretion. A PPI network of DEGs was constructed, consisting of 43 nodes and 87 edges. Twelve genes were considered as hub genes owing to high degrees in the network. Hsa-miR-29c, hsa-miR-30c, hsa-miR-335, hsa-miR-33b, and hsa-miR-101 might play a crucial role in hub genes regulation. In addition, the transcription factors-hub genes pairs were displayed with 182 edges and 102 nodes. The high expression of 7 out of 12 hub genes was associated with worse OS, including COL4A1, VCAN, THBS2, TIMP1, COL1A2, SERPINH1, and COL6A3.
CONCLUSIONS: The miRNA and TFs regulation network of hub genes in GC may promote understanding of the molecular mechanisms underlying the development of gastric cancer and provide potential targets for GC diagnosis and treatment.
Thrombospondin-2 (TSP2) is an anti-angiogenic matricellular protein that inhibits tumor growth and angiogenesis. Tumor-associated blood vascular endothelial cells (BECs) were isolated from human invasive bladder cancers and from matched normal bladder tissue by immuno-laser capture microdissection. Exon expression profiling analyses revealed a particularly high expression of a short TSP2 transcript containing only the last 9 (3') exons of the full-length TSP2 transcript. Using 5' and 3' RACE (rapid amplification of cDNA ends) and Sanger sequencing, we confirmed the existence of the shorter transcript of TSP2 (sTSP2) and determined its sequence which completely lacked the anti-angiogenic thrombospondin type 1 repeats domain. The largest open reading frame predicted within the transcript comprises 209 amino acids and matches almost completely the C-terminal lectin domain of full-length TSP2. We produced recombinant sTSP2 and found that unlike the full-length TSP2, sTSP2 did not inhibit vascular endothelial growth factor-A-induced proliferation of cultured human BECs, but in contrast when combined with TSP2 blocked the inhibitory effects of TSP2 on BEC proliferation. In vivo studies with stably transfected A431 squamous cell carcinoma cells revealed that full-length TSP2, but not sTSP2, inhibited tumor growth and angiogenesis. This study reveals that the transcriptional program of tumor stromal cells can change to transcribe a new version of an endogenous angiogenesis inhibitor that has lost its anti-angiogenic activity.
Fei HJ, Chen SC, Zhang JY, et al.Identification of significant biomarkers and pathways associated with gastric carcinogenesis by whole genome-wide expression profiling analysis.
Int J Oncol. 2018; 52(3):955-966 [PubMed
] Related Publications
The incidence of gastric cancer (GC) is extremely high in East Asia. GC is also one of the most common and lethal forms of cancer from a global perspective. However, to date, we have not been able to determine one or several genes as biomarkers in the diagnosis of GC and have also been unable to identify the genes which are important in the therapy of GC. In this study, we analyzed all genome-wide expression profiling arrays uploaded onto the Gene Expression Omnibus (GEO) database to filtrate the differentially expressed genes (DEGs) between normal stomach tissues and GC tissues. GSE13911, GSE19826 and GSE79973 were based on the GPL570 platform, and GSE29272 was based on the GPL96 platform. We screened out the DEGs from the two platforms and by selecting the intersection of these two platforms, we identified the common DEGs in the sequencing data from different laboratories. Finally, we obtained 3 upregulated and 34 downregulated DEGs in GC from 384 samples. As the number of downregulated DEGs was greater than that of the upregulated DEGs, functional analysis and pathway enrichment analysis were performed on the downregulated DEGs. Through our analysis, we identified the most significant genes associated with GC, such as secreted phosphoprotein 1 (SPP1), sulfatase 1 (SULF1), thrombospondin 2 (THBS2), ATPase H+/K+ transporting beta subunit (ATP4B), gastric intrinsic factor (GIF) and gastrokine 1 (GKN1). The prognostic power of these genes was corroborated in the Oncomine database and by Kaplan-Meier plotter (KM-plotter) analysis. Moreover, gastric acid secretion, collecting duct acid secretion, nitrogen metabolism and drug metabolism were significantly related to GC. Thus, these genes and pathways may be potential targets for improving the diagnosis and clinical effects in patients with GC.
MicroRNAs have implicated in the relapse and metastasis of cervical cancer, which is the leading cause of cervical cancer-related mortality. However, the underlying molecular mechanisms need further elucidation. Our present study revealed that miR-221-3p is transcriptionally promoted in metastatic cervical cancer tissues compared with non-metastatic cervical cancer tissues. Forced overexpression of miR-221-3p facilitated EMT and promoted cell migration and invasion in vitro and lymphatic metastasis in vivo. Twist homolog 2 (TWIST2) was found to be a key transcription factor binding to the promoter of miR-221-3p. Inhibitors of miR-221-3p drastically reduced the induction of EMT and decreased cell migration and invasion mediated by TWIST2. By combined computational and experimental approaches, THBS2 was recognized to be an important downstream target gene of miR-221-3p. In cervical cancer tissues, especially with lymphatic metastasis, miR-221-3p and TWIST2 were increased and THBS2 was decreased, suggesting that TWIST2 induces miR-221-3p expression and consequently suppresses its direct target THBS2 in lymphatic metastasis CC. Our findings uncover a mechanistic role for miR-221-3p in lymph node metastasis, suggesting that miR-221-3p is upregulated by the transcription factor TWIST2 and downregulates its target THBS2, which may potentially promote lymph node metastasis in cervical cancer.
Icay K, Liu C, Hautaniemi SDynamic visualization of multi-level molecular data: The Director package in R.
Comput Methods Programs Biomed. 2018; 153:129-136 [PubMed
] Related Publications
BACKGROUND AND OBJECTIVE: High-throughput measurement technologies have triggered a rise in large-scale cancer studies containing multiple levels of molecular data. While there are a number of efficient methods to analyze individual data types, there are far less that enhance data interpretation after analysis. We present the R package Director, a dynamic visualization approach to linking and interrogating multiple levels of molecular data after analysis for clinically meaningful, actionable insights.
METHODS: Sankey diagrams are traditionally used to represent quantitative flows through multiple, distinct events. Regulation can be interpreted as a flow of biological information through a series of molecular interactions. Functions in Director introduce novel drawing capabilities to make Sankey diagrams robust to a wide range of quantitative measures and to depict molecular interactions as regulatory cascades. The package streamlines creation of diagrams using as input quantitative measurements identifying nodes as molecules of interest and paths as the interaction strength between two molecules.
RESULTS: Director's utility is demonstrated with quantitative measurements of candidate microRNA-gene networks identified in an ovarian cancer dataset. A recent study reported eight miRNAs as master regulators of signature genes in epithelial-mesenchymal transition (EMT). The Sankey diagrams generated with data from this study furthers interpretation of the miRNAs' roles by revealing potential co-regulatory behavior in the extracellular matrix (ECM). An additional analysis identified 32 genes differentially expressed between good and poor prognosis patients in four significant pathways (FDR ≤ 0.1), three of which support a complementary role of the ECM in ovarian cancer. The resulting diagram created with Director suggest elevated levels of COL11A1, INHBA, and THBS2 - a signature feature of metastasis  - and decreased levels of their targeting miRNAs define poor prognosis.
CONCLUSION: We have demonstrated a visualization approach suitable for implementation in an analysis workflow, linking multiple levels of molecular data to gain novel perspective on candidate biomarkers in a complex disease. The diagrams are dynamic, easily replicable, and rendered locally as HTML files to facilitate sharing. The R package Director is simple to use and widely available on all operating systems through Bioconductor (http://bioconductor.org/packages/Director) and GitHub (http://kzouchka.github.io/Director).
Ao R, Guan L, Wang Y, Wang JNSilencing of COL1A2, COL6A3, and THBS2 inhibits gastric cancer cell proliferation, migration, and invasion while promoting apoptosis through the PI3k-Akt signaling pathway.
J Cell Biochem. 2018; 119(6):4420-4434 [PubMed
] Related Publications
This study explores the effect of COL1A2, COL6A3, and THBS2 gene silencing on proliferation, migration, invasion, and apoptosis of gastric cancer cells through the PI3K-Akt signaling pathway. The gastric cancer microarray expression data (GSE19826, GSE79973, and GSE65801) was analyzed. Gastric cancer tissues and corresponding adjacent normal tissues were extracted from patients. Positive expression rate of PI3K, Akt, and p-Akt was measured with immunohistochemistry. Two cell lines, BGC-823 and SGC-7901, were transfected and cells were grouped into blank, negative control, COL1A2-shRNA, COL6A3-shRNA, and THBS2-shRNA groups. Expressions of COL1A2, COL6A3, and THBS2 in gastric cancer cells transfected with corresponding silencing sequences were evaluated by RT-qPCR and Western blot. MTT assay, Transwell, and cell scratch tests were conducted to evaluate cell proliferation, invasion, and migration capacity, respectively. Flow cytometry was used to evaluate cell cycle distribution and apoptosis. The positive expression of PI3K, Akt, and p-Akt was higher in gastric cancer tissues compared with adjacent normal tissues, and the mRNA expression of COL1A2, COL6A3, and THBS2 was increased in gastric cancer tissues. Akt, p-Akt, and PI3K expression drastically decreased in cells transfected with COL1A2, COL6A3, and THBS2 silencing sequences. Cells transfected with COL1A2, COL6A3, and THBS2 silencing sequences exhibited promoted apoptosis but inhibited proliferation, migration, and invasion. This study demonstrates that COL1A2, COL6A3, and THBS2 gene silencing inhibits gastric cancer cell proliferation, migration, and invasion while promoting apoptosis through the PI3K-Akt signaling pathway.
Bogusławska J, Rodzik K, Popławski P, et al.TGF-β1 targets a microRNA network that regulates cellular adhesion and migration in renal cancer.
Cancer Lett. 2018; 412:155-169 [PubMed
] Related Publications
In our previous study we found altered expression of 19 adhesion-related genes in renal tumors. In this study we hypothesized that disturbed expression of adhesion-related genes could be caused by microRNAs: short, non-coding RNAs that regulate gene expression. Here, we found that expression of 24 microRNAs predicted to target adhesion-related genes was disturbed in renal tumors and correlated with expression of their predicted targets. miR-25-3p, miR-30a-5p, miR-328 and miR-363-3p directly targeted adhesion-related genes, including COL5A1, COL11A1, ITGA5, MMP16 and THBS2. miR-363-3p and miR-328 inhibited proliferation of renal cancer cells, while miR-25-3p inhibited adhesion, promoted proliferation and migration of renal cancer cells. TGF-β1 influenced the expression of miR-25-3p, miR-30a-5p, and miR-328. The analyzed microRNAs, their target genes and TGF-β1 formed a network of strong correlations in tissue samples from renal cancer patients. The expression signature of microRNAs linked with TGF-β1 levels correlated with poor survival of renal cancer patients. The results of our study suggest that TGF-β1 coordinates the expression of microRNA network that regulates cellular adhesion in cancer.
The PI3K/AKT-signaling pathway is one of the most frequently activated signal-transduction pathways in cancer. We examined how dysregulated gene expression is associated with miRNA expression in this pathway in colorectal cancer (CRC). We used data from 217 CRC cases to evaluate differential pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most associated with CRC (fold change (FC) of >1.5 or <0.67) that were statistically significant after adjustment for multiple comparisons. Of the 304 genes evaluated, 76 had a FC of <0.67, and 57 had a FC of >1.50; 47 of these genes were associated with miRNA differential expression. There were 145 mRNA:miRNA seed-region matches of which 26 were inversely associated suggesting a greater likelihood of a direct association. Most miRNA:mRNA associations were with factors that stimulated the pathway. For instance, both IL6R and PDGFRA had inverse seed-region matches with seven miRNAs, suggesting that these miRNAs have a direct effect on these genes and may be key elements in activation of the pathway. Other miRNA:mRNA associations with similar impact on the pathway were miR-203a with ITGA4, miR-6071 with ITGAV, and miR-375 with THBS2, all genes involved in extracellular matrix function that activate PI3Ks. Gene expression in the PI3K/Akt-signaling pathway is dysregulated in CRC. MiRNAs were associated with many of these dysregulated genes either directly or in an indirect manner.
Li J, Yu H, Ma YF, et al.Identification of genes associated with lung cancer by bioinformatics analysis.
Eur Rev Med Pharmacol Sci. 2017; 21(10):2397-2404 [PubMed
] Related Publications
OBJECTIVE: This study was aimed to explore the underlying genes associated with lung cancer (LC) by bioinformatics analysis.
DATA AND METHODS: Gene expression profile GSE2514 was downloaded from the Gene Expression Omnibus database. Twenty lung and nineteen para-carcinoma tissue samples were used to identify the differentially expressed genes (DEGs) by paired t-test. Pathway enrichment analysis of DEGs was performed, followed by the construction of protein-protein interaction (PPI) network. Functional enrichment analysis of the module identified from PPI network was performed, and the enriched term with the highest enrichment scores was selected for pathway enrichment analysis.
RESULTS: Total 257 DEGs including 179 up-regulated DEGs such as monoamine oxidase A (MAOA) and intercellular adhesion molecule 2 (ICAM2), and 78 down-regulated DEGs such as thrombospondin-2 (THBS2) were identified. Up-regulated DEGs were enriched in 7 pathways, such as drug metabolism, tyrosine metabolism and cell adhesion molecules (CAMs). Down-regulated DEGs were enriched in extracellular cell matrix receptor interaction and focal adhesion pathways. In the PPI network, interleukin-6 (IL6) had the highest connectivity degree of 39. Module 1 with the highest functional enrichment scores of 5.457 containing 13 hub genes such as KIAA0101.
CONCLUSIONS: DEGs of LC were mainly enriched in the pathways related to metabolism and cell adhesion. The DEGs such as MAOA, ICAM2, IL6, THBS2 and KIAA0101 may be the potential targets for LC diagnosis and treatment.
Pekow J, Hutchison AL, Meckel K, et al.miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling.
Inflamm Bowel Dis. 2017; 23(8):1328-1337 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: As mechanisms of neoplasia in patients with ulcerative colitis (UC) remain poorly understood, we sought to identify pathways of carcinogenesis in this high-risk population.
METHODS: MicroRNA (miRNA) and mRNA expression was examined in nondysplastic rectosigmoid mucosa from UC patients with (n = 19) or without remote colon neoplasia (n = 23). We developed a method to identify miRNA-regulated pathways based on differentially expressed miRNAs and their putative mRNAs targets in the same samples. One key pathway identified in the analysis, miR-4728-3p regulation of focal adhesion signaling was further evaluated in vitro and through examination of expression in UC-cancers.
RESULTS: There were 101 significantly up-regulated and 98 down-regulated miRNAs (adjusted P < 0.05) in the rectal mucosa of UC patients harboring proximal neoplasia. Bioinformatic analysis identified miR-4728-3p as a regulator of 3 proteins involved in focal adhesion signaling, CAV1, THBS2, and COL1A2. Real-time PCR validated down-regulation of miR-4728-3p in nondysplastic tissue remote from UC-neoplasia and in UC-associated colon cancers. miR-4728-3p transfection into colon cancer cells down-regulated expression levels and decreased luciferase activities in cells expressing a wild type 3' untranslated region compared with a mutant 3' untranslated region for all 3 genes. Exogenous transfected miR-4728-3p also delayed wound healing and decreased formation of focal adhesion complexes.
CONCLUSIONS: Patients with long-standing UC who harbor neoplasia can be identified based on miRNA and mRNA profiles in nondysplastic tissue. Using a method to analyze miRNA and mRNA expression from the same tissues, we identified that miR-4728-3p is likely an important tumor suppressor in UC-associated colon carcinogenesis.
Colorectal cancer (CRC) is one of the most common malignances in the gut. Liver is the most common metastasis site of CRC. This study focuses on the primary CRC and its liver metastasis, aiming to discover several liver metastasis related genes and provide therapeutic candidates. We compared gene expression patterns among the groups of normal colorectal mucosa, primary tumor and the liver metastasis using a CRC gene expression dataset. 84 genes were found to be upregulated in both primary tumor and liver metastases. Function enrichment analysis indicated that these genes are enriched in pathways such as chemotaxis, coagulation and lipid metabolism which are crucial in multi-step cancer metastasis. Gene network analysis identified several important hub genes that may be involved in carcinogenesis and liver metastasis. Then we used a validation dataset containing 562 CRC samples with detailed clinical information, to screen prognostic biomarkers for overall survival (OS) and relapse free survival (RFS). Finally, overexpression of THBS2 (thrombospondin 2), INHBB (inhibin, beta B) and BGN (biglycan) were proved to be correlated with poor OS and RFS. In conclusion, this study indicated that chemotaxis, coagulation and lipid metabolism might play critical roles in the processes of carcinogenesis and liver metastasis. THBS2, INHBB and BGN are prognostic markers and potential therapeutic targets for CRC.
Procházková I, Lenčo J, Fučíková A, et al.Targeted proteomics driven verification of biomarker candidates associated with breast cancer aggressiveness.
Biochim Biophys Acta Proteins Proteom. 2017; 1865(5):488-498 [PubMed
] Related Publications
Breast cancer is the most common and molecularly relatively well characterized malignant disease in women, however, its progression to metastatic cancer remains lethal for 78% of patients 5years after diagnosis. Novel markers could identify the high risk patients and their verification using quantitative methods is essential to overcome genetic, inter-tumor and intra-tumor variability and translate novel findings into cancer diagnosis and treatment. We recently identified 13 proteins associated with estrogen receptor, tumor grade and lymph node status, the key factors of breast cancer aggressiveness, using untargeted proteomics. Here we verified these findings in the same set of 96 tumors using targeted proteomics based on selected reaction monitoring with mTRAQ labeling (mTRAQ-SRM), transcriptomics and immunohistochemistry and validated in 5 independent sets of 715 patients using transcriptomics. We confirmed: (i) positive association of anterior gradient protein 2 homolog (AGR2) and periostin (POSTN) and negative association of annexin A1 (ANXA1) with estrogen receptor status; (ii) positive association of stathmin (STMN1), cofilin-1 (COF1), plasminogen activator inhibitor 1 RNA-binding protein (PAIRBP1) and negative associations of thrombospondin-2 (TSP2) and POSTN levels with tumor grade; and (iii) positive association of POSTN, alpha-actinin-4 (ACTN4) and STMN1 with lymph node status. This study highlights a panel of gene products that can contribute to breast cancer aggressiveness and metastasis, the understanding of which is important for development of more precise breast cancer treatment.
Zhuo C, Li X, Zhuang H, et al.Elevated THBS2, COL1A2, and SPP1 Expression Levels as Predictors of Gastric Cancer Prognosis.
Cell Physiol Biochem. 2016; 40(6):1316-1324 [PubMed
] Related Publications
BACKGROUND/AIMS: Gastric cancer (GC) is an important health problem. Classification based on molecular subtypes may help to determine the prognosis of patients with GC. Tumor invasion and metastasis are important factors affecting the prognosis of cancer. We aimed to identify genes related to tumor invasion and metastasis, which may serve as indicators of good GC prognosis.
METHODS: Tumor tissues and adjacent normal tissues were collected from 105 patients with primary GC who were treated by undergoing radical surgery. Samples were used for tissue microarray analysis. Identified genes with altered expression were further analyzed using the Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The expression levels of THBS2, COL1A2 and SPP1 were analyzed by RT-PCR, western blot and immunohistochemistry. The overall survival curves of patients with high and low expression of each gene of interest were plotted and compared.
RESULTS: Forty-three genes were identified. THBS2, COL1A2 and SPP1 were selected for further analysis. Altered expression levels of THBS2, COL1A2 and SPP1 in tumor tissues were confirmed. Patients with low THBS2 expression had a better prognosis; the expression of COL1A2 and SPP1 might not affect the prognosis of patients with GC.
CONCLUSION: THBS2, but not COL1A2 and SPP1, may serve as an indicator of GC prognosis.
Yan L, Zhan C, Wang S, et al.Genetic analysis of radiation-specific biomarkers in sinonasal squamous cell carcinomas.
Tumour Biol. 2016; 37(9):12001-12009 [PubMed
] Related Publications
The aim of this study was to investigate the differences in the gene expression profiles of radiation-sensitive (RS) and radiation-resistant (RR) sinonasal squamous cell carcinoma (SNSCC) and to identify prognostic markers for the radiation reaction of SNSCC. We first examined the differentially expressed genes (DEGs) in RS and RR SNSCC tissues by analyzing clinical samples with GeneChip Human Transcriptome Array 2.0 (HTA 2.0).To understand the functional significance of the molecular changes, we examined the DEGs with Gene Ontology (GO) and pathway analyses to identify the core genes. The expression of several core genes (CCND2, COL5A2, GADD45B, and THBS2) was confirmed with reverse transcription quantitative PCR (RT-qPCR) in a larger series of tissues. We identified 208 DEGs, of which 76 were upregulated and 132 downregulated in the RS tissues relative to the RR tissues. The DEGs were mainly involved in the regulation of cell proliferation, the NF-kappaB signaling pathway, the cell adhesion molecule signaling pathway, and the extracellular matrix-receptor interaction signaling pathway. RT-qPCR confirmed that the CCND2, COL5A2, GADD45B, and THBS2 genes were significantly differentially expressed in the RS and RR tissues, consistent with the GeneChip data. These results extend our understanding of the molecular mechanisms underlying the sensitivity of SNSCC to radiation. The DEGs are involved in the differential response to radiation therapy and the dysregulated core genes identified in this study can be used to predict radiation sensitivity in SNSCC.
BACKGROUND: Glioma is one of the most common primary malignancies in the brain or spine. The transcription factor (TF) CCAAT/enhancer binding protein beta (CEBPB) is important for maintaining the tumor initiating capacity and invasion ability. To investigate the regulation mechanism of CEBPB in glioma, microarray data GSE47352 was analyzed.
METHODS: GSE47352 was downloaded from Gene Expression Omnibus, including three samples of SNB19 human glioma cells transduced with non-target control small hairpin RNA (shRNA) lentiviral vectors for 72 h (normal glioma cells) and three samples of SNB19 human glioma cells transduced with CEBPB shRNA lentiviral vectors for 72 h (CEBPB-silenced glioma cells). The differentially expressed genes (DEGs) were screened using limma package and then annotated. Afterwards, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) software was applied to perform enrichment analysis for the DEGs. Furthermore, the protein-protein interaction (PPI) network and transcriptional regulatory network were constructed using Cytoscape software.
RESULTS: Total 529 DEGs were identified in the normal glioma cells compared with the CEBPB-silenced glioma cells, including 336 up-regulated and 193 down-regulated genes. The significantly enriched pathways included chemokine signaling pathway (which involved CCL2), focal adhesion (which involved THBS1 and THBS2), TGF-beta signaling pathway (which involved THBS1, THBS2, SMAD5, and SMAD6) and chronic myeloid leukemia (which involved TGFBR2 and CCND1). In the PPI network, CCND1 (degree = 29) and CCL2 (degree = 12) were hub nodes. Additionally, CEBPB and TCF12 might function in glioma through targeting others (CEBPB → TCF12, CEBPB → TGFBR2, and TCF12 → TGFBR2).
CONCLUSIONS: CEBPB might act in glioma by regulating CCL2, CCND1, THBS1, THBS2, SMAD5, SMAD6, TGFBR2, and TCF12.
Colorectal cancer is one of the most common leading causes of death worldwide. Prognostic at an early stage is a useful way that decrease and avoid mortality. Although remarkable progress has been made to investigate the underlying mechanism, the understanding of the complicated carcinogenesis process was enormously hindered by large-scale tumor heterogeneity. Here we proposed that the prognosis-related gene THBS2, responsible for cooperativity disorientation, probably contain untapped prognostic resource of colorectal cancer. We originally established Spearman correlation transition, Kaplan-Meier survival analysis and meta-analysis that combine public dataset and clinical samples to quantify the prognostic value of THBS2. THBS2 could be considered as a novel prognostic marker in colorectal cancer.
Thrombospondin 1 and thrombospondin 2 (THBS1 and THBS2) share similar multifunctional domains, and are known to be antiangiogenic. However, the expression pattern of THBS1 and THBS2 is different, and the specific role of THBS2 in different subtypes of lung cancer remains largely unclear. To evaluate the significance of THBS1 and THBS2 in the development of lung cancer, the present study performed a microarray-based systematic-analysis to determine the transcript levels of thrombospondins and their relation to the prognosis in lung cancer. THBS1 was in general underexpressed in lung cancer; in contrast, mRNA levels of THBS2 were markedly overexpressed in a number of datasets of non-small cell lung carcinoma (NSCLC), including lung adenocarcinoma (AC) and squamous cell carcinoma. Similar expression pattern of THBS1 and THBS2 was verified in pulmonary AC cell lines with real-time PCR analysis. The survival of lung AC patients with high THBS2 mRNA expression levels was poorer than patients with low levels of expression of THBS2. In a microarray-based analysis, genes coexpressed with THBS1 or THBS2 were determined. Pulmonary AC patients with a high expression level of sevenTSHB1-coexpressed genes (CCL5, CDH11, FYB, GZMK, LA-DQA1, PDE4DIP, and SELL) had better survival rates than those with a low expression level. Patients with a high expression of seven TSHB2-coexpressed genes (CHI3L1, COL5A2, COL11A1, FAP, MXRA5, THY1, and VCAN) had poor survival rates. Downregulation of VCAN and THBS2 with shRNA inhibited the cell proliferation in the A549 cell line. In summary, THBS1 functions as a tumor suppressor in lung adenocarcinoma. However, THBS2 may play a double-edged role in the progression of lung AC, i.e. anti-angiogenic and oncogenic function. Further study on the mechanism underlying the activity of THBS2 is warranted to have further implications for cancer diagnosis and treatment of pulmonary AC.
Myxoid/round cell (RC) liposarcomas (MLS) were originally classified into two distinct populations based on histological differences; a myxoid component and a RC component. It is notable that, depending on an increase of the RC component, the prognosis significantly differs. Hence, the RC component is associated with metastasis and poor prognosis. However, the molecular mechanisms that contribute to the malignancy of the RC component still remain largely unknown. Here, we report microRNA-135b (miR-135b), a key regulator of the malignancy, highly expressed in the RC component and promoting MLS cell invasion in vitro and metastasis in vivo through the direct suppression of thrombospondin 2 (THBS2). Decreased THBS2 expression by miR-135b increases the total amount of matrix metalloproteinase 2 (MMP2) and influences cellular density and an extracellular matrix structure, thereby resulting in morphological change in tumor. The expression levels of miR-135b and THBS2 significantly correlated with a poor prognosis in MLS patients. Overall, our study reveals that the miR-135b/THBS2/MMP2 axis is tightly related to MLS pathophysiology and has an important clinical implication. This work provides noteworthy evidence for overcoming metastasis and improving patient outcomes, and sheds light on miR-135b and THBS2 as novel molecular targets for diagnosis and therapy in MLS.
Dvorkina M, Nieddu V, Chakelam S, et al.A Promyelocytic Leukemia Protein-Thrombospondin-2 Axis and the Risk of Relapse in Neuroblastoma.
Clin Cancer Res. 2016; 22(13):3398-409 [PubMed
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PURPOSE: Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system with a complex biology, prone to metastasize and relapse. High-risk, metastatic cases are explained in part by amplification or mutation of oncogenes, such as MYCN and ALK, and loss of tumor suppressor genes in chromosome band 1p. However, it is fundamental to identify other pathways responsible for the large portion of neuroblastomas with no obvious molecular alterations.
EXPERIMENTAL DESIGN: Neuroblastoma cell lines were used for the assessment of tumor growth in vivo and in vitro Protein expression in tissues and cells was assessed using immunofluorescence and IHC. The association of promyelocytic leukemia (PML) expression with neuroblastoma outcome and relapse was calculated using log-rank and Mann-Whitney tests, respectively. Gene expression was assessed using chip microarrays.
RESULTS: PML is detected in the developing and adult sympathetic nervous system, whereas it is not expressed or is low in metastatic neuroblastoma tumors. Reduced PML expression in patients with low-risk cancers, that is, localized and negative for the MYCN proto-oncogene, is strongly associated with tumor recurrence. PML-I, but not PML-IV, isoform suppresses angiogenesis via upregulation of thrombospondin-2 (TSP2), a key inhibitor of angiogenesis. Finally, PML-I and TSP2 expression inversely correlates with tumor angiogenesis and recurrence in localized neuroblastomas.
CONCLUSIONS: Our work reveals a novel PML-I-TSP2 axis for the regulation of angiogenesis and cancer relapse, which could be used to identify patients with low-risk, localized tumors that might benefit from chemotherapy. Clin Cancer Res; 22(13); 3398-409. ©2016 AACR.
Boguslawska J, Kedzierska H, Poplawski P, et al.Expression of Genes Involved in Cellular Adhesion and Extracellular Matrix Remodeling Correlates with Poor Survival of Patients with Renal Cancer.
J Urol. 2016; 195(6):1892-902 [PubMed
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PURPOSE: Renal cell carcinoma is the most common highly metastatic kidney malignancy. Adhesion has a crucial role in the metastatic process. TGF (transforming growth factor)-β1 is a pleiotropic cytokine that influences cancerous transformation. We hypothesized that 1) changes in the expression of adhesion related genes may influence survival rate of patients with renal cell carcinoma and 2) TGF-β1 may contribute to changed expression of adhesion related genes.
MATERIALS AND METHODS: Two-step quantitative real-time polymerase chain reaction arrays were used to analyze the expression of adhesion related genes in 77 tumors and matched pair controls. The prognostic significance of genes was evaluated in TCGA (The Cancer Genome Atlas) data on 468 patients with renal cell carcinoma. Quantitative real-time polymerase chain reaction and Western blot were applied for TGF-β1 analysis. TGF-β1 mediated regulation of gene expression was analyzed by TGF-β1 supplementation of Caki-2 cells and quantitative real-time polymerase chain reaction.
RESULTS: The expression of 19 genes related to adhesion and extracellular matrix remodeling was statistically significantly disturbed in renal cell carcinoma compared with controls. The 10-gene expression signature (COL1A1, COL5A1, COL11A1, FN1, ICAM1, ITGAL, ITGAM, ITGB2, THBS2 and TIMP1) correlated with poor survival (HR 2.85, p = 5.7e-10). TGF-β1 expression was 22 times higher in renal cell carcinoma than in controls (p <0.0001). TGF-β1 induced expression of TGFBI, COL1A1, COL5A1, COL8A1, FN1, ITGA5, ITGAM and TIMP1 in a renal cell carcinoma derived cell line.
CONCLUSIONS: Disturbed expression of genes involved in adhesion and extracellular matrix remodeling develops early during renal cell carcinoma carcinogenesis and correlates with poor survival. TGF-β1 contributes to changed expression of extracellular matrix and adhesion related genes. Bioinformatic analysis performed on a broad panel of cancers of nonkidney origin suggests that disturbed expression of genes related to extracellular matrix and adhesion may be a universal feature of cancerous progression.
BACKGROUND: Colorectal cancer (CRC) development is accompanied by changes in expression for several genes; but the details of the underlying regulatory procesess remain unknown. Our aims were to assess the role of epigenetic processes in tumour formation and to identify characteristic DNA methylation and miRNA alterations in the colorectal adenoma-carcinoma sequence.
METHODS: Whole genome expression profiling was performed on colonic biopsy samples (49 healthy normal, 49 colorectal adenoma (AD), 49 CRC); on laser capture microdissected (LCM) epithelial and stromal cells from 6 CRC-normal adjacent tissue (NAT) samples pairs, and on demethylated human CRC cell lines using HGU133 Plus 2.0 microarrays (Affymetrix). Methylation status of genes with gradually altering expression along the AD-CRC sequence was further analysed on 10-10 macrodissected and 5-5 LCM samples from healthy colon, from adenoma and from CRC biopsy samples using bisulfite-sequencing PCR (BS-PCR) followed by pyrosequencing. In silico miRNA prediction for the selected genes was performed with miRWALK algorithm, miRNA expression was analysed on 3 CRC-NAT sample pairs and 3 adenoma tissue samples using the Human Panel I + II (Exiqon). SFRP1 immunohistochemistry experiments were performed.
RESULTS: A set of transcripts (18 genes including MAL, SFRP1, SULT1A1, PRIMA1, PTGDR) showed decreasing expression (p < 0.01) in the biopsy samples along the adenoma-carcinoma sequence. Three of those (COL1A2, SFRP2, SOCS3) showed hypermethylation and THBS2 showed hypomethylation both in AD and in CRC samples compared to NAT, while BCL2, PRIMA1 and PTGDR showed hypermethylation only in the CRC group. miR-21 was found to be significantly (p < 0.01) upregulated in adenoma and tumour samples compared to the healthy colonic tissue controls and could explain the altered expression of genes for which DNA methylation changes do not appear to play role (e.g. BCL2, MAL, PTGS2). Demethylation treatment could upregulate gene expression of genes that were found to be hypermethylated in human CRC tissue samples. Decreasing protein levels of SFRP1 was also observed along the adenoma-carcinoma sequence.
CONCLUSION: Hypermethylation of the selected markers (MAL, PRIMA1, PTGDR and SFRP1) can result in reduced gene expression and may contribute to the formation of colorectal cancer.
Tian ZQ, Li ZH, Wen SW, et al.Identification of Commonly Dysregulated Genes in Non-small-cell Lung Cancer by Integrated Analysis of Microarray Data and qRT-PCR Validation.
Lung. 2015; 193(4):583-92 [PubMed
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BACKGROUND: Non-small-cell lung cancer (NSCLC), the most common lung cancer, leads to the largest number of cancer-related deaths worldwide. There are many studies to identify the differentially expressed genes (DEGs) between NSCLC and normal control (NC) tissues by means of microarray technology. Because of the inconsistency of the microarray data sets, we performed an integrated analysis to identify DEGs and analyzed their biological function.
METHODS AND RESULTS: We combined 15 microarray data sets and identified 1063 DEGs between NSCLC and NC tissues; in addition, we found that the DEGs were enriched in regulation of cell proliferation process and focal adhesion signaling pathway. The protein-protein interaction network analysis for the top 20 significantly DEGs revealed that CAV1, COL1A1, and ADRB2 were the significant hub proteins. Finally, we employed qRT-PCR to validate the meta-analysis approach by determining the expression of the top 10 most significantly DEGs and found that the expression of these genes were significantly different between tumor and NC tissues, in accordance with the results of meta-analysis.
CONCLUSION: qRT-PCR results indicated that the meta-analysis approach in our study was acceptable. Our data suggested that some of the DEGs, including MMP12, COL11A1, THBS2, FAP, and CAV1, may participate in the pathology of NSCLC and could be applied as potential markers or therapeutic targets for NSCLC.
Melaiu O, Melissari E, Mutti L, et al.Expression status of candidate genes in mesothelioma tissues and cell lines.
Mutat Res. 2015; 771:6-12 [PubMed
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In order to broaden knowledge on the pathogenesis of malignant pleural mesothelioma (MPM), we reviewed studies on the MPM-transcriptome and identified 119 deregulated genes. However, there was poor consistency among the studies. Thus, the expression of these genes was further investigated in the present work using reverse transcriptase-quantitative PCR (RT-qPCR) in 15 MPM and 20 non-MPM tissue samples. Fifty-nine genes showed a statistically significant deregulation and were further evaluated in two epithelioid MPM cell lines (compared to MET-5A, a non-MPM cell line). Nine genes (ACSL1, CCNO, CFB, PDGFRB, SULF1, TACC1, THBS2, TIMP3, XPOT) were deregulated with statistical significance in both cell lines, 12 (ASS1, CCNB1, CDH11, COL1A1, CXADR, EIF4G1, GALNT7, ITGA4, KRT5, PTGIS, RAN, SOD1) in at least one cell line, whereas 7 (DSP, HEG1, MCM4, MSLN, NME2, NMU, TNPO2) were close but did not reach the statistical significance in any of the cell line. Patients whose MPM tissues expressed elevated mRNA levels of BIRC5, DSP, NME2, and THBS2 showed a statistically significant shorter overall survival. Although MPM is a poorly studied cancer, some features are starting to emerge. Novel cancer genes are suggested here, in particular those involved in cell-cell and cell-matrix interactions.
Zubor P, Hatok J, Moricova P, et al.Gene expression abnormalities in histologically normal breast epithelium from patients with luminal type of breast cancer.
Mol Biol Rep. 2015; 42(5):977-88 [PubMed
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The gene expression profile of breast cancer has been described as a great breakthrough on the way to comprehend differences in cancer origin, behavior and therapy. However, gene expression profile in histologically normal epithelium (HNEpi) which could harbor genetic abnormalities predisposing breast tissue to develop malignancy was minor scope for scientists in the past. Thus, we aimed to analyze gene expressions in HNEpi and breast cancer tissue (BCTis) in order to establish its value as potential diagnostic marker for cancer development. We evaluated a panel of disease-specific genes in luminal type (A/B) of breast cancer and tumor surrounding HNEpi by qRT-PCR Array in 32 microdissected samples. There was 20.2 and 2.4% deregulation rate in genes with at least 2-fold or 5-fold over-expression between luminal (A/B) type breast carcinomas and tumor surrounding HNEpi, respectively. The high-grade luminal carcinomas showed higher number of deregulated genes compared to low-grade cases (50.6 vs. 23.8% with at least 2-fold deregulation rate). The main overexpressed genes in HNEpi were KLK5, SCGB1D2, GSN, EGFR and NGFR. The significant differences in gene expression between BCTis and HNEpi samples were revealed for BAG1, C3, CCNA2, CD44, FGF1, FOSL1, ID2, IL6R, NGFB, NGFR, PAPPA, PLAU, SERPINB5, THBS1 and TP53 gene (p < 0.05) and BCL2L2, CTSB, ITGB4, JUN, KIT, KLF5, SCGB1D2, SCGB2A1, SERPINE1 (p < 0.01), and EGFR, GABRP, GSN, MAP2K7 and THBS2 (p < 0.001), and GSN, KLK5 (p < 0.0001). The ontological gene analyses revealed high deregulations in gene group directly associated with breast cancer prognosis and origin.
BACKGROUND: Thrombospondins (THBSs) are a family of multidomain and secreted matricellular Ca(2+)-binding glycoproteins which has at least five members encoded by independent genes. As a THBSs family member, Thrombospondin2 (THBS2) has been reported to regulate angiogenesis. Nevertheless, the functions and clinical significance of THBS2 still remains unclear in gastric cancer.
METHODS: The mRNA and protein expression levels of THBS2 were assessed in 14 paired of gastric cancer specimens and corresponding normal mucosas using quantitative real-time PCR and western blot analysis. Immunohistochemistry of THBS2 and CD34 on population-based tissue microarrays consisting of 129 gastric cancer cases were used to evaluate the prognostic significance of THBS2 and microvessel density (MVD) of each sample. Survival analyses were performed by Kaplan-Meier method and Cox's proportional hazards model. Colony formation assay, endothelial cell tube formation assay, cell migration assay and apoptosis analysis in MKN-45 and SGC-7901 cell lines were carried out to evaluate the effects of THBS2 on gastric cancer in vitro.
RESULTS: 85.71% (12 of 14) gastric cancer tissues expressed remarkably lower THBS2 in both mRNA and protein levels than the corresponding normal controls. Consistently, tissue microarray (TMA) results showed THBS2 levels were also inhibited in gastric cancer tissues compared with the normal controls. Moreover, we observed that patients with higher levels of THBS2 were significantly correlated with more favourable prognosis while decreased THBS2 expression were associated with poorer histological grades of gastric cancer. Additionally, our in vitro experiments further demonstrated that overexpression of THBS2 could impede both the proliferation rate and the tube formation of Human umbilical vein endothelial cells (HUVECs) in MKN-45 and SGC-7901 cell lines.
CONCLUSION: Our study suggests THBS2 is aberrantly expressed in gastric cancer and plays a critical role in cancer progression, which can be a potential prognosis predictor of gastric cancer.