Gene Summary

Gene:TFPI; tissue factor pathway inhibitor
Aliases: EPI, TFI, LACI, TFPI1
Summary:This gene encodes a Kunitz-type serine protease inhibitor that regulates the tissue factor (TF)-dependent pathway of blood coagulation. The coagulation process initiates with the formation of a factor VIIa-TF complex, which proteolytically activates additional proteases (factors IX and X) and ultimately leads to the formation of a fibrin clot. The product of this gene inhibits the activated factor X and VIIa-TF proteases in an autoregulatory loop. Inhibition of the encoded protein restores hemostasis in animal models of hemophilia. This gene encodes multiple protein isoforms that differ in their inhibitory activity, specificity and cellular localization. [provided by RefSeq, Jul 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tissue factor pathway inhibitor
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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).

Latest Publications: TFPI (cancer-related)

Gào X, Zhang Y, Burwinkel B, et al.
The associations of DNA methylation alterations in oxidative stress-related genes with cancer incidence and mortality outcomes: a population-based cohort study.
Clin Epigenetics. 2019; 11(1):14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Reactive oxygen species may be involved in epigenetic gene activation or silencing. We aimed to identify CpG sites, at which DNA methylation is related to urinary 8-isoprostane levels (biomarker of lipid peroxidation) and cancer or mortality outcomes. This investigation was based on a German, population-based cohort with linkage to cancer and mortality registry data (2000-2016).
RESULTS: Blood DNA methylation in promoter regions of 519 genes, known to be involved in pathways from oxidative stress (OS) to cancer, was obtained at the cohort's baseline examination. Inverse associations of DNA methylation at cg25365794 (ALOXE3) and cg08862778 (MTOR) with 8-isoprostane levels were observed in a derivation set (n = 1000) and validated in two independent subsets of the cohort (n = 548 and n = 741). Multivariate regression models were used to evaluate the associations of DNA methylation at the two CpG sites with lung, colorectal, prostate, breast, and overall cancer incidence as well as CVD, cancer, and all-cause mortality. DNA methylation at cg25365794 (ALOXE3) was inversely associated with lung and prostate cancer incidence. DNA methylation at cg08862778 (MTOR) was associated with a 43% lower breast cancer incidence in the top vs. bottom tertile.
CONCLUSION: The finding for ALOXE3 may not be causal. As ALOXE3 is mainly expressed in skin tissue, the observed association might reflect the fact that both DNA methylation at the ALOXE3 gene and urinary 8-isoprostane concentrations depend on the level of OS in tissues. Contrarily, the finding for the MTOR gene and breast cancer is biologically plausible because the MTOR protein plays an important role in PI3K/Akt signaling, which is a pathway related to cancer development and cell senescence.

Kobayashi H, Yamada Y, Kawahara N, et al.
Integrating modern approaches to pathogenetic concepts of malignant transformation of endometriosis.
Oncol Rep. 2019; 41(3):1729-1738 [PubMed] Related Publications
In the present study, we summarize the role of the shared and independent (epi)genetic background between endometrioid carcinoma (EC) and clear cell carcinoma (CCC), two histological subtypes of endometriosis-associated ovarian cancer (EAOC). Using the PubMed database, we conducted a literature review of various studies related to the malignant transformation of endometriosis. Both endometriosis and EAOC face potential environmental hazards, including hemoglobin (Hb), heme and free iron, which induces DNA damage and mutations. Although EC is distinguished from CCC due to different morphologies, both represent common environmental profiles and maintain the similar (epi)genomic abnormalities with multiple overlaps and share similar molecular signatures. By contrast, EAOC also has disease-specific gene signatures corresponding with each histological subtype: Estrogen receptor promotes EC cell proliferation ('go') and hepatocyte nuclear factor-1β (HNF-1β) induces CCC cell cycle arrest ('stop') under oxidative stress conditions. This model underscores a subtype-dependent 'go or stop' dichotomy, possibly through better ability to adapt in a changing environment. It was found that cyst fluid Hb and iron concentrations were significantly lower in EAOC when compared to benign ovarian endometrioma (OE), supporting the hypothesis that the redox imbalance plays a key role in the pathogenesis of EAOC. There are at least two phases of iron carcinogenesis and tumor progression: The initial wave of iron-induced oxidative stress and DNA mutations would be followed by the second big wave of subsequent synthesis of the antioxidants, which diminishes cellular oxidative stress capacity, increases apoptosis resistance and promotes tumor initiation and progression. Special emphasis is given to novel pathophysiological concepts of malignant transformation of endometriosis.

Bagherpour M, Gharibzad K, Rassi H
Association of CDH1 and TERT Single-Nucleotide Polymorphisms with Susceptibility to Familial Breast Cancer Risk.
Monoclon Antib Immunodiagn Immunother. 2018; 37(6):239-244 [PubMed] Related Publications
Breast cancer (BC) is a multistep disease that is thought to result from an interaction between genetic background and environmental factors. In Iran, one of the strongest risk factors for developing BC is a positive family history of the disease. Recently, various polymorphisms of E-cadherin (CDH1) and TERT have been found to be associated with increased BC risk worldwide. This study aimed to analyze the association of CDH1 and TERT single-nucleotide polymorphisms with susceptibility to familial BC (FBC) risk in the Iranian patients. One hundred five patients with FBC and 110 non-FBC (NFBC) were genotyped to elucidate the potential association between CDH1 rs5030625 polymorphism and TERT rs2736098 polymorphism by polymerase chain reaction-restriction fragment length polymorphism. Then, results were evaluated by electrophoresis and Epi Info(™) 2012 software. A significant association was found between CDH1 rs5030625 GAGA genotype and FBC risk. Compared with the control group, the FBC patients had a lower frequency of GG genotype (69% vs. 85%) and a higher frequency of GAGA (5% vs. 2%, P < 0.02). Furthermore, the patients with FBC had a lower frequency of TERT rs2736098 GG genotype (38% vs. 49%, P = 0.001) and a higher frequency of rs2736098 AA genotype (12% vs. 5%, P = 0.001) compared with the NFBC. In contrast, the TERT rs2736098 GG genotype potentially increased the recurring risk of FBC (odds ratio = 3.17, P < 0.01). Allele genotypic frequencies in the FBC patients differed from those of the controls. Interestingly, tumors in FBC patients with rs2736098 GG genotype and rs5030625 GAGA exhibited higher mitotic activity, higher grade, lower estrogen receptor, and progesterone receptor than the other genotypes. In conclusion, CDH1 rs5030625 GAGA genotype and TERT rs2736098 GG genotype in combination with clinical parameters may be prognostic factors rather than susceptibility factors during the progression of FBC.

Markman RL, Webber LP, Nascimento Filho CHV, et al.
Interfering with bromodomain epigenome readers as therapeutic option in mucoepidermoid carcinoma.
Cell Oncol (Dordr). 2019; 42(2):143-155 [PubMed] Related Publications
PURPOSE: Emerging evidence indicates that bromodomains comprise a conserved class of epigenome readers involved in cancer development and inflammation. Bromodomains are associated with epigenetic modifications of gene transcription through interactions with lysine residues of histone tails. Particularly, the bromodomain and extra-terminal domain (BET) family member BRD4 has been found to be involved in the control over oncogenes, including c-MYC, and in the maintenance of downstream inflammatory processes. The objective of this study was to evaluate the effect of pharmacologically displacing BRD4 in mucoepidermoid carcinoma (MEC) cells.
METHODS: We assessed the presence of BRD4 levels in a panel of human MEC tissue samples in conjunction with histological grading and clinical information. In vitro studies were carried out using human MEC-derived cell lines. The BET inhibitor iBET762 was administered to MEC cells to assess the impact of disrupted BRD4 signaling on colony forming capacities and cell cycle status. The activation of cellular senescence induced by iBET762 was determined by immunohistochemical staining for p16
RESULTS: We found that primary human MECs and MEC-derived cell lines are endowed with high BRD4 expression levels compared to those in normal salivary glands. We also found that, by displacing BRD4 from chromatin using the BET inhibitor iBET762, MEC cells lose their colony forming capacities and undergo G1 cell cycle arrest and senescence. Finally, we found that targeted displacement of BRD4 from chromatin results in depletion of cancer stem cells from the overall MEC cell populations.
CONCLUSIONS: Our findings indicate that bromodomain-mediated gene regulation constitutes an epigenetic mechanism that is deregulated in MEC cells and that the use of BET inhibitors may serve as a feasible therapeutic strategy to manage MECs.

Bahreyni A, Alibolandi M, Ramezani M, et al.
A novel MUC1 aptamer-modified PLGA-epirubicin-PβAE-antimir-21 nanocomplex platform for targeted co-delivery of anticancer agents in vitro and in vivo.
Colloids Surf B Biointerfaces. 2019; 175:231-238 [PubMed] Related Publications
Conventional chemotherapy suffers from several drawbacks, including toxic side effects together with the development of resistance to the chemical agents. Therefore, exploring alternative therapeutic approaches as well as developing targeted delivery systems are in demand. Oligonucleotide-based therapy has emerged as a promising and alternative procedure for treating malignancies involving gene-related diseases. In the current study, a targeted delivery system was designed to target cancer cells based on two biocompatible polymers of poly (β amino ester) (PβAE) and poly (d, l-lactide-co-glycolide) (PLGA). In this system, antimir-21 as an inhibitor of microRNA-21 (miR-21) which is an oncomiR overexpressed in several human cancers was condensed with PβAE polymer and then PLGA was electrostatically deposited on this complex and provided a reservoir for positively charged drug, epirubicin (Epi). At the final stage, MUC1 aptamer as a targeting agent was covalently attached to the nanoparticles for selectively guided therapeutic delivery. The obtained results demonstrated that the fabricated MUC1 aptamer-modified nanocomplex could efficiently be internalized into MCF7 (human breast carcinoma cell) and C26 (murine colon carcinoma cell) cells through interaction between MUC1 aptamer and its receptor on the surfaces of these cell lines and decline cell viability in these cells but not in CHO cells (Chinese hamster ovary cell) as nontarget cells (MUC1 negative cells). The safety of PLGA-Epi-PβAE-antimir-21 nanocomplex and synergetic effect of Epi and antimir-21 in reducing cell viability of target cells were confirmed by treating MCF-7 and CHO cells with nanocomplex and MUC1 aptamer-modified nanocomplex. Moreover, it was demonstrated that MUC1 aptamer-modified nanocomplex could remarkably inhibit tumor growth in tumor-bearing mice compared with Epi alone.

Castel D, Philippe C, Kergrohen T, et al.
Transcriptomic and epigenetic profiling of 'diffuse midline gliomas, H3 K27M-mutant' discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location.
Acta Neuropathol Commun. 2018; 6(1):117 [PubMed] Free Access to Full Article Related Publications
Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail.Two hundred and fifteen patients younger than 18 years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (n = 140) and methylation (n = 80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG.Tumor classification based on gene expression (GE) data highlighted the similarity of K27M DMG independently of their location along the midline. T-distributed Stochastic Neighbor Embedding (tSNE) analysis of methylation profiling confirms the discrimination of DMG from other well defined supratentorial tumor subgroups. Patients with diffuse intrinsic pontine gliomas (DIPG) and thalamic DMG exhibited a similarly poor prognosis (11.1 and 10.8 months median overall survival, respectively). Interestingly, H3.1-K27M and H3.3-K27M primary tumor samples could be distinguished based both on their GE and DNA methylation profiles, suggesting that they might arise from a different precursor or from a different epigenetic reorganization.These differences in DNA methylation profiles were conserved in glioma stem-like cell culture models of DIPG which mimicked their corresponding primary tumor. ChIP-seq profiling of H3K27me3 in these models indicate that H3.3-K27M mutated DIPG stem cells exhibit higher levels of H3K27 trimethylation which are correlated with fewer genes expressed by RNAseq. When considering the global distribution of the H3K27me3 mark, we observed that intergenic regions were more trimethylated in the H3.3-K27M mutated cells compared to the H3.1-K27M mutated ones.H3 K27M-mutant DMG represent a homogenous group of neoplasms compared to other pediatric gliomas that could be further separated based on the type of histone H3 variant mutated and their respective epigenetic landscapes. As these characteristics drive different phenotypes, these findings may have important implication for the design of future trials in these specific types of neoplasms.

Vaijayanthi T, Pandian GN, Sugiyama H
Chemical Control System of Epigenetics.
Chem Rec. 2018; 18(12):1833-1853 [PubMed] Related Publications
Epigenetics represents the inheritable changes to the chemical control system governing the gene expression with no ensuing changes to the underlying DNA sequence. Environment-mediated modification of the natural epigenetic interactions can perturb the cellular homeostasis and drive cells to a diseased state by switching therapeutically essential genes ON and OFF. Contemporary bioinformatics tools have revealed the structural chemical modifications of the epigenetic enzymes associated with several complex diseases, including cancers, immune disorders, and neurodegenerative disorders at the fundamental level. The amenable nature of the epigenetic enzymes to chemical modifications aided the screening and identification of synthetic small-molecule inhibitors. Continuing the current steady progress in the development of these small-molecule inhibitors as 'epi-drugs' in preclinical studies requires further advances to enable existing clinical barriers to be overcome. Recently, an epigenetic modifier complemented with selective DNA-binding small molecules was shown to function as an artificial biomimetic epigenetic code. Herein, we summarize the chemical aspects of the natural epigenetic control system and detail the recent advances in the synthetic strategies to mimic the genetic and epigenetic control system.

Yuniarti L, Mustofa M, Aryandono T, Haryana SM
Synergistic Action of 1,2-Epoxy-3 (3- (3,4-dimethoxyphenyl)- 4H-1-benzopiyran-4-on) Propane with Doxorubicin and Cisplatin through Increasing of p53, TIMP-3, and MicroRNA-34a in Cervical Cancer Cell Line (HeLa)
Asian Pac J Cancer Prev. 2018; 19(10):2955-2962 [PubMed] Free Access to Full Article Related Publications
Objective: Cervical cancer is the second most common cancer among women worldwide, with a high mortality rate especially in developing countries. Insufficient treatment for cervical cancer, multiple side effects, and high drug prices encourage researchers to look for effective and selective cancer drugs with appropriate molecular targets. This study explored the cytotoxicity of (1,2-epoxy-3(3-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-on) propane (EPI) synthesized from clove leaves oil on HeLa cells, its combination with doxorubicin (DOX) and cisplatin (CIS), and also their influence on p53, TIMP-3, and miR-34a as therapeutic targets. Materials and Methods: This research was an experimental in vitro study on cervical cancer uteri culture. The cytotoxicity was analyzed by MTT assay. The drug combination synergisms were indicated by the combination index (CI) (using CompuSyn 1.4). HeLa cells in 32 wells were divided into eight groups as negative control, which were given EPI ½IC50, EPI IC50, EPI 2IC50, DOX IC50, combination of EPI+DOX, CIS, and the combination of EPI+CIS. The p53 and TIMP-3 concentrations were measured using ELISA, and expressions of miR-34a with qRT-PCR. One-way ANOVA and post hoc Tukey tests were performed to determine the mean difference of all variables between the study groups. Results: IC50 for EPI was 33.24 (±3.01) μg/ml, while DOX and CIS were 4.8 μg/ml (±0.1), and 23.34 μg/ml (±3.01), respectively, while CI values for EPI-DOX were <0.1 and for EPI-CIS <0.9. Expression of p53 in group 6 (1.67±0.31) μg/ml and 8 (1.18±0.18) μg/ml, TIMP-3 6 (3.81±0.49) μg/ml and 8 (2.93±0.42) μg/ml were significantly higher compared to the control group (p<0.05). All treatment groups showed significantly increased miR-34a expressions compared to the control group (p<0.05). Conclusion: The combinations showed a very strong synergism and a moderate slight synergism for EPI-DOX and EPI-CIS. Both combinations were able to increase the expressions of p53, TIMP-3 proteins, and MiR-34a in the HeLa cells.

Wang C, Gu Y, Zhang E, et al.
A cancer-testis non-coding RNA LIN28B-AS1 activates driver gene LIN28B by interacting with IGF2BP1 in lung adenocarcinoma.
Oncogene. 2019; 38(10):1611-1624 [PubMed] Related Publications
Our previous work found cancer-testis (CT) genes as a new source of epi-driver candidates of cancer. LIN28B was a CT gene, but the "driver" ability and the activation mechanism in lung adenocarcinoma (LUAD) remain unclear. We observed that LIN28B expression was restricted in testis. It was re-activated in LUAD patients without known genomic alterations in oncogenes and was related to poorer survival. In vitro and In vivo experiments confirmed that the activation of LIN28B could promote the proliferation and metastasis of LUAD cells and can influence cell cycle, DNA damage repair, and genome instability. In addition to the known let-7-LIN28B regulation loop, our results further revealed a let-7-independent Cis-regulator of LIN28B: LIN28B-AS1. LIN28B-AS1 is a CT long non-coding RNA (CT-lncRNA). It altered the messenger RNA stability of LIN28B by directly interacting with another CT protein IGF2BP1 but not with LIN28B and constituted a novel regulation network. In sum, we identify that LIN28B is an "epi-driver" of LUAD and clarify a new lncRNA-activated mechanism of LIN28B, which provide new candidate targets for precise anticancer therapy in the future.

Ghavifekr Fakhr M, Rezaie Kahkhaie K, Shanehbandi D, et al.
Scrophularia Atropatana Extract Reverses TP53 Gene Promoter Hypermethylation and Decreases Survivin Antiapoptotic Gene Expression in Breast Cancer Cells
Asian Pac J Cancer Prev. 2018; 19(9):2599-2605 [PubMed] Free Access to Full Article Related Publications
Background: In many cases of breast cancer, the aberrant methylation of TP53 gene leads to uncontrolled cell proliferation and apoptosis inhibition. Moreover, expression of oncogenes which are under the control of P53 protein could be altered. Survivin as a conspicuous example of this category plays important roles in tumorigenesis, drug resistance and apoptosis inhibition. The present study was done to reveal the effects of Scrophularia atropatana extract on epigenetic situation of TP53 gene promoter and the expression levels of anti-apoptotic gene, survivin and its potential for production of cancer epi-drugs. Methods: Cytotoxic effect of dichloromethane extracts of Scrophularia plant on MCF-7 cell line was assessed in our previous study. Cell death ELISA (enzyme-linked immunosorbent assay) and TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) tests were used to investigate the occurrence of apoptosis in the treated cells. Methylation Specific PCR (MSP) was employed to assess the changes in methylation status of the TP53 gene promoter. Furthermore, quantitative real time PCR was utilized to evaluate the resulting changes in TP53 and survivin genes expression. Results: Cell death ELISA and TUNEL assays confirmed the occurrence of apoptosis. MSP test revealed a significant change in the methylation status of TP53 promoter. QRT-PCR showed an increased TP53 gene expression in the treated cells while a significant decrease in survivin mRNA was evident. Conclusions: According to the outcomes, dichloromethane extract of S. atropatana returned the TP53 gene promoter hypermethylation to normal state. This plant could be a promising source for production of epi-drugs due to its apoptotic effects and reversal of TP53 epigenetic alterations.

McKiernan J, Donovan MJ, Margolis E, et al.
A Prospective Adaptive Utility Trial to Validate Performance of a Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer in Patients with Prostate-specific Antigen 2-10ng/ml at Initial Biopsy.
Eur Urol. 2018; 74(6):731-738 [PubMed] Related Publications
BACKGROUND: Discriminating indolent from clinically significant prostate cancer (PCa) in the initial biopsy setting remains an important issue. Prospectively evaluated diagnostic assays are necessary to ensure efficacy and clinical adoption.
OBJECTIVE: Performance and utility assessment of ExoDx Prostate (IntelliScore) (EPI) urine exosome gene expression assay versus standard clinical parameters for discriminating Grade Group (GG) ≥2 PCa from GG1 PCa and benign disease on initial biopsy.
DESIGN, SETTING, AND PARTICIPANTS: A two-phase adaptive clinical utility study (NCT03031418) comparing EPI results with biopsy outcomes in men, with age ≥50 yr and prostate-specific antigen (PSA) 2-10ng/ml, scheduled for initial prostate biopsy. After EPI performance assessment during phase I, a clinical implementation document (ie, CarePath) was developed for utilizing the EPI test in phase II, where the biopsy decision is uncertain.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Performance evaluation of the EPI test in patients enrolled in phase I and publication of a consensus CarePath for phase II.
RESULTS AND LIMITATIONS: In a total of 503 patients, with median age of 64 yr, median PSA 5.4ng/ml, 14% African American, 70% Caucasian, 53% positive biopsy rate (22% GG1, 17% GG2, and 15% ≥ GG3), EPI was superior to an optimized model of standard clinical parameters with an area under the curve (AUC) 0.70 versus 0.62, respectively, comparable with previously published results (n=519 patients, EPI AUC 0.71). Validated cut-point 15.6 would avoid 26% of unnecessary prostate biopsies and 20% of total biopsies, with negative predictive value (NPV) 89% and missing 7% of ≥GG2 PCa. Alternative cut-point 20 would avoid 40% of unnecessary biopsies and 31% of total biopsies, with NPV 89% and missing 11% of ≥GG2 PCa. The clinical investigators reached consensus recommending use of the 15.6 cut-point for phase II. Outcome of the decision impact cohort in phase II will be reported separately.
CONCLUSIONS: EPI is a noninvasive, easy-to-use, gene expression urine assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies.
PATIENT SUMMARY: It is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2-10ng/ml. This study further demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥GG2 PCa at initial biopsy and defer unnecessary biopsies better than existing risk calculator's and standard clinical data.

Bernal Rubio YL, González-Reymúndez A, Wu KH, et al.
Whole-Genome Multi-omic Study of Survival in Patients with Glioblastoma Multiforme.
G3 (Bethesda). 2018; 8(11):3627-3636 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) has been recognized as the most lethal type of malignant brain tumor. Despite efforts of the medical and research community, patients' survival remains extremely low. Multi-omic profiles (including DNA sequence, methylation and gene expression) provide rich information about the tumor. These profiles are likely to reveal processes that may be predictive of patient survival. However, the integration of multi-omic profiles, which are high dimensional and heterogeneous in nature, poses great challenges. The goal of this work was to develop models for prediction of survival of GBM patients that can integrate clinical information and multi-omic profiles, using multi-layered Bayesian regressions. We apply the methodology to data from GBM patients from The Cancer Genome Atlas (TCGA, n = 501) to evaluate whether integrating multi-omic profiles (SNP-genotypes, methylation, copy number variants and gene expression) with clinical information (demographics as well as treatments) leads to an improved ability to predict patient survival. The proposed Bayesian models were used to estimate the proportion of variance explained by clinical covariates and omics and to evaluate prediction accuracy in cross validation (using the area under the Receiver Operating Characteristic curve, AUC). Among clinical and demographic covariates, age (AUC = 0.664) and the use of temozolomide (AUC = 0.606) were the most predictive of survival. Among omics, methylation (AUC = 0.623) and gene expression (AUC = 0.593) were more predictive than either SNP (AUC = 0.539) or CNV (AUC = 0.547). While there was a clear association between age and methylation, the integration of age, the use of temozolomide, and either gene expression or methylation led to a substantial increase in AUC in cross-validaton (AUC = 0.718). Finally, among the genes whose methylation was higher in aging brains, we observed a higher enrichment of these genes being also differentially methylated in cancer.

Forget A, Martignetti L, Puget S, et al.
Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling.
Cancer Cell. 2018; 34(3):379-395.e7 [PubMed] Related Publications
The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.

Memari F, Joneidi Z, Taheri B, et al.
Epigenetics and Epi-miRNAs: Potential markers/therapeutics in leukemia.
Biomed Pharmacother. 2018; 106:1668-1677 [PubMed] Related Publications
Epigenetic variations can play remarkable roles in different normal and abnormal situations. Such variations have been shown to have a direct role in the pathogenesis of various diseases either through inhibition of tumor suppressor genes or increasing the expression of oncogenes. Enzymes involving in epigenetic machinery are the main actors in tuning the epigenetic-based controls on gene expressions. Aberrant expression of these enzymes can trigger a big chaos in the cellular gene expression networks and finally lead to cancer progression. This situation has been shown in different types of leukemia, where high or low levels of an epigenetic enzyme are partly or highly responsible for involvement or progression of a disease. DNA hypermethylation, different histone modifications, and aberrant miRNA expressions are three main epigenetic variations, which have been shown to play a role in leukemia progression. Epigenetic based treatments now are considered as novel and effective therapies in order to decrease the abnormal epigenetic modifications in patient cells. Different epigenetic-based approaches have been developed and tested to inhibit or reverse the unusual expression of epigenetic agents in leukemia. The reciprocal behavior of miRNAs in the regulation of epigenetic modifiers, while being regulated by them, unlocks a new opportunity in order to design some epigenetic-based miRNAs able to silence or sensitize these effectors in leukemia.

De Robertis M, Poeta ML, Signori E, Fazio VM
Current understanding and clinical utility of miRNAs regulation of colon cancer stem cells.
Semin Cancer Biol. 2018; 53:232-247 [PubMed] Related Publications
Cancer stem cells (CSCs) in colorectal tumorigenesis are suggested to be responsible for initiation, development and propagation of colorectal cancer (CRC) and have been extensively characterized by the expression of phenotypic determinants, such as surface or intracellular proteins. The generation of CSCs is likely due to a dysregulation of the signaling pathways that principally control self-renewal and pluripotency in normal intestinal stem cells (ISCs) through different (epi)genetic changes that define cell fate, identity, and phenotype of CSCs. These aspects are currently under intense investigation. In the framework of the oncogenic signaling pathways controlled by microRNAs (miRNAs) during CRC development, a plethora of data suggests that miRNAs can play a key role in several regulatory pathways involving CSCs biology, epithelial-mesenchymal transition (EMT), angiogenesis, metastatization, and pharmacoresistance. This review examines the most relevant evidences about the role of miRNAs in the etiology of CRC, through the regulation of colon CSCs and the principal differences between colorectal CSCs and benign stem cells. In this perspective, the utility of the principal CSCs-related miRNAs changes is explored, emphasizing their use as potential biomarkers to aid in diagnosis, prognosis and predicting response to therapy in CRC patients, but also as promising targets for more effective and personalized anti-CRC treatments.

de Ruiter JR, Wessels LFA, Jonkers J
Mouse models in the era of large human tumour sequencing studies.
Open Biol. 2018; 8(8) [PubMed] Free Access to Full Article Related Publications
Cancer is a complex disease in which cells progressively accumulate mutations disrupting their cellular processes. A fraction of these mutations drive tumourigenesis by affecting oncogenes or tumour suppressor genes, but many mutations are passengers with no clear contribution to tumour development. The advancement of DNA and RNA sequencing technologies has enabled in-depth analysis of thousands of human tumours from various tissues to perform systematic characterization of their (epi)genomes and transcriptomes in order to identify (epi)genetic changes associated with cancer. Combined with considerable progress in algorithmic development, this expansion in scale has resulted in the identification of many cancer-associated mutations, genes and pathways that are considered to be potential drivers of tumour development. However, it remains challenging to systematically identify drivers affected by complex genomic rearrangements and drivers residing in non-coding regions of the genome or in complex amplicons or deletions of copy-number driven tumours. Furthermore, functional characterization is challenging in the human context due to the lack of genetically tractable experimental model systems in which the effects of mutations can be studied in the context of their tumour microenvironment. In this respect, mouse models of human cancer provide unique opportunities for pinpointing novel driver genes and their detailed characterization. In this review, we provide an overview of approaches for complementing human studies with data from mouse models. We also discuss state-of-the-art technological developments for cancer gene discovery and validation in mice.

Zhang W, Qiao B, Fan J
Overexpression of miR-4443 promotes the resistance of non-small cell lung cancer cells to epirubicin by targeting INPP4A and regulating the activation of JAK2/STAT3 pathway.
Pharmazie. 2018; 73(7):386-392 [PubMed] Related Publications
We aimed to elucidate the roles and regulatory mechanism of miR-4443 in regulating the resistance of non-small cell lung cancer (NSCLC) cells to epirubicin (EPI). Fifty-four advanced NSCLC patients were classified as ''insensitive'' or ''sensitive'' according to patient's responses following EPI-based chemotherapy and then the expression of miR-4443 was determined. The EPI-resistant H1299 cells were collected and transfected with miR-4443 mimics, whereas parental H1299 cells were transfected with miR-4443 inhibitors. The inhibition of growth (IC50), cell cycle or apoptosis of different transfected groups were investigated. Additionally, the potential target of miR-3188 was identified and verified by luciferase reporter assay. Besides, the regulatory relationship between miR-3188 and JAK2/STAT3 pathway was explored. miR-4443 was highly expressed in insensitive NSCLC patients to EPT-based chemotherapy and EPI-resistant H1299 cells. Inhibition of miR-4443 increased the sensitivity of EPI-resistant H1299 cells to EPI by decreasing IC50 of EPI, inducing cell apoptosis and G0/G1 cell cycle arrest, while overexpression of miR-4443 promoted the resistance of parental H1299 cells to EPI. Furthermore, inositol polyphosphate 4-phosphatase type I gene (INPP4A) was a target of miR-4443 and its expression could be negatively regulated by miR-4443. Overexpression of miR-4443 promoted the resistance of parental H1299 cells to EPI by targeting INPP4A. Besides, overexpression of miR-4443 activated JAK2/STAT3 pathway in parental H1299 cells to EPI. Overexpression of miR-4443 may promote the resistance of NSCLC cells to EPI by targeting INPP4A and regulating the activation of JAK2/STAT3 pathway. miR-4443 may serve as a drug target for NSCLC.

Liu X, Liu X, Wu Y, et al.
MicroRNA-34a Attenuates Metastasis and Chemoresistance of Bladder Cancer Cells by Targeting the TCF1/LEF1 Axis.
Cell Physiol Biochem. 2018; 48(1):87-98 [PubMed] Related Publications
BACKGROUND/AIMS: Chemoresistance is largely responsible for relapses of bladder cancer during clinical therapy. However, the molecular mechanisms involved in the chemoresistance of bladder cancer are unclear. Growing evidence supports the theory that microRNAs (miRNAs) play an important role in chemotherapeutic drug resistance because they are downregulated in many malignancies that have been implicated in the regulation of diverse processes in cancer cells. More specifically, the extent and precise mechanism of the involvement of miR-34as in chemoresistance to epirubicin (EPI) in the treatment of bladder cancer remains unclear.
METHODS: In this study, real-time quantitative polymerase chain reaction (PCR) was used to analyze the expression of miR-34a in bladder cancer cell line BIU87 and its EPI chemoresistant cell line BIU87/ADR. The miR-34a profiles in bladder cancer tissues were obtained from The Cancer Genome Atlas database. The effect of miR-34a on chemosensitivity was evaluated by cell viability assays, colony formation assays, and in vivo experimentation. Apoptosis and the cell cycle were examined by flow cytometry. A luciferase reporter assay was used to assess the target genes of miR-34a. Western blot and qPCR were used to analyze the expression of target proteins and downstream molecules.
RESULTS: The downregulation of miR-34a in bladder cancer serves as an independent predictor of reduced patient survival. The CCK-8 assay showed that miR-34a overexpression resulted in increased sensitivity to EPI, while miR-34a downregulation resulted in chemoresistance to EPI in vitro. Moreover, it was found that miR-34a increased the sensitivity of BIU87/ADR cells to chemotherapy in vivo. The luciferase reporter assay ascertained that TCF1 and LEF1 are direct target genes of miR-34a. It was found that miR-34a increased chemosensitivity in BIU87/ADR cells by inhibiting the TCF1/LEF1 axis.
CONCLUSIONS: The results of this study indicate that miR-34a contributes to the chemosensitivity of BIU87/ADR by inhibiting the TCF1/LEF1 axis. Consequently, miR-34a is a determinant of BIU87 chemosensitivity and may therefore serve as a potential therapeutic target in bladder cancer treatment.

Pardini B, De Maria D, Francavilla A, et al.
MicroRNAs as markers of progression in cervical cancer: a systematic review.
BMC Cancer. 2018; 18(1):696 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Invasive cervical cancer (ICC) is caused by high-risk human papillomavirus types (HR-HPVs) and is usually preceded by a long phase of intraepithelial neoplasia (CIN). Before invasion, (epi) genetic changes, potentially applicable as molecular markers within cervical screening, occur in HPV host cells. Epigenetic alterations, such as dysregulation of microRNA (miRNA) expression, are frequently observed in ICC. The mechanisms and role of miRNA dysregulation in cervical carcinogenesis are still largely unknown.
METHODS: We provide an overview of the studies investigating miRNA expression in relation to ICC progression, highlighting their common outcomes and their weaknesses/strengths. To achieve this, we systematically searched through Pubmed database all articles between January 2010 and December 2017.
RESULTS: From the 24 studies retrieved, miR-29a and miR-21 are the most frequently down- and up-regulated in ICC progression, respectively. Microarray-based studies show a small overlap, with miR-10a, miR-20b, miR-9, miR-16 and miR-106 found repeatedly dysregulated. miR-34a, miR-125 and miR-375 were also found dysregulated in cervical exfoliated cells in relation to cancer progression.
CONCLUSIONS: The pivotal role of miRNAs in ICC progression and initial development is becoming more and more relevant. Available studies are essentially based on convenience material, entailing possible selection bias, and frequently of small size: all these points still represent a limitation to a wide comprehension of miRNAs relevant for ICC. The targeted approach instead of a genome-wide investigation still precludes the identification of all the relevant miRNAs in the process. The implementation of deep sequencing on large scale population-based studies will help to discover and validate the relation between altered miRNA expression and CC progression for the identification of biomarkers. Optimally, once explored on a miRNome scale, small specific miRNA signatures maybe used in the context of screening.

Russo M, Lamba S, Lorenzato A, et al.
Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies.
Nat Commun. 2018; 9(1):2287 [PubMed] Free Access to Full Article Related Publications
Attempts at eradicating metastatic cancers with targeted therapies are limited by the emergence of resistant subclones bearing heterogeneous (epi)genetic changes. We used colorectal cancer (CRC) to test the hypothesis that interfering with an ancestral oncogenic event shared by all the malignant cells (such as WNT pathway alterations) could override heterogeneous mechanisms of acquired drug resistance. Here, we report that in CRC-resistant cell populations, phylogenetic analysis uncovers a complex subclonal architecture, indicating parallel evolution of multiple independent cellular lineages. Functional and pharmacological modulation of WNT signalling induces cell death in CRC preclinical models from patients that relapsed during the treatment, regardless of the drug type or resistance mechanisms. Concomitant blockade of WNT and MAPK signalling restrains the emergence of drug-resistant clones. Reliance upon the WNT-APC pathway is preserved throughout the branched genomic drift associated with emergence of treatment relapse, thus offering the possibility of a common therapeutic strategy to overcome secondary drug resistance.

Nebbioso A, Tambaro FP, Dell'Aversana C, Altucci L
Cancer epigenetics: Moving forward.
PLoS Genet. 2018; 14(6):e1007362 [PubMed] Free Access to Full Article Related Publications
Defects in chromatin modifiers and remodelers have been described both for hematological and solid malignancies, corroborating and strengthening the role of epigenetic aberrations in the etiology of cancer. Furthermore, epigenetic marks-DNA methylation, histone modifications, chromatin remodeling, and microRNA-can be considered potential markers of cancer development and progression. Here, we review whether altered epigenetic landscapes are merely a consequence of chromatin modifier/remodeler aberrations or a hallmark of cancer etiology. We critically evaluate current knowledge on causal epigenetic aberrations and examine to what extent the prioritization of (epi)genetic deregulations can be assessed in cancer as some type of genetic lesion characterizing solid cancer progression. We also discuss the multiple challenges in developing compounds targeting epigenetic enzymes (named epidrugs) for epigenetic-based therapies. The implementation of acquired knowledge of epigenetic biomarkers for patient stratification, together with the development of next-generation epidrugs and predictive models, will take our understanding and use of cancer epigenetics in diagnosis, prognosis, and treatment of cancer patients to a new level.

Felipe AV, Oliveira J, Moraes AA, et al.
Reversal of Multidrug Resistance in an Epirubicin-Resistant Gastric Cancer Cell Subline
Asian Pac J Cancer Prev. 2018; 19(5):1237-1242 [PubMed] Free Access to Full Article Related Publications
Background: Gastric cancer is one of the most common malignancies worldwide. Epirubicin (EPI) is used extensively in the treatment of multiple cancers despite its tendency to induce multidrug resistance though overexpression of the ABCB1 efflux pump. However, this overexpression can be disrupted using short interfering RNAs (siRNAs). Objective and Methods: The aim of this study was to explore approaches to reverse EPI resistance and thus increase the success of chemotherapy treatment in an EPI-resistant gastric cancer cell subline (AGS/EPI). Methods: The study focused on effects of ABCB1 knockdown by siRNA technology using TaqMan gene expression assays with quantitative real-time reverse-transcription PCR (qRT-PCR). MTT assays were performed to evaluate viability and prolifer in subline. ABCB1 protein localization and EPI intracellular fluorescence intensity in AGS/EPI cells were detected by confocal microscopy. Results: The siRNA efficiently downregulated ABCB1 mRNA in AGS/EPI cells. Thus MDR reversal was clearly demonstrated in the AGS/EPI cells, offering the possibility of future in vitro chemoresistance assays for the GC field. Conclusions: ABCB1 knockdown decreased EPI efflux and increased EPI sensitivity in AGS/EPI cells. This result provides a novel strategy for targeted gene therapy to reverse EPI resistance in gastric cancer.

Xu X, Zhang L, He X, et al.
TGF-β plays a vital role in triple-negative breast cancer (TNBC) drug-resistance through regulating stemness, EMT and apoptosis.
Biochem Biophys Res Commun. 2018; 502(1):160-165 [PubMed] Related Publications
Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer in which the cell surface lacks usual targets for drug to exhibit its effects. Epirubicin (Epi) is widely used for TNBC, but a substantial number of patients develop Epi resistance that is usually associated with poor prognosis. Transforming growth factor (TGF-β) is a multifunctional cytokine. In recent study, it appears that TGF-β influences the cancer stem cell population, thus, the drug resistance of cancer may also be affected. We used epirubicin to treat MDA-MB-231 (MB-231) cells and found that TGF-β and breast cancer stem cell markers CD44

Ma X, Tan YT, Yang Y, et al.
Pre-diagnostic urinary 15-F
Int J Cancer. 2018; 143(8):1896-1903 [PubMed] Article available free on PMC after 15/10/2019 Related Publications
Oxidative stress has been hypothesized to affect cancer development via various mechanisms, but the evidence from human is limited and inconclusive. 15-F

Zou Q, Xiao X, Liang Y, et al.
miR-19a-mediated downregulation of RhoB inhibits the dephosphorylation of AKT1 and induces osteosarcoma cell metastasis.
Cancer Lett. 2018; 428:147-159 [PubMed] Related Publications
Osteosarcoma is a primary malignancy that develops in bone, along with serious recurrence and metastasis. As an isoform of Rho family GTPases, RhoB could suppress cell proliferation, invasion, and anti-angiogenesis. But it is not clear how RhoB involves in tumor metastasis. Here we found that expression of RhoB was decreased in osteosarcoma primary samples and cell lines. Ectopic expression of RhoB restrains the migration of osteosarcoma cells in vitro and in vivo, and induces osteosarcoma cell apopotsis. Further study showed that overexpression of RhoB could increase the proportion of B55 in PP2A complex and enhance the dephosphorylation of AKT1 by interacting with B55. Moreover, we demonstrated that miR-19a, which exhibits abnormal expression in highly metastatic osteosarcoma cell lines, could inhibit the expression of RhoB and promote the lung metastasis of osteosarcoma cells in vivo. Our results indicate that miR-19a-mediated RhoB is a critical regulator for the dephosphorylation of AKT1 in osteosarcoma cells. It may have a possible strategy on suppressing osteosarcoma metastasis by miR-19a inhibitory oligonucleotides. The miR-19a/RhoB/AKT1 network may help us to better understand the mechanism of osteosarcoma metastasis.

Panja S, Hayati S, Epsi NJ, et al.
Integrative (epi) Genomic Analysis to Predict Response to Androgen-Deprivation Therapy in Prostate Cancer.
EBioMedicine. 2018; 31:110-121 [PubMed] Article available free on PMC after 15/10/2019 Related Publications
Therapeutic resistance is a central problem in clinical oncology. We have developed a systematic genome-wide computational methodology to allow prioritization of patients with favorable and poor therapeutic response. Our method, which integrates DNA methylation and mRNA expression data, uncovered a panel of 5 differentially methylated sites, which explain expression changes in their site-harboring genes, and demonstrated their ability to predict primary resistance to androgen-deprivation therapy (ADT) in the TCGA prostate cancer patient cohort (hazard ratio = 4.37). Furthermore, this panel was able to accurately predict response to ADT across independent prostate cancer cohorts and demonstrated that it was not affected by Gleason, age, or therapy subtypes. We propose that this panel could be utilized to prioritize patients who would benefit from ADT and patients at risk of resistance that should be offered an alternative regimen. Such approach holds a long-term objective to build an adaptable accurate platform for precision therapeutics.

Lannagan TRM, Lee YK, Wang T, et al.
Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis.
Gut. 2019; 68(4):684-692 [PubMed] Article available free on PMC after 15/10/2019 Related Publications
OBJECTIVE: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene,
DESIGN: We use organoid culture combined with CRISPR/Cas9 genome engineering to sequentially introduce genetic alterations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair.
RESULTS: Targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not
CONCLUSION: We generate rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of our models alongside patient data has led to the identification of a potential susceptibility for this tumour type.

Rajagopalan D, Jha S
An epi(c)genetic war: Pathogens, cancer and human genome.
Biochim Biophys Acta Rev Cancer. 2018; 1869(2):333-345 [PubMed] Related Publications
Cancer is characterized by inter- and intra-tumor heterogeneity and this is also observed in the context of cancers caused by pathogens. Nearly 20% of all cancers are attributable to pathogenic organisms. Pathogenic infections result in deregulation of gene expression both by genetic and epigenetic mechanisms, thereby causing malignant transformation. Another characteristic of pathogen-induced cancers is the occurrence of chronic inflammation due to activation of the innate and adaptive arms of the immune system. This review focuses on the epigenetic changes induced by oncoviruses, parasites, cancer-causing bacteria and 'endogenous pathogens' to trigger host cell proliferation indefinitely as well as the inflammation associated with pathogen-induced cancers. The opportunity of targeting components of both pathogen and host epigenetic machinery to limit tumor progression is also discussed.

Sun Y, Huang YH, Huang FY, et al.
3'-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/Akt/mTOR axis in lung cancer cells.
Theranostics. 2018; 8(7):2044-2060 [PubMed] Article available free on PMC after 15/10/2019 Related Publications

Ribeiro IP, Rodrigues JM, Mascarenhas A, et al.
Cytogenetic, genomic, and epigenetic characterization of the HSC-3 tongue cell line with lymph node metastasis.
J Oral Sci. 2018; 60(1):70-81 [PubMed] Related Publications
Oral carcinoma develops from squamous epithelial cells by the acquisition of multiple (epi) genetic alterations that target different genes and molecular pathways. Herein, we performed a comprehensive genomic and epigenetic characterization of the HSC-3 cell line through karyotyping, multicolor fluorescence in situ hybridization, array comparative genomic hybridization, and methylation-specific multiplex ligation-dependent probe amplification. HSC-3 turned out to be a near-triploid cell line with a modal number of 61 chromosomes. Banding and molecular cytogenetic analyses revealed that nonrandom gains of chromosomal segments occurred more frequently than losses. Overall, gains of chromosome 1, 3q, 5p, 7p, 8q, 9q, 10, 11p, 11q13, 12, 13, 14, 17, 18p, 20, Yp, and Xq were observed. The largest region affected by copy number loss was observed at chromosome 18q. Several of the observed genomic imbalances and their mapped genes were already associated with oral carcinoma and/or adverse prognosis, invasion, and metastasis in cancer. The most common rearrangements observed were translocations in the centromeric/near-centromeric regions. RARB, ESR1, and CADM1 genes were methylated and showed copy number losses, whereas TP73 and GATA5 presented with methylation and copy number gains. Thus, the current study presents a comprehensive characterization of the HSC-3 cell line; the use of this cell line may contribute to enriching the resources available for oral cancer research, especially for the testing of therapeutic agents.

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