Gene Summary

Gene:TFPI2; tissue factor pathway inhibitor 2
Aliases: PP5, REF1, TFPI-2
Summary:This gene encodes a member of the Kunitz-type serine proteinase inhibitor family. The protein can inhibit a variety of serine proteases including factor VIIa/tissue factor, factor Xa, plasmin, trypsin, chymotryspin and plasma kallikrein. This gene has been identified as a tumor suppressor gene in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tissue factor pathway inhibitor 2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: TFPI2 (cancer-related)

Li M, Tang Y, Li Q, et al.
Mono-ADP-ribosylation of H3R117 traps 5mC hydroxylase TET1 to impair demethylation of tumor suppressor gene TFPI2.
Oncogene. 2019; 38(18):3488-3503 [PubMed] Related Publications
Recently, nuclear poly-ADP-ribosylation had aroused research interest in epigenetics, but little attempt to explore functions of mono-ADP-ribosylation of histone, the major formation of histone ADP-ribosylated modification. We have previously reported a novel mono-ADP-ribosylation of H3R117, which promoted proliferation of LoVo cells. Here we showed that mono-ADP-ribosylated H3R117 of LoVo cells depressed demethylation of tumor suppressor TFPI2 promoter by suppressing TET1 expression and adjusting H3K9me3 enrichment of TFPI2 promoter to attenuate affinity of TET1, besides, since high H3K27me3 level was associated with hypermethylation, mono-ADP-ribosylated-H3R117-depended-H3K27me3 of TFPI2 promoter may contribute to hypermethylation of TFPI2. However, H3R117A mutation increased poly-ADP-ribosylated modification of TET1 promoter not TFPI2 promoter, which resulted in boosting transcription and expression of TET1 by altering DNA methylated modification, chromatin accessibility, and histone-methylated modification of TET1 promoter, while knockout TET1 of H3R117A LoVo cells directly led to hypermethylation of TFPI2 promoter and depression of TFPI2 secretion as well as enhanced proliferation, suggested that TET1 played a key role in demethylation of TFPI2, production of TFPI2, and cell proliferation. Bioinformatics analyses reveal prevalent hypermethylation of TFPI2 was an early event in tumorigenesis of colorectal caner, and expression of TET1 and TFPI2 was positive correlation in colorectal cancer and normal tissue. These data suggested that mono-ADP-ribosylation of H3R117 upregulated methylation of TFPI2 by impact TET1, since hypermethyaltion of TFPI2 was an early event in tumorigenesis, selectively target mono-ADP-ribosylation of H3R117 deficiency could be a feasible way to block tumorigenesis of colorectal cancer.

Sachkova A, Sperling S, Mielke D, et al.
Combined Applications of Repurposed Drugs and Their Detrimental Effects on Glioblastoma Cells.
Anticancer Res. 2019; 39(1):207-214 [PubMed] Related Publications
BACKGROUND/AIM: Glioblastoma multiforme (GBM) is a malignant primary brain tumor with high rates of recurrence. This study aimed to investigate the effect of repurposed drug combinations on GBM.
MATERIALS AND METHODS: Viability of U87 MG and 11ST patient-derived GMB cell lines, after valproic acid, tranylcypromine or riluzole alone, in different combinations, as well as combined with standard temozolomide chemotherapy was examined using the MTT assay. Proliferation, mRNA level of tissue factor pathway inhibitor 2 (TFPI2), and cell invasion were evaluated using anti-Ki-67 antibody staining, reverse transcriptase-polymerase chain reaction and xCELLigence system.
RESULTS: The strongest effect on cell viability was achieved by the combination of riluzole with valproic acid (U87MG: 27.2%, 11ST: 25.99%). Tranylcypromine significantly enhanced the effect of temozolomide when used in combination, as did valproic acid. The normally high proliferation of GBM significantly declined under treatment with valproic acid with tranylcypromine (p=0.01). Finally, we observed reduction of invasion comparing single tranylcypromine to its combination with valproic acid or riluzole.
CONCLUSION: These results support the idea that combinations of drugs could increase the treatment efficiency of GBM.

Li K, Zeng L, Wei H, et al.
Identification of gene-specific DNA methylation signature for Colorectal Cancer.
Cancer Genet. 2018; 228-229:5-11 [PubMed] Related Publications
BACKGROUND: Colorectal Cancer (CC), a common disease causing approximately million deaths annually, has been the third most frequent type of malignancy. We aimed to identify gene-specific DNA methylation signature to function as prognostic and predictive markers for CC patient survival.
METHODS: Expression profiles of gene-specific DNA methylation and the corresponding clinical information of 201 CC patients were downloaded from The Cancer Genome Atlas (TCGA) dataset and differentially expressed gene-specific DNA methylation was identified after tumor subtype classification. A risk score model was further built by analyzing the expression data of these gene-specific DNA methylations from the training dataset of CC patients.
RESULTS: Totally, 214 gene-specific DNA methylations were found to be expressed significantly between different subtypes of CC, including 150 up-regulated and 64 down-regulated ones. Up-regulated gene-specific DNA methylation accounted for 70.1% and the down-regulated gene-specific DNA methylation accounted for 29.9%. Hereinto, six gene-specific DNA methylations were obtained, including methy_vimentin and methy_ TFPI2, which were found significantly correlated with overall survival status of patients with CC.
CONCLUSIONS: With the six gene-specific DNA methylation signatures, patients in the training set were divided into low-risk and high- risk groups. What's more, gene-specific DNA methylation target genes were highly associated with protein phosphorylation, which indicated that further research on phosphorylation of target gene-coding protein might provide new sight on the treatment of CC.

Dumitrache LC, Shimada M, Downing SM, et al.
Apurinic endonuclease-1 preserves neural genome integrity to maintain homeostasis and thermoregulation and prevent brain tumors.
Proc Natl Acad Sci U S A. 2018; 115(52):E12285-E12294 [PubMed] Free Access to Full Article Related Publications
Frequent oxidative modification of the neural genome is a by-product of the high oxygen consumption of the nervous system. Rapid correction of oxidative DNA lesions is essential, as genome stability is a paramount determinant of neural homeostasis. Apurinic/apyrimidinic endonuclease 1 (APE1; also known as "APEX1" or "REF1") is a key enzyme for the repair of oxidative DNA damage, although the specific role(s) for this enzyme in the development and maintenance of the nervous system is largely unknown. Here, using conditional inactivation of murine

Cao Y, Guo C, Yin Y, et al.
Lysine‑specific demethylase 2 contributes to the proliferation of small cell lung cancer by regulating the expression of TFPI‑2.
Mol Med Rep. 2018; 18(1):733-740 [PubMed] Free Access to Full Article Related Publications
The present study aimed to investigate the effect of lysine‑specific demethylase 2 (LSD2) in small cell lung cancer (SCLC) and explore its underlying regulatory mechanism. Cell growth was tested by MTT assay and mRNA and protein expression was determined by quantitative polymerase chain reaction (q‑PCR) and western blot analysis, respectively. Chromatin immunoprecipitation (ChIP) was used to investigate the degree of H3K4me2 enrichment in the promoter region of tissue factor pathway inhibitor‑2 (TFPI‑2). SCLC tissues and cell lines presented significantly higher expression of LSD2 and DNA methyltransferase 3B (DNMT3B) and lower expression of TFPI‑2 compared with the controls. In H1417 cells LSD2 overexpression increased the mRNA and protein expression of DNMT3B, while inhibiting the mRNA and protein expression of TFPI‑2. Following transfection with short interfering (si) RNA‑DNMT3B, the expression of TFPI‑2 increased in H1417 cells. The results of ChIP demonstrated that compared with the controls, H3K4me1 enrichment in the TFPI‑2 promoter region was to a lower degree in the H1417 cells with LSD2 overexpression and a higher degree in the H1417 cells with LSD2 silencing. MTT assays revealed that LSD2 overexpression significantly promoted the growth of H69, DMS‑114 and H1417 cells, which was contradictory to the effect on LSD2 silencing. Compared with the LSD2 overexpression cells, SCLC cells with simultaneous overexpression of LSD2 and TFPI‑2 demonstrated a decreased proliferation. These results suggest that LSD2 achieves a promoting effect on SCLC by indirectly regulating TFPI‑2 expression through the mediation of DNMT3B expression or through the regulation of the demethylation of H3K4me1 in the promoter region of the TFPI‑2 gene.

Tsuchiya H, Oura S
Involvement of MAFB and MAFF in Retinoid-Mediated Suppression of Hepatocellular Carcinoma Invasion.
Int J Mol Sci. 2018; 19(5) [PubMed] Free Access to Full Article Related Publications
Retinoids exert antitumor effects through the retinoic acid receptor α (RARα). In the present study, we sought to identify the factors involved in the RARα-mediated transcriptional regulation of the tumor suppressor gene and the tissue factor pathway inhibitor 2 (TFPI2) in hepatocellular carcinoma (HCC). All-

Chettouh H, Mowforth O, Galeano-Dalmau N, et al.
Methylation panel is a diagnostic biomarker for Barrett's oesophagus in endoscopic biopsies and non-endoscopic cytology specimens.
Gut. 2018; 67(11):1942-1949 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Barrett's oesophagus is a premalignant condition that occurs in the context of gastro-oesophageal reflux. However, most Barrett's cases are undiagnosed because of reliance on endoscopy. We have developed a non-endoscopic tool: the Cytosponge, which when combined with trefoil factor 3 immunohistochemistry, can diagnose Barrett's oesophagus. We investigated whether a quantitative methylation test that is not reliant on histopathological analysis could be used to diagnose Barrett's oesophagus.
DESIGN: Differentially methylated genes between Barrett's and normal squamous oesophageal biopsies were identified from whole methylome data and confirmed using MethyLight PCR in biopsy samples of squamous oesophagus, gastric cardia and Barrett's oesophagus. Selected genes were then tested on Cytosponge BEST2 trial samples comprising a pilot cohort (n=20 cases, n=10 controls) and a validation cohort (n=149 cases, n=129 controls).
RESULTS: Eighteen genes were differentially methylated in patients with Barrett'soesophagus compared with squamous controls. Hypermethylation of TFPI2, TWIST1, ZNF345 and ZNF569 was confirmed in Barrett's biopsies compared with biopsies from squamous oesophagus and gastric cardia (p<0.05). When tested in Cytosponge samples, these four genes were hypermethylated in patients with Barrett's oesophagus compared with patients with reflux symptoms (p<0.001). The optimum biomarker to diagnose Barrett's oesophagus was TFPI2 with a sensitivity and specificity of 82.2% and 95.7%, respectively.
CONCLUSION: TFPI2, TWIST1, ZNF345 and ZNF569 methylation have promise as diagnostic biomarkers for Barrett's oesophagus when used in combination with a simple and cost effective non-endoscopic cell collection device.

Wang G, Zeng Y, Chen S, et al.
Localization of TFPI-2 in the nucleus modulates MMP-2 gene expression in breast cancer cells.
Sci Rep. 2017; 7(1):13575 [PubMed] Free Access to Full Article Related Publications
TFPI-2 has recently been recognized as a tumor suppressor, which not only plays a fundamental role in modulation of ECM integrity, but also involves the regulation of many oncogenes. In this study, we investigated the potential mechanism of TFPI-2 in the suppression of breast cancer growth and invasion. We showed that, with either over-expression of TFPI-2 or after treatment with exogenous rTFPI-2, breast cancer cells exhibited reduced proliferation and invasion. We demonstrated that in addition to being secreted, TFPI-2 was also distributed throughout the cytoplasm and nucleus. Nuclear localization of TFPI-2 contributed to inhibition of MMP-2 mRNA expression, which could be reversed after the nuclear localization signal was deleted. In the nucleus, interaction of TFPI-2 with Ap-2α attenuated the binding of AP-2α to the MMP-2 promoter, therefore reducing the transcriptional activity of the gene. Our results suggest that one of the mechanisms by which TFPI-2 inhibits breast cancer cell invasion could be via the regulation of MMP-2 gene transcription.

Henriksen SD, Madsen PH, Larsen AC, et al.
Promoter hypermethylation in plasma-derived cell-free DNA as a prognostic marker for pancreatic adenocarcinoma staging.
Int J Cancer. 2017; 141(12):2489-2497 [PubMed] Related Publications
Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell-free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work-up and treatment. Patients were staged according to the TNM classification. Methylation-specific PCR of 28 genes was performed. Prognostic prediction models for staging of pancreatic adenocarcinoma were developed by multivariable logistic regression analysis using stepwise backwards elimination. Ninety-five patients with pancreatic adenocarcinoma were included. The mean number of hypermethylated genes was identical for stage I, II and III disease (7.09 (95% CI; 5.51-8.66), 7.00 (95% CI; 5.93-8.07) and 6.77 (95% CI; 5.08-8.46)), respectively, and highly significantly different from stage IV disease (10.24 (95% CI; 8.88-11.60)). The prediction model (SEPT9v2, SST, ALX4, CDKN2B, HIC1, MLH1, NEUROG1, and BNC1) enabled the differentiation of stage IV from stage I-III disease (AUC of 0.87 (cut point 0.55; sensitivity 74%, specificity 87%)). Model (MLH1, SEPT9v2, BNC1, ALX4, CDKN2B, NEUROG1, WNT5A, and TFPI2) enabled the differentiation of stage I-II from stage III-IV disease (AUC of 0.82 (cut point 0.66; sensitivity 73%, specificity 80%)). Cell-free DNA promoter hypermethylation has the potential to be blood-based prognostic markers for pancreatic adenocarcinoma, as panels of hypermethylated genes enables the differentiation according to cancer stage. However, further validation is required.

Azizi M, Fard-Esfahani P, Mahmoodzadeh H, et al.
MiR-377 reverses cancerous phenotypes of pancreatic cells via suppressing DNMT1 and demethylating tumor suppressor genes.
Epigenomics. 2017; 9(8):1059-1075 [PubMed] Related Publications
AIM: The aim was to investigate the effect of miR-377 on DNMT1 expression and cancer phenotype in pancreatic cancer cells.
MATERIALS & METHODS: Real-time PCR, luciferase assay, MTT and Annexin-PI staining were used.
RESULTS: Decreased miR-377 and increased DNMT1 (verified as a target for mir-377) levels in pancreatic cancer tissues and cell lines in comparison with normal tissues was confirmed to be influenced by promoter methylation. Also hypermethylation of BNIP3, SPARC, TFPI2 and PENK promoters was observed in tumor samples but not in normal tissues which negatively correlated with their expression. Restoration of miR-377 resulted in a reduction of the expression of DNMT1 and reactivation of BNIP3 and SPARC genes via promoter demethylation. Furthermore, enhanced expression of miR-377 could significantly inhibit cell proliferation and induce apoptosis.
CONCLUSION: Our findings showed that miR-377 through targeting DNMT1 could reduce DNA methylation of some tumor suppressor genes and restore their expression in pancreatic cancer cells.

Chen YL, Hung MH, Chu PY, et al.
Protein phosphatase 5 promotes hepatocarcinogenesis through interaction with AMP-activated protein kinase.
Biochem Pharmacol. 2017; 138:49-60 [PubMed] Related Publications
The serine-threonine protein phosphatase family members are known as critical regulators of various cellular functions, such as survival and transformation. Growing evidence suggests that pharmacological manipulation of phosphatase activity exhibits therapeutic benefits. Ser/Thr protein phosphatase 5 (PP5) is known to participate in glucocorticoid receptor (GR) and stress-induced signaling cascades that regulate cell growth and apoptosis, and has been shown to be overexpressed in various human malignant diseases. However, the role of PP5 in hepatocellular carcinoma (HCC) and whether PP5 may be a viable therapeutic target for HCC treatment are unknown. Here, by analyzing HCC clinical samples obtained from 215 patients, we found that overexpression of PP5 is tumor specific and associated with worse clinical outcomes. We further characterized the oncogenic properties of PP5 in HCC cells. Importantly, both silencing of PP5 with lentiviral-mediated short hairpin RNA (shRNA) and chemical inhibition of PP5 phosphatase activity using the natural compound cantharidin/norcantharidin markedly suppressed the growth of HCC cells and tumors in vitro and in vivo. Moreover, we identified AMP-activated protein kinase (AMPK) as a novel downstream target of oncogenic PP5 and demonstrated that the antitumor mechanisms underlying PP5 inhibition involve activation of AMPK signaling. Overall, our results establish a pathological function of PP5 in hepatocarcinogenesis via affecting AMPK signaling and suggest that PP5 inhibition is an attractive therapeutic approach for HCC.

Gao F, Wang FG, Liu RR, et al.
Epigenetic silencing of miR-130a ameliorates hemangioma by targeting tissue factor pathway inhibitor 2 through FAK/PI3K/Rac1/mdm2 signaling.
Int J Oncol. 2017; 50(5):1821-1831 [PubMed] Related Publications
Hemangiomas are the most common vascular tumors that occur frequently in prematures and females. microRNA (miR)-130a is associated with the growth and invasion in many tumors, and its role in hemangiomas has not been addressed so far. The present study revealed that miR‑130a was overexpressed in infantile hemangioma tissues compared with matched tumor-adjacent tissues. The inhibitor of miR-130a restrained cell growth and induced cell apoptosis in vitro. miR‑130a inhibitor also induced a cell cycle arrest at G2/M phase. Further studies revealed that tissue factor pathway inhibitor 2 (TFPI2) was a novel miR-130a target, due to miR-130a bound directly to its 3'-untranslated region and miR-130a inhibitor enhanced the expression of TFPI2. Contrary to the effects of miR-130a inhibitor, TFPI2 siRNA strongly promoted cell growth and colony formation, whereas TFPI2 overexpression contributed to the suppressing effect of miR-130a inhibitor in cell viability. Furthermore, miR-130a inhibitor reduced the activation of focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/Rac1/anti-mouse double minute (mdm2) pathway proteins, inhibited the expression and nuclear translocation of mdm2. Moreover, FAK overexpression prevented miR-130a inhibitor-induced cell cycle arrest and decrease of cell viability. In vivo experiments, miR-130a inhibition effectively suppressed the tumor growth, restrained angiogenesis by decreasing the expression of angiogenesis markers and the percentage of CD31+ and CD34+. Taken together, our research indicated that miR-130a functions as an oncogene by targeting TFPI2, miR-130a inhibition reduced the growth and angiogenesis of hemangioma by inactivating the FAK/PI3K/Rac1/mdm2 pathway. Thus, miR-130a may serve as a potential therapeutic strategy for the treatment of hemangioma.

McInnes T, Zou D, Rao DS, et al.
Genome-wide methylation analysis identifies a core set of hypermethylated genes in CIMP-H colorectal cancer.
BMC Cancer. 2017; 17(1):228 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant DNA methylation profiles are a characteristic of all known cancer types, epitomized by the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). Hypermethylation has been observed at CpG islands throughout the genome, but it is unclear which factors determine whether an individual island becomes methylated in cancer.
METHODS: DNA methylation in CRC was analysed using the Illumina HumanMethylation450K array. Differentially methylated loci were identified using Significance Analysis of Microarrays (SAM) and the Wilcoxon Signed Rank (WSR) test. Unsupervised hierarchical clustering was used to identify methylation subtypes in CRC.
RESULTS: In this study we characterized the DNA methylation profiles of 94 CRC tissues and their matched normal counterparts. Consistent with previous studies, unsupervized hierarchical clustering of genome-wide methylation data identified three subtypes within the tumour samples, designated CIMP-H, CIMP-L and CIMP-N, that showed high, low and very low methylation levels, respectively. Differential methylation between normal and tumour samples was analysed at the individual CpG level, and at the gene level. The distribution of hypermethylation in CIMP-N tumours showed high inter-tumour variability and appeared to be highly stochastic in nature, whereas CIMP-H tumours exhibited consistent hypermethylation at a subset of genes, in addition to a highly variable background of hypermethylated genes. EYA4, TFPI2 and TLX1 were hypermethylated in more than 90% of all tumours examined. One-hundred thirty-two genes were hypermethylated in 100% of CIMP-H tumours studied and these were highly enriched for functions relating to skeletal system development (Bonferroni adjusted p value =2.88E-15), segment specification (adjusted p value =9.62E-11), embryonic development (adjusted p value =1.52E-04), mesoderm development (adjusted p value =1.14E-20), and ectoderm development (adjusted p value =7.94E-16).
CONCLUSIONS: Our genome-wide characterization of DNA methylation in colorectal cancer has identified 132 genes hypermethylated in 100% of CIMP-H samples. Three genes, EYA4, TLX1 and TFPI2 are hypermethylated in >90% of all tumour samples, regardless of CIMP subtype.

Kinugawa Y, Uehara T, Sano K, et al.
Methylation of Tumor Suppressor Genes in Autoimmune Pancreatitis.
Pancreas. 2017 May/Jun; 46(5):614-618 [PubMed] Related Publications
OBJECTIVES: Autoimmune pancreatitis (AIP) is a representative IgG4-related and inflammatory disease of unknown etiology. To clarify mechanisms of carcinogenesis resulting from AIP, we focused on methylation abnormalities and KRAS mutations in AIP.
METHODS: Six tumor suppressor genes (NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16) that exhibited hypermethylation in pancreatic carcinoma were selected for quantitative SYBR green methylation-specific polymerase chain reaction in 10 AIP specimens, 10 pancreatic adenocarcinoma cases without history of AIP containing carcinoma areas (CAs) and noncarcinoma areas (NCAs), and 11 normal pancreas (NP) samples. KRAS mutation in codons 12, 13, and 61 were also investigated using direct sequencing.
RESULTS: Hypermethylation events (≥10%) were identified in NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16 in 1, 2, 2, 0, 2, and 0 CA cases, respectively, but not in these 6 candidate genes in AIP, NCA, and NP. However, the TFPI2 methylation ratio was significantly higher in AIP than NCA and NP. Direct sequencing results for KRAS showed no single-point mutations in AIP.
CONCLUSIONS: These are the first studies characterizing methylation abnormalities in AIP. AIP's inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.

Li H, Fu C, Miao X, et al.
Multifunctional magnetic co-delivery system coated with polymer mPEG-PLL-FA for nasopharyngeal cancer targeted therapy and MR imaging.
J Biomater Appl. 2017; 31(8):1169-1181 [PubMed] Related Publications
The gene and drug co-delivery system has become one of the primary strategies to overcome cancers. Here, we designed a multifunctional magnetic co-delivery system for nasopharyngeal carcinoma-targeted therapy and MR imaging. Aldehyde sodium alginate (ASA) was used to decorate the oxide iron and load cisplain through coordinate bond to form a core complex. The polymer shell poly(l-lysine)-methoxy-polyethylene glycol-folate was used to coat the core complex through electric interaction to give this nano-medicine a target ability. And this polymer could also give the nano-medicine abilities to adhere and protect DNA, and enhance its solubleness in water. After being transfected with this nano-medicine, the plasmids which contain cancer suppressor gene TFPI2 could enter and express in HNE-1 cells. It caused a higher death and apoptosis rate, inhibited nasopharyngeal carcinoma cells' migration and cloning by the synergic effect together with cisplain. Besides, clear images of this nano-medicine could be got under T2 MR imaging. This magnetic co-delivery system demonstrates a potential as a powerful multifunctional vector for drug delivery and gene vector applications in nasopharyngeal carcinoma.

Hu B, Wang X, Hu S, et al.
miR-21-mediated Radioresistance Occurs via Promoting Repair of DNA Double Strand Breaks.
J Biol Chem. 2017; 292(8):3531-3540 [PubMed] Free Access to Full Article Related Publications
miR-21, as an oncogene that overexpresses in most human tumors, is involved in radioresistance; however, the mechanism remains unclear. Here, we demonstrate that miR-21-mediated radioresistance occurs through promoting repair of DNA double strand breaks, which includes facilitating both non-homologous end-joining (NHEJ) and homologous recombination repair (HRR). The miR-21-promoted NHEJ occurs through targeting

Han K, Gan Z, Lin S, et al.
Elevated expression of serine/threonine phosphatase type 5 correlates with malignant proliferation in human osteosarcoma.
Acta Biochim Pol. 2017; 64(1):11-16 [PubMed] Related Publications
Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults. However, the involvement of serine/threonine phosphatase type 5 (PP5) in osteosarcoma remains unclear. The aim of this study was to evaluate the functional role of PP5 in osteosarcoma cells. Firstly, we found that PP5 is widely expressed in several human osteosarcoma cell lines. Then we used lentivirus-delivered siRNA to silence PP5 expression in Saos-2 and U2OS cell lines. Knockdown of endogenous PP5 expression by shRNA-expressing lentivirus significantly decreased the viability and proliferation of the osteosarcoma cells. Moreover, FACS analysis showed that knockdown of PP5 expression induced a significant arrest in the G0/G1 phase of the cell cycle, which was associated with the inhibition of cell proliferation. Therefore, knockdown of PP5 is likely to provide a novel alternative to targeted therapy of osteosarcoma and deserves further investigation.

Henriksen SD, Madsen PH, Larsen AC, et al.
Cell-free DNA promoter hypermethylation in plasma as a diagnostic marker for pancreatic adenocarcinoma.
Clin Epigenetics. 2016; 8:117 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pancreatic cancer has a 5-year survival rate of only 5-7%. Difficulties in detecting pancreatic cancer at early stages results in the high mortality and substantiates the need for additional diagnostic tools. Surgery is the only curative treatment and unfortunately only possible in localized tumours. A diagnostic biomarker for pancreatic cancer will have a major impact on patient survival by facilitating early detection and the possibility for curative treatment. DNA promoter hypermethylation is a mechanism of early carcinogenesis, which can cause inactivation of tumour suppressor genes. The aim of this study was to examine promoter hypermethylation in a panel of selected genes from cell-free DNA, as a diagnostic marker for pancreatic adenocarcinoma.
METHODS: Patients with suspected or biopsy-verified pancreatic cancer were included prospectively and consecutively. Patients with chronic/acute pancreatitis were included as additional benign control groups. Based on an optimized accelerated bisulfite treatment protocol, methylation-specific PCR of a 28 gene panel was performed on plasma samples. A diagnostic prediction model was developed by multivariable logistic regression analysis using backward stepwise elimination.
RESULTS: Patients with pancreatic adenocarcinoma (
CONCLUSIONS: Cell-free DNA promoter hypermethylation has the potential to be a diagnostic marker for pancreatic adenocarcinoma and differentiate between malignant and benign pancreatic disease. This study brings us closer to a clinical useful diagnostic marker for pancreatic cancer, which is urgently needed. External validation is, however, required before the test can be applied in the clinic.

Weinberger P, Ponny SR, Xu H, et al.
Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma.
Thyroid. 2017; 27(2):236-252 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes.
METHODS: The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways.
RESULTS: There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 (MMP1, ANLN, CEP55, and TFPI2) are known to play a role in ATC progression; however, 6/10 genes (TMEM158, CXCL5, E2F7, DLGAP5, MME, and ASPM) had not been specifically implicated in ATC. Similarly, 3/10 (SFTA3, LMO3, and C2orf40) of the most globally downregulated genes were novel in this context, while 7/10 genes (SLC26A7, TG, TSHR, DUOX2, CDH1, PDE8B, and FOXE1) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors (KLF16, SP3, ETV6, FOXC1, SP1, EGFR1, and MAFK) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that "mitotic cell cycle" is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p-value <10
CONCLUSIONS: By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

Li M, Gao F, Xia Y, et al.
Filtrating colorectal cancer associated genes by integrated analyses of global DNA methylation and hydroxymethylation in cancer and normal tissue.
Sci Rep. 2016; 6:31826 [PubMed] Free Access to Full Article Related Publications
Recently, 5-hydroxymethylcytosine patterning across the tumor genome was considered as a hallmark of cancer development and progression. However, locus-specific difference of hydroxymethylation between colorectal cancer and normal tissue is unknown. In this study, we performed a newly developed method, HMST-seq, to profile 726 aberrant methylated loci and 689 aberrant hydroxymethylated loci synchronously in genome wide of colorectal cancers, majority of which presented higher methylation or lower hydroxymethylationin than in normal group. Besides, abnormal hydroxymethylated modification was more frequently occur at proximal regions close to TSSs and TSSs regions than abnormal methylation. Subsequently, we screened four genes (ALOX15, GHRHR, TFPI2 and TKTL1) with aberrant methylation and aberrant hydroxymethylation at some genome position by functional enrichment analysis as candidate genes associated with colorectal cancer. Our results may allow us to select differentially epigenetically modified target genes implicated in colorectal cancer tumorigenesis.

Liu JF, Li YS, Drew PA, Zhang C
The effect of celecoxib on DNA methylation of CDH13, TFPI2, and FSTL1 in squamous cell carcinoma of the esophagus in vivo.
Anticancer Drugs. 2016; 27(9):848-53 [PubMed] Related Publications
This study examined the in-vivo effect of the NSAID celecoxib on DNA methylation in the promoter region of the tumor-suppressor genes cadherin 13, tissue factor pathway inhibitor 12, and follistatin-like protein 1, and on apoptosis, in esophageal squamous cell carcinoma (ESCC). Forty-five patients who underwent an esophagectomy for ESCC were allocated to either a treatment group (n=22) or a control group (n=23). Patients in the treatment group were administered 800 mg/day of celecoxib for 14 days before surgery. Patients in the control group did not take any type of NSAID. Biopsies of the tumor were collected before surgery and tissue from the resection specimens after surgery. Methylation-specific PCR was used to measure DNA methylation and apoptosis was measured by flow cytometry. There was no difference in the proportion of patients with methylation for each of the genes between the patient groups before treatment. In those patients with pretreatment methylation, there was a significant reduction in the proportion with methylation and a significant increase in the corresponding messenger RNA expression after treatment with celecoxib. In those tissues in which there was a reduction in methylation following celecoxib treatment, there was a significant increase in the percentage of apoptotic cells, but not in the tissues with no change in methylation. In ESCC, in-vivo treatment with celecoxib is associated with a reduction in DNA methylation and increase in messenger RNA expression of tumor-suppressor genes, and increases in apoptosis.

Park SK, Song CS, Yang HJ, et al.
Field Cancerization in Sporadic Colon Cancer.
Gut Liver. 2016; 10(5):773-80 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIMS: Aberrant DNA methylation has a specific role in field cancerization. Certain molecular markers, including secreted frizzled-related protein 2 (SFRP2), tissue factor pathway inhibitor 2 (TFPI2 ), N-Myc downstream-regulated gene 4 (NDRG4) and bone morphogenic protein 3 (BMP3), have previously been shown to be hypermethylated in colorectal cancer (CRC). We aim to examine field cancerization in CRC based on the presence of aberrant DNA methylation in normal-appearing tissue from CRC patients.
METHODS: We investigated promoter methylation in 34 CRC patients and five individuals with normal colonoscopy results. CRC patients were divided into three tissue groups: tumor tissue, adjacent and nonadjacent normal-appearing tissue. The methylation status (positive: methylation level >20%) of SFRP2 , TFPI2 , NDRG4 , and BMP3 promoters was investigated using methylation-specific PCR.
RESULTS: The methylation frequencies of the SFRP2 , TFPI2 , NDRG4 and BMP3 promoters in tumor/adjacent/nonadjacent normal-appearing tissue were 79.4%/63.0%/70.4%, 82.4%/53.6%/60.7%, 76.5%/61.5%/69.2%, 41.2%/35.7%/50.0%, respectively. The methylation levels of the SFRP, TFPI2, NDRG4 and BMP3 promoters in tumor tissues were significantly higher than those in normal-appearing tissue (SFRP2, p=0.013; TFPI2, p<0.001; NDRG4, p=0.003; BMP3, p=0.001). No significant correlation was observed between the methylation levels of the promoters and the clinicopathological variables.
CONCLUSIONS: The field effect is present in CRC and affects both the adjacent and nonadjacent normal-appearing mucosa.

Ma K, Cao B, Guo M
The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma.
Clin Epigenetics. 2016; 8:43 [PubMed] Free Access to Full Article Related Publications
Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC). Tobacco smoking and alcohol consumption are two major risk factors for ESCC, and both tobacco and alcohol were found to induce methylation changes in ESCC. Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression. DNA methylation may occur in the key components of cancer-related signaling pathways. Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-β, and NF-κB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382. Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17. CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC. FHIT methylation is associated with poor prognosis in ESCC. Aberrant DNA methylation changes may serve as diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies.

Nadir Y, Brenner B
Heparanase procoagulant activity in cancer progression.
Thromb Res. 2016; 140 Suppl 1:S44-8 [PubMed] Related Publications
Heparanase is an endo-β-D-glucuronidase that is capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans on cell surfaces and the extracellular matrix. This activity is strongly implicated in tumor metastasis and angiogenesis. We have earlier demonstrated that apart of its well characterized enzymatic activity, heparanase may also affect the hemostatic system in a non-enzymatic manner. We showed that heparanase up-regulated the expression of the blood coagulation initiator-tissue factor (TF) and interacted with the tissue factor pathway inhibitor (TFPI) on the cell surface membrane of endothelial and tumor cells, leading to dissociation of TFPI and resulting in increased cell surface coagulation activity. Moreover, we demonstrated that heparanase directly enhanced TF activity, which led to increased factor Xa production and subsequent activation of the coagulation system. In patients with cancer, increased heparanase procoagulant activity appeared to be a potential predictor of survival. We have also shown that JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor, a finding that may point to a new mechanism of thrombosis in JAK-2 positive patents with essential thrombocytosis. Recently, we found that the solvent accessible surface of TFPI-2 first Kunitz domain had a role in TF/heparanase complex inhibition. Peptides derived from TFPI-2 inhibitory site were shown to reduce coagulation activation induced by heparanase and to attenuate sepsis severity and tumor growth in a mouse model, without predisposing to significant bleeding tendency. These data imply that inhibition of heparanase procoagulant domain is potentially a good target for sepsis and cancer therapy.

Rasmussen SL, Krarup HB, Sunesen KG, et al.
Hypermethylated DNA as a biomarker for colorectal cancer: a systematic review.
Colorectal Dis. 2016; 18(6):549-61 [PubMed] Related Publications
AIM: Improved methods for early detection of colorectal cancer (CRC) are essential for increasing survival. Hypermethylated DNA in blood or stool has been proposed as a biomarker for CRC. Biochemical methods have improved in recent years, and several hypermethylated genes that are sensitive and specific for CRC have been proposed. Articles describing the use of hypermethylated promoter regions in blood or stool as biomarkers for CRC were systematically reviewed.
METHOD: A systematic literature search was performed using the Medline, Web of Science and Embase databases. Studies were included if they analysed hypermethylated genes from stool or blood samples in correlation with CRC. Studies in languages other than English and those based on animal models or cell lines were excluded.
RESULTS: The literature search yielded 74 articles, including 43 addressing blood samples and 31 addressing stool samples. In blood samples, hypermethylated ALX4, FBN2, HLTF, P16, TMEFF1 and VIM were associated with poor prognosis, hypermethylated APC, NEUROG1, RASSF1A, RASSF2A, SDC2, SEPT9, TAC1 and THBD were detected in early stage CRC and hypermethylated P16 and TFPI2 were associated with CRC recurrence. In stool samples, hypermethylated BMP3, PHACTR3, SFRP2, SPG20, TFPI2 and TMEFF2 were associated with early stage CRC.
CONCLUSION: Hypermethylation of the promoters of specific genes measured in blood or stool samples could be used as a CRC biomarker and provide prognostic information. The majority of studies, however, include only a few patients with poorly defined control groups. Further studies are therefore needed before hypermethylated DNA can be widely applied as a clinical biomarker for CRC detection and prognosis.

Liu T, Zhang X, Ke B, et al.
F-127-PEI co-delivering docetaxel and TFPI-2 plasmid for nasopharyngeal cancer therapy.
Mater Sci Eng C Mater Biol Appl. 2016; 61:269-77 [PubMed] Related Publications
The co-delivery of drug and gene has become the primary strategy in cancer therapy. However, to construct one safe co-delivering system with higher drug loading and gene transfection efficiency for cancer therapy is still challenging. Herein, a novel degradable nanocarriers were synthesized and characterized in this study, which was composed of polyethylenimine (PEI)-linked PEO-PPO-PEO (Pluronic F127), called F127-PEI. Then the nanocarrier was used for hydrophobic docetaxel (DOC) and functional gene (TFPI-2 plasmid) co-delivery to treat nasopharyngeal cancer (NPC). The results indicated that F127-PEI nanocarriers had higher DOC loading amount and possessed good gene delivery effect in vitro. For co-delivery analysis, the obtained F127-PEI/DOC/TFPI-2 complexes could induce a more significant apoptosis than DOC or TFPI-2 alone, and decreased invasive capacity of NPC HNE-1 cells more obviously. Moreover, the F127-PEI copolymer exhibited better blood compatibility and lower cytotoxicity compared to PEI-25k by the hemolysis and MTT assays, which suggests a promising potential for NPC therapy.

Huisman C, van der Wijst MG, Schokker M, et al.
Re-expression of Selected Epigenetically Silenced Candidate Tumor Suppressor Genes in Cervical Cancer by TET2-directed Demethylation.
Mol Ther. 2016; 24(3):536-47 [PubMed] Free Access to Full Article Related Publications
DNA hypermethylation is extensively explored as therapeutic target for gene expression modulation in cancer. Here, we re-activated hypermethylated candidate tumor suppressor genes (TSGs) (C13ORF18, CCNA1, TFPI2, and Maspin) by TET2-induced demethylation in cervical cancer cell lines. To redirect TET2 to hypermethylated TSGs, we engineered zinc finger proteins (ZFPs), which were first fused to the transcriptional activator VP64 to validate effective gene re-expression and confirm TSG function. ChIP-Seq not only revealed enriched binding of ZFPs to their intended sequence, but also considerable off-target binding, especially at promoter regions. Nevertheless, results obtained by targeted re-expression using ZFP-VP64 constructs were in line with cDNA overexpression; both revealed strong growth inhibition for C13ORF18 and TFPI2, but not for CCNA1 and Maspin. To explore effectivity of locus-targeted demethylation, ZFP-TET2 fusions were constructed which efficiently demethylated genes with subsequent gene re-activation. Moreover, targeting TET2 to TFPI2 and C13ORF18, but not CCNA1, significantly decreased cell growth, viability, and colony formation in cervical cancer cells compared to a catalytically inactive mutant of TET2. These data underline that effective re-activation of hypermethylated genes can be achieved through targeted DNA demethylation by TET2, which can assist in realizing sustained re-expression of genes of interest.

Koroknai V, Ecsedi S, Vízkeleti L, et al.
Genomic profiling of invasive melanoma cell lines by array comparative genomic hybridization.
Melanoma Res. 2016; 26(2):100-7 [PubMed] Related Publications
Malignant melanoma is one of the most aggressive human cancers. Invasion of cells is the first step in metastasis, resulting in cell migration through tissue compartments. We aimed to evaluate genomic alterations specifically associated with the invasive characteristics of melanoma cells. Matrigel invasion assays were used to determine the invasive properties of cell lines that originated from primary melanomas. Array comparative genomic hybridization analyses were carried out to define the chromosome copy number alterations (CNAs). Several recurrent CNAs were identified by array comparative genomic hybridization that affected melanoma-related genes. Invasive primary cell lines showed high frequencies of CNAs, including the loss of 7q and gain of 12q chromosomal regions targeting PTPN12, ADAM22, FZD1, TFPI2, GNG11, COL1A2, SMURF1, VGF, RELN and GLIPR1 genes. Gain of the GDNF (5p13.1), GPAA1, PLEC and SHARPIN (8q24.3) genes was significantly more frequent in invasive cell lines compared with the noninvasive ones. Importantly, copy number gains of these genes were also found in cell lines that originated from metastases, suggesting their role in melanoma metastasis formation. The present study describes genomic differences between invasive and noninvasive melanoma cell lines that may contribute toward the aggressive phenotype of human melanoma cells.

Wu L, Zhang J, Wu H, Han E
DNA-PKcs interference sensitizes colorectal cancer cells to a mTOR kinase inhibitor WAY-600.
Biochem Biophys Res Commun. 2015; 466(3):547-53 [PubMed] Related Publications
Colorectal cancer (CRC) is one leading contributor of cancer-related mortalities. Mammalian target of rapamycin (mTOR), existing in two complexes (mTORC1/2), is a valuable target for possible CRC interference. In the current study, we showed that WAY-600, a potent mTOR inhibitor, only exerted moderate activity against primary and HT-29 CRC cells. We proposed that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) could be the major resistance factor of WAY-600 in CRC cells. DNA-PKcs inhibitors, including NU7026 and NU7441, dramatically enhanced WAY-600-induced cytotoxic and pro-apoptotic effect against the CRC cells. Further, WAY-600-exerted cytotoxicity was significantly increased in DNA-PKcs-silenced (by targeted siRNA/shRNA) CRC cells, but was attenuated with DNA-PKcs overexpression. Our evidence suggested that DNA-PKcs Thr-2609 phosphorylation might be critical for WAY-600's resistance. Mutation of this site through introducing a dominant negative DNA-PKcs (T2609A) dramatically potentiated WAY-600's sensitivity in HT-29 cells. Meanwhile, overexpression of protein phosphatase 5 (PP5) dephosphorylated DNA-PKcs at Thr-2609, and significantly increased WAY-600's sensitivity in HT-29 cells. In vivo, WAY-600-induced anti-HT-29 xenograft growth activity was significantly potentiated with NU7026 co-administration. These results suggest that DNA-PKcs could be the major resistance factor of WAY-600 in CRC cells.

Ghilardi C, Silini A, Figini S, et al.
Trypsinogen 4 boosts tumor endothelial cells migration through proteolysis of tissue factor pathway inhibitor-2.
Oncotarget. 2015; 6(29):28389-400 [PubMed] Free Access to Full Article Related Publications
Proteases contribute to cancer in many ways, including tumor vascularization and metastasis, and their pharmacological inhibition is a potential anticancer strategy. We report that human endothelial cells (EC) express the trypsinogen 4 isoform of the serine protease 3 (PRSS3), and lack both PRSS2 and PRSS1. Trypsinogen 4 expression was upregulated by the combined action of VEGF-A, FGF-2 and EGF, angiogenic factors representative of the tumor microenvironment. Suppression of trypsinogen 4 expression by siRNA inhibited the angiogenic milieu-induced migration of EC from cancer specimens (tumor-EC), but did not affect EC from normal tissues. We identified tissue factor pathway inhibitor-2 (TFPI-2), a matrix associated inhibitor of cell motility, as the functional target of trypsinogen 4, which cleaved TFPI-2 and removed it from the matrix put down by tumor-EC. Silencing tumor-EC for trypsinogen 4 accumulated TFPI2 in the matrix. Showing that angiogenic factors stimulate trypsinogen 4 expression, which hydrolyses TFPI-2 favoring a pro-migratory situation, our study suggests a new pathway linking tumor microenvironment signals to endothelial cell migration, which is essential for angiogenesis and blood vessel remodeling. Abolishing trypsinogen 4 functions might be an exploitable strategy as anticancer, particularly anti-vascular, therapy.

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