Gene Summary

Gene:PRTN3; proteinase 3
Aliases: MBN, MBT, NP4, P29, PR3, ACPA, AGP7, NP-4, PR-3, CANCA, C-ANCA
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 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 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: PRTN3 (cancer-related)

Ogihara K, Kikuchi E, Okazaki S, et al.
Sulfasalazine could modulate the CD44v9-xCT system and enhance cisplatin-induced cytotoxic effects in metastatic bladder cancer.
Cancer Sci. 2019; 110(4):1431-1441 [PubMed] Free Access to Full Article Related Publications
The prognostic role of CD44v9, a variant isoform of CD44 and a new cell surface marker of cancer stem cells, remains unclear in bladder cancer (BC) patients. Furthermore, limited information is available on the functional role of sulfasalazine (SSZ), which could modulate the CD44v9-xCT system in order to enhance cisplatin (CDDP)-induced cytotoxicity and inhibit the metastatic potential of BC. CD44v9 protein expression was examined immunohistochemically in 63 muscle invasive BC (MIBC) patients who underwent radical cystectomy. CD44v9 expression was independently associated with disease recurrence and cancer-specific death in MIBC. Cytotoxic effects, glutathione levels, and reactive oxygen species production by SSZ and CD44v9 and phospho-p38

Wang Q, Yu M, Ma Y, et al.
PHF20L1 antagonizes SOX2 proteolysis triggered by the MLL1/WDR5 complexes.
Lab Invest. 2018; 98(12):1627-1641 [PubMed] Related Publications
Transcriptional factor SOX2 regulates stem cell pluripotency, cell differentiation and tumorigenesis. As a key factor, the expression of SOX2 is tightly regulated at transcriptional and post-translational levels. However, the underlying mechanism of SOX2 protein stability remains to be elucidated. Here we show that the histone-lysine N-methyltransferase MLL1/WDR5 complexes physically interact with SOX2 and evoke SOX2 proteolysis, possibly through methylation on a potential site lysine 42 (K42). Small interfering RNA (siRNA)-mediated gene silencing of the components of the MLL1/WDR5 complexes WDR5, MLL1, RBBP5, and ASH2L lead to the accumulation of SOX2, while forced expression of WDR5 promotes SOX2 ubiquitination and proteolysis. Conversely, PHD finger protein 20-like protein 1 (PHF20L1) associates with SOX2, antagonizes SOX2 ubiquitination and the sequential degradation induced by the MLL1/WDR5 complexes. RNA interferences of PHF20L1 promote the degradation of SOX2, while forced expression of PHF20L1 stabilizes SOX2. Co-silencing of MLL1/WDR5 components and PHF20L1 preclude degradation of SOX2 induced by knockdown of PHF20L1. Moreover, co-expression of PHF20L1 and WDR5 prevent ubiquitination of SOX2 triggered by WDR5 over-expression. However, SOX2 mutant K42R is non-sensitive to the MLL1/WDR5 complexes or PHF20L1. In addition, PHF20L1 may regulate the stability of SOX2 through its malignant brain tumor (MBT) domain, since the degradation of SOX2 is accelerated by UNC1215 and UNC669, inhibitors that bind to the MBT domain. Furthermore, abundant expression of SOX2 is highly correlated to immature ovarian teratoma. Loss of PHF20L1 weakened the tumor initiation ability of PA-1 cells while ablation of MLL1 promoted the growth of tumors. Thus, our studies reveal an antagonistic mechanism by which the protein stability of SOX2 is regulated by the MLL1/WDR5 complexes and PHF20L1, possibly through methylation of SOX2 protein, and provide a novel perspective on SOX2-positive cancer treatment.

Lin R, Wang Y, Chen Q, et al.
TRPM2 promotes the proliferation and invasion of pancreatic ductal adenocarcinoma.
Mol Med Rep. 2018; 17(6):7537-7544 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to investigate transient receptor potential cation channel subfamily M member 2 (TRPM2), a promising therapeutic target and biomarker for pancreatic ductal adenocarcinoma (PDAC) prognosis, in addition to determining its effects regarding tumor progression and invasion. PDAC is a fatal disease with a poor prognosis, and its associated pathogenic molecular mechanisms remain to be determined. In the present study, combined analysis using genomic and transcriptomic data from two PDAC studies was performed to discover a survival‑associated biomarker of PDAC. Survival analysis for genes mutated in ≥10 patients was performed using a Kaplan‑Meier curve and tested for significance using a log‑rank test. Furthermore, gene‑expression correlation analysis was performed to determine the genes with the strongest correlations to TRPM2. In addition, a Cell Counting Kit‑8 assay, a scratch wound‑healing assay and a Transwell assay were performed in the present study to investigate the proliferative, invasive and metastatic ability of PANC‑1 cells in TRPM2‑overexpressing and downregulated groups. The mutated TRPM2 gene had a strong negative correlation with patient survival probability compared with the normal control group (P=1.06x10‑4). Expression of TRPM2 was strongly correlated with expression of probable phospholipid‑transporting ATPase IM, γ‑parvin, tudor domain containing 9, Toll‑like receptor 7 and Scm‑like with four MBT domains protein 2 according to the criterion of a correlation coefficient >0.5. Furthermore, the results of the present study demonstrated that the TRPM2 overexpression in a PDAC cell line (PANC‑1) promoted cell proliferation, invasion and metastatic ability. TRPM2 represents a potential therapeutic target and prognostic marker for patients with PDAC. TRPM2 regulates cell proliferation, invasion and migration; however, the underlying mechanism requires further investigation in future studies.

Rossi F, Attolini CS, Mosquera JL, Gonzalez C
G3 (Bethesda). 2018; 8(4):1205-1214 [PubMed] Free Access to Full Article Related Publications
Single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) are found at different rates in human cancer. To determine if these genetic lesions appear in Drosophila tumors we have sequenced the genomes of 17 malignant neoplasms caused by mutations

Rossi F, Molnar C, Hashiyama K, et al.
Open Biol. 2017; 7(8) [PubMed] Free Access to Full Article Related Publications
Using transgenic RNAi technology, we have screened over 4000 genes to identify targets to inhibit malignant growth caused by the loss of function of

Chung YH, Li SC, Kao YH, et al.
MiR-30a-5p Inhibits Epithelial-to-Mesenchymal Transition and Upregulates Expression of Tight Junction Protein Claudin-5 in Human Upper Tract Urothelial Carcinoma Cells.
Int J Mol Sci. 2017; 18(8) [PubMed] Free Access to Full Article Related Publications
The involvement of microRNAs (miRNAs) in cancer development and their potential as prognostic biomarkers are becoming increasingly known. However, the signature of miRNAs and their regulatory roles in tumorigenesis of upper tract urothelial carcinoma (UTUC) remain to be elucidated. This study aimed to profile the miRNA expression pattern in UTUC tumor tissues and identify candidate miRNAs with prognostic and/or therapeutic functions.
METHODS AND RESULTS: We collected 22 UTUC tissue and adjacent normal tissues samples from patients who underwent nephroureterectomy. The miRNAs signatures of three selected UTUC samples using next-generation sequencing showed that miR-30a-5p was significantly downregulated in UTUC tumors compared to adjacent normal tissues. The differentially-expressed miRNAs were specifically validated by quantitative real-time polymerase chain reaction. In addition, the miRNA expression signatures were analyzed with the transcriptome profile characterized by microarray. Further in vitro studies indicated that overexpression of miR-30a-5p significantly suppressed proliferation, migration, and epithelial-to-mesenchymal transition (EMT) in cultured BFTC-909 UTUC cells
CONCLUSIONS: Taken together, our findings demonstrated that miR-30a-5p inhibits proliferation, metastasis, and EMT, and upregulates the expression of tight junction claudin-5 in UTUC cells. Thus, miR-30a-5p may provide a promising therapeutic strategy for UTUC treatment.

Liu L, Xu Q, Hao S, Chen Y
A Quasi-direct LC-MS/MS-based Targeted Proteomics Approach for miRNA Quantification via a Covalently Immobilized DNA-peptide Probe.
Sci Rep. 2017; 7(1):5669 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) play a vital role in regulating gene expression and are associated with a variety of cancers, including breast cancer. Their distorted and unique expression is a potential marker in clinical diagnoses and prognoses. Thus, accurate determination of miRNA expression levels is a prerequisite for their applications. However, the assays currently available for miRNA detection typically require pre-enrichment, amplification and labeling steps, and most of the assays are only semi-quantitative. Therefore, we developed a quasi-direct liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted proteomics approach to quantify target miRNA by innovatively converting the miRNA signal into the mass response of a reporter peptide via a covalently immobilized DNA-peptide probe. Specifically, the probe containing the targeted proteomics-selected substrate/reporter peptide, GDRAVQLGVDPFR/AVQLGVDPFR, and the DNA sequence complementary to the target miRNA (i.e., miR-21) was first immobilized on APMTS modified silica nanoparticles using PDITC. After the immobilized probe was recognized and hybridized with the target miRNA, the excess probe was degraded using MBN and followed by a trypsin digestion of the hybrids. The reporter peptide was released and quantified using LC-MS/MS. The obtained LOQ was 5 pM. Finally, the developed assay was used for the quantitative analysis of miR-21 in breast cells and tissue samples.

Rahman K, Kumar P, Gupta R, et al.
Role of CD200 in differential diagnosis of mature B-cell neoplasm.
Int J Lab Hematol. 2017; 39(4):384-391 [PubMed] Related Publications
INTRODUCTION: CD 200 is a type I immunoglobulin super family membrane glycoprotein, which is expressed in various mature B-cell neoplasm (MBN). This study aimed at analyzing the expression pattern of CD200 by flow cytometry immunophenotyping (FCI) and to evaluate its utility in narrowing down the differential diagnosis of MBN, particularly in low-grade lymphomas.
METHODS: A total of 160 samples were evaluated by FCI over a period of 2 years (July 2014-June 2016), by a panel of antibodies including CD200. The mean fluorescence intensity (MFI) of CD200 in the neoplastic population was noted and compared among several groups of MBN.
RESULTS: All the 98 cases of chronic lymphocytic leukemia (CLL), five being CD23-negative, expressed CD200 with moderate-to-bright intensity (median MFI: 1174). None of the 24 mantle cell lymphoma (MCL) cases, two being CD23-positive, expressed CD200 (median MFI: 10). All six hairy cell leukemia (HCL) cases expressed CD200. CD200 expression in HCL was brightest among all the MBNs, with a median MFI of 5050. Other MBN (n = 32) expressed CD200 in a proportion of cases and with variable intensity, usually dimmer than CLL.
CONCLUSION: CD200 has a valid role in differentiating CLL from MCL, especially in the cases with immunophenotypic overlap. HCL has a consistent and brightest expression of CD200. It would be prudent to include CD200 in the primary panel of antibodies for MBN analysis.

Rossig C, Pule M, Altvater B, et al.
Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia.
Leukemia. 2017; 31(5):1087-1095 [PubMed] Related Publications
Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein-Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10

Gwak J, Shin JY, Lee K, et al.
SFMBT2 (Scm-like with four mbt domains 2) negatively regulates cell migration and invasion in prostate cancer cells.
Oncotarget. 2016; 7(30):48250-48264 [PubMed] Free Access to Full Article Related Publications
Metastatic prostate cancer is the leading cause of morbidity and mortality in men. In this study, we found that expression level of SFMBT2 is altered during prostate cancer progression and has been associated with the migration and invasion of prostate cancer cells. The expression level of SFMBT2 is high in poorly metastatic prostate cancer cells compared to highly metastatic prostate cancer cells. We also found that SFMBT2 knockdown elevates MMP-2, MMP-3, MMP-9, and MMP-26 expression, leading to increased cell migration and invasion in LNCaP and VCaP cells. SFMBT2 interacts with YY1, RNF2, N-CoR and HDAC1/3, as well as repressive histone marks such as H3K9me2, H4K20me2, and H2AK119Ub which are associated with transcriptional repression. In addition, SFMBT2 knockdown decreased KAI1 gene expression through up-regulation of N-CoR gene expression. Expression of SFMBT2 in prostate cancer was strongly associated with clinicopathological features. Patients having higher Gleason score (≥ 8) had substantially lower SFMBT2 expression than patients with lower Gleason score. Moreover, tail vein or intraprostatic injection of SFMBT2 knockdown LNCaP cells induced metastasis. Taken together, our findings suggest that regulation of SFMBT2 may provide a new therapeutic strategy to control prostate cancer metastasis as well as being a potential biomarker of metastatic prostate cancer.

Jiang Z, Song Q, Zeng R, et al.
MicroRNA-218 inhibits EMT, migration and invasion by targeting SFMBT1 and DCUN1D1 in cervical cancer.
Oncotarget. 2016; 7(29):45622-45636 [PubMed] Free Access to Full Article Related Publications
Repeated infection with high-risk HPV is a major cause for the development and metastasis of human cervical cancer, even though the mechanism of the metastasis is still not completely understood. Here, we reported that miR-218 (microRNA-218) was downregulated in cervical cancer tissues, especially in metastatic cancer tissues. We found that miR-218 expression was associated with clinicopathological characteristics of patients with cervical cancer. MiR-218 overexpression inhibited Epithelial-Mesenchymal Transition (EMT), migration and invasiveness of cervical cancer cells in vitro. Moreover, miR-218 repressed the expression of SFMFBT1 (Scm-like with four MBT domains 1) and DCUN1D1 (defective in cullin neddylation 1, domain containing 1) by direct binding to the 3'UTRs of the mRNAs. The overexpression of SFMBT1 induced EMT and increased the migration and invasiveness of cervical cancer cells, while the overexpression of DCUN1D1 increased the migration and invasiveness of these cells, but did not induce EMT. An inverse correlation was observed between the expression of miR-218 and DCUN1D1 protein in cervical cancer tissues. Importantly, HPV16 E6 downregulated the expression of miR-218 in cervical cancer, while miR-218 rescued the promotion effect of HPV16 E6 on the expression of SFMBT1 and DCUN1D1. Taken together, our results revealed that HPV16 E6 promoted EMT and invasion in cervical cancer via the repression of miR-218, while miR-218 inhibited EMT and invasion in cervical cancer by targeting SFMBT1 and DCUN1D1.

Ayari C, Besançon M, Bergeron A, et al.
Poly(I:C) potentiates Bacillus Calmette-Guérin immunotherapy for bladder cancer.
Cancer Immunol Immunother. 2016; 65(2):223-34 [PubMed] Related Publications
Non-specific immunotherapy consisting of intravesical instillation of Bacillus Calmette-Guérin (BCG) is currently the best available treatment to prevent non-muscle-invasive bladder tumor recurrence and progression. This treatment however is suboptimal, and more effective immunotherapeutic approaches are needed. Toll-like receptors (TLRs) play a major role in the activation of the immune system in response to pathogens and danger signals but also in anti-tumor responses. We previously showed that human urothelial cells express functional TLRs and respond to TLR2 and TLR3 agonists. In this study, we analyzed the potential of polyinosinic:polycytidylic acid [poly(I:C)], a TLR3 agonist, to replace or complement BCG in the treatment of non-muscle-invasive bladder cancer. We observed that poly(I:C) had an anti-proliferative, cytotoxic, and apoptotic effect in vitro on two low-grade human bladder cancer cell lines, MGH-U3 and RT4. In MGH-U3 cells, poly(I:C) induced growth arrest at the G1-S transition. Poly(I:C) also increased the immunogenicity of MGH-U3 and RT4 cells, inducing the secretion of MHC class I molecules and of pro-inflammatory cytokines. By comparison, poly(I:C) had less in vitro impact on two high-grade human bladder cancer cell lines, 5637 and T24, and on MBT-2 murine high-grade bladder cancer cells. The latter can be used as an immunocompetent model of bladder cancer. The combination poly(I:C)/BCG was much more effective in reducing MBT-2 tumor growth in mice than either treatment alone. It completely cured 29% of mice and also induced an immunological memory response. In conclusion, our study suggests that adding poly(I:C) to BCG may enhance the therapeutic effect of BCG.

Zhang S, Shi W, Chen Y, et al.
Overexpression of SYF2 correlates with enhanced cell growth and poor prognosis in human hepatocellular carcinoma.
Mol Cell Biochem. 2015; 410(1-2):1-9 [PubMed] Related Publications
SYF2, also known as p29/NTC31/CBPIN, encodes a nuclear protein that interacts with Cyclin D-type binding-protein 1. SYF2 has been reported to be involved in pre-mRNA splicing and cell cycle regulation. In the present study, we observed that SYF2 was obviously upregulated in HCC tumor tissues and cell lines, and its level was positively correlated with the tumor grade and Ki-67 expression, as well as poor prognosis of HCC. In vitro, using serum starvation-refeeding experiment, our results suggested that SYF2 was upregulated in proliferating HCC cells, and was positive correlated with the expression of PCNA and Cyclin D1. In addition, depletion of SYF2 decreased PCNA and Cyclin D1 levels. Accordingly, interference of SYF2 resulted in cells cycle arrest at G1/S phase in Huh7 HCC cells. Furthermore, we found that SYF2 might interact with Cyclin D1 and could confer doxorubicin resistance in HCC cells. These findings revealed that SYF2 might play a regulatory role in the proliferation of HCC cells. In summary, SYF2 may be a novel prognostic marker and serve as a potential therapeutic target in HCC.

Vu HL, Rosenbaum S, Purwin TJ, et al.
RAC1 P29S regulates PD-L1 expression in melanoma.
Pigment Cell Melanoma Res. 2015; 28(5):590-8 [PubMed] Free Access to Full Article Related Publications
Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5-9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD-L1 is upregulated suggests that oncogenic RAC1 P29S may promote suppression of the antitumor immune response. This is a new insight into the biological function of RAC1 P29S mutations with potential clinical implications as PD-L1 is a candidate biomarker for increased benefit from treatment with anti-PD1 or anti-PD-L1 antibodies.

Matsushima M, Kikuchi E, Matsumoto K, et al.
Intravesical dual PI3K/mTOR complex 1/2 inhibitor NVP-BEZ235 therapy in an orthotopic bladder cancer model.
Int J Oncol. 2015; 47(1):377-83 [PubMed] Related Publications
NVP-BEZ235 is an inhibitor of both phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin complex 1/2 (mTORC1/2), and its antitumor activity is expected to be higher than that of mTORC1 inhibitors because it inhibits the upregulation of pAkt through mTORC2. We examined the efficacy of intravesical NVP-BEZ235 therapy in the treatment of bladder cancer using an orthotopic bladder cancer model. The cytotoxic effects of various concentrations of NVP-BEZ235 in MBT-2 cells were examined using a WST assay. The expression of pAkt, pS6 and p4EBP1 was evaluated in MBT-2 cells treated with NVP-BEZ235 using western blotting. Orthotopic models were established by implanting MBT-2 cells into the bladders of female C3H/He mice. We assigned C3H/He mice to 2 groups: a control group treated with vehicle control (n=15), and a group intravesically administered 40 µM (18.78 mg/l) of NVP-BEZ235 (n=15). NVP-BEZ235 inhibited the viability of MBT-2 cells in a dose-dependent manner. Furthermore, the expression of pAkt, pS6, and p4EBP1 was inhibited in NVP-BEZ235-treated MBT-2 cells. Bladder weights were significantly lower in the NVP-BEZ235-treated group than in the control group (P<0.05). An analysis of the tumor tissues revealed that the NVP-BEZ235 treatment strongly reduced pAkt, pS6 and p4EBP1 levels. An immunohistochemical analysis showed that NVP-BEZ235 significantly inhibited the expression of pS6. Intravesically administered NVP-BEZ235 exerted significant antitumor effects in the orthotopic bladder cancer model by inhibiting the PI3K/Akt/mTOR pathway. The intravesical instillation of a dual PI3K/mTORC1/2 inhibitor may represent a novel therapy for the treatment of bladder cancer.

Sağlam Ö, Ünal ZS, Subaşı C, et al.
IL-6 originated from breast cancer tissue-derived mesenchymal stromal cells may contribute to carcinogenesis.
Tumour Biol. 2015; 36(7):5667-77 [PubMed] Related Publications
Tumor microenvironment is an important factor, which sustains and promotes the tumors by inflammatory signals. Interleukin-6 (IL-6) is known as a multifunctional cytokine, which is a major activator of the signaling pathway of Janus kinases (JAKs)/signal transducer and activator of transcription 3 (STAT3). In this study, we aimed to investigate the effect of IL-6 in the tumor microenvironment on carcinogenesis. For this purpose, healthy breast tissue-derived stromal cells (HBT-SCs) and malign breast tissue-derived stromal cells (MBT-SCs) were co-cultured with MCF-7 (human breast adenocarcinoma cell line) cells using semipermeable membranes. The cell proliferation was monitored with water-soluble tetrazolium (WST) and carboxyfluorescein succinimidyl ester (CFSE) assays. Protein levels were measured by enzyme-linked immunosorbent assay (ELISA) and Western blot hybridization, while gene expressions were measured by real-time PCR. The results demonstrated that IL-6 protein levels increased significantly in the supernatants of MBT-SCs when they were co-cultured with MCF-7 cells. In accordance with this, the expression of IL-6 was significantly higher in MBT-SCs. Additionally, the expression of STAT3 in MCF-7 cells increased slightly when they were co-cultured with MBT-SCs. Considering together, there is an important interaction between tumor microenvironment and tumor cells mediated by IL-6 signaling. Thereby, the targeting on IL-6 signaling in the treatment of cancer might effectively prevent the tumor progression.

Yan S, Deng Y, Qiang Y, et al.
SYF2 is upregulated in human epithelial ovarian cancer and promotes cell proliferation.
Tumour Biol. 2015; 36(6):4633-42 [PubMed] Related Publications
SYF2 is reported to be as a cell cycle regulator at the G1/S transition and encodes a nuclear protein that interacts with cyclin-D-type binding protein 1. In our study, we investigated the role of SYF2 in human epithelial ovarian cancer (EOC) progression. Western blot and immunohistochemistry analysis displayed that SYF2 was overexpressed in EOC tissues and EOC cell lines. In addition, the immunoreactivity of SYF2 was positively correlated with tumor grade and Ki-67 expression. In vitro, serum starvation-refeeding experiment and SYF2-siRNA transfection assay demonstrated that the expression of SYF2 was promoted in the proliferative progression of EOC cells, while knockdown of SYF2 expression decreased and inhibited cell growth rate of EOC cells. With all the results, we support that SYF2 might contribute to EOC progression via modulation of proliferation in EOC cells and would provide a novel therapeutic target of human EOC.

Liu Y, Ni T, Xue Q, et al.
Involvement of p29/SYF2/fSAP29/NTC31 in the progression of NSCLC via modulating cell proliferation.
Pathol Res Pract. 2015; 211(1):36-42 [PubMed] Related Publications
p29, also known as SYF2/fSAP29/NTC31, is a protein associated with chromatin and involved in DNA damage response, cell cycle arrest and pre-mRNA splicing. In p29-depleted cells, DNA replication was reduced and cell population in G1 phase increased. In this study, we investigated the potential role of p29 in the regulation of non-small cell lung cancer (NSCLC) progression. Western blot and immunohistochemistry staining showed that p29 was up-regulated in clinical NSCLC tissues compared with adjacent non-cancerous tissues, and the expression of p29 had a positive correlation with clinical stage and histological differentiation, as well as expression of Ki-67, a proliferating marker. Kaplan-Meier analysis indicated that patients with high level of p29 expression had poor overall survival. In addition, small interfering RNA of p29 was performed, and the effects on NSCLC growth were examined. Interference of p29 blocked S phase entry, inhibited proliferation of A549 cells and up-regulated level of p21 expression. Taken together, these results suggested that p29 might contribute to the progression of NSCLC by enhancing cell proliferation, implicating that targeting p29 might provide beneficial effects on the clinical therapy of NSCLC.

Berlin C, Kowalewski DJ, Schuster H, et al.
Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy.
Leukemia. 2015; 29(3):647-59 [PubMed] Related Publications
Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.

Potrony M, Puig-Butillé JA, Aguilera P, et al.
Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling.
J Am Acad Dermatol. 2014; 71(5):888-95 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cyclin-dependent kinase inhibitor 2A (CDKN2A) is the major high-risk susceptibility gene for melanoma.
OBJECTIVE: We sought to evaluate the effect of CDKN2A mutations in Spanish patients with a high risk of developing melanoma and the association with clinical and family history features.
METHODS: A cross-sectional study design was used to analyze the CDKN2A impact in 702 Spanish patients with a high risk of developing melanoma.
RESULTS: The CDKN2A mutation prevalence was 8.5% in patients with sporadic multiple primary melanoma and 14.1% in familial melanoma. Number of cases in the family, number of primary melanomas, and age of onset were associated with the presence of CDKN2A mutation. Having a CDKN2A mutation in the family increased the prevalence of other cancers (prevalence ratio [PR] 2.99, P=.012) and prevalence of pancreatic (PR 2.97, P=.006), lung (PR 3.04, P<.001), and breast (PR 2.19, P=.018) cancers but not nephrourologic or colon cancer.
LIMITATIONS: Smoking status was not assessed in the individuals with lung cancer.
CONCLUSIONS: Melanoma-prone families with mutations in CDKN2A have an increased prevalence of a broad spectrum of cancers including lung, pancreatic, and breast cancer. This information should be included in genetic counseling and cancer prevention programs for CDKN2A mutation carriers.

Guo J, Yang L, Huang J, et al.
Knocking down the expression of SYF2 inhibits the proliferation of glioma cells.
Med Oncol. 2014; 31(8):101 [PubMed] Related Publications
SYF2 is thought to be a cell cycle regulator at the G1/S transition, which encodes a nuclear protein that interacts with cyclin D-type binding-protein 1. In the present study, we investigated the role of SYF2 in human glioma progression. Immunohistochemical and Western blot analyses were performed in human glioma tissues. High SYF2 expression (located in cell nuclei) was observed in 80 samples, and its level was correlated with the grade of malignancy. A strongly positive correlation was observed between SYF2 and Ki-67 expression (P < 0.01). More importantly, high expression of SYF2 was associated with a poor outcome. In vitro, after the release of U87 cell lines from serum starvation, the expression of SYF2 was upregulated, as well as PCNA and cyclin D1. In addition, knockdown of SYF2 by small interfering RNA transfection diminished the expression of PCNA, cyclin D1 and arrested cell growth at G1 phase. These results indicate that SYF2 in glioma is essential for cell proliferation; thus, targeting SYF2 or its downstream targets may lead to novel therapies for glioblastomas.

Assmann G, Shihadeh K, Poeschel V, et al.
Prevalence of anti-citrullinated protein antibodies (ACPA) in patients with diffuse large B-cell lymphoma (DLBCL): a case-control study.
PLoS One. 2014; 9(2):e88177 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Antibodies against citrullinated proteins (ACPA) have been recognised as the most specific serum marker for rheumatoid arthritis. However, serum autoantibodies such as anti-nuclear antibodies have also been detected in the sera of different lymphatic malignancies without accompanying rheumatologic disease. Therefore, we conducted a study to evaluate the prevalence of ACPA in diffuse large B-cell non-Hodgkin lymphoma (DLBCL).
METHODS: Sera of 395 DLBCL patients and 258 age-matched healthy controls were investigated to evaluate the prevalence of ACPA and RF. ACPA-positive data were stratified into subgroups of RF positivity and established prognostic parameters for DLBCL, including overall survival. In addition, the ACPA serum concentrations levels were compared to an ACPA-positive RA cohort (n = 175). The statistics were performed with χ2 test and Mann- Whitney-U test; Kaplan-Meyer curves (log rank test) were used to analyse the overall survival. P-value <0.05 was statistically significant.
RESULTS: ACPA, but not RF, occurred significantly more frequently in the sera of DLBCL patients than in healthy controls (3.5% versus 0.8%, p = 0.030). However, the ACPA serum concentration levels were significantly lower than in RA patients (median 10.4 versus 124.1 U/ml, p = 0.0001). After subgroup stratification, ACPA positivity in DLBCL was significantly associated with male gender (4.4% versus 0%, p = 0.022; odds ratio 1.046, CI 1.014-1.079) and with RF-IgM seropositivity (1.77% versus 0%, p = 0.043), but not with prognostic parameters for DLBCL.
CONCLUSIONS: DLBCL is associated with a significantly higher prevalence of ACPA, with an increased prevalence in male patients, and simultaneous RF-IgM positivity. However, ACPA is not prognostic for DLBCL. The prevalence of RF-IgM, -IgA, or -IgG did not differ from healthy controls.

Park MA, Choi KC
Effects of 4-nonylphenol and bisphenol A on stimulation of cell growth via disruption of the transforming growth factor-β signaling pathway in ovarian cancer models.
Chem Res Toxicol. 2014; 27(1):119-28 [PubMed] Related Publications
Transforming growth factor β (TGF-β) signaling pathway is a major pathway in cellular processes such as cell growth, apoptosis, and cellular homeostasis. The signaling pathway activated by 17β-estadiol (E2) appeared to inhibit the TGF-β signaling pathway by cross-talk with the TGF-β components in estrogen receptor (ER) positive cells. In this study, we examined the inhibitory effects of endocrine disrupting chemicals (EDCs), including 4-nonylphenol (NP), 4-otylphenol (OP), bisphenol A (BPA), and benzophenon-1 (BP-1), in the TGF-β signaling pathway in BG-1 ovarian cancer cells expressing estrogen receptors (ERs). The transcriptional and translational levels of TGF-β related genes were examined by reverse transcription-PCR (RT-PCR), Western blot analysis, and xenograft mouse models of ovarian cancer cells. As a result, treatment with NP, OP, and BPA induced the expressions of SnoN, a TGF-β pathway inhibitor, and c-Fos, a TGF-β target transcription factor. Treatment with NP, BPA, and BP-1 resulted in decreased phosphorylation of Smad3, a downstream target of TGF-β. These results indicate that NP and BPA may stimulate the proliferation of BG-1 cells via inhibition of the TGF-β signaling pathway. In a xenograft mouse model, transplanted BG-1 ovarian cancer cells showed significantly decreased phosphorylation of Smad3 and increased expression of SnoN in the ovarian tumor masses following treatment with E2, NP, or BPA. In parallel with an in vitro model, the expressions of these TGF-β signaling pathway were similarly regulated by NP or BPA in a xenograft mouse model. These results support the fact that the existence of an unproven relationship between EDCs/ER-α and TGF-β signaling pathway and a further study are required in order to verify more profound and distinct mechanism(s) for the disturbance of the TGF-β signaling pathway by diverse EDCs.

Feichtinger J, Larcombe L, McFarlane RJ
Meta-analysis of expression of l(3)mbt tumor-associated germline genes supports the model that a soma-to-germline transition is a hallmark of human cancers.
Int J Cancer. 2014; 134(10):2359-65 [PubMed] Free Access to Full Article Related Publications
Evidence is starting to emerge indicating that tumorigenesis in metazoans involves a soma-to-germline transition, which may contribute to the acquisition of neoplastic characteristics. Here, we have meta-analyzed gene expression profiles of the human orthologs of Drosophila melanogaster germline genes that are ectopically expressed in l(3)mbt brain tumors using gene expression datasets derived from a large cohort of human tumors. We find these germline genes, some of which drive oncogenesis in D. melanogaster, are similarly ectopically activated in a wide range of human cancers. Some of these genes normally have expression restricted to the germline, making them of particular clinical interest. Importantly, these analyses provide additional support to the emerging model that proposes a soma-to-germline transition is a general hallmark of a wide range of human tumors. This has implications for our understanding of human oncogenesis and the development of new therapeutic and biomarker targets with clinical potential.

Tang M, Shen H, Jin Y, et al.
The malignant brain tumor (MBT) domain protein SFMBT1 is an integral histone reader subunit of the LSD1 demethylase complex for chromatin association and epithelial-to-mesenchymal transition.
J Biol Chem. 2013; 288(38):27680-91 [PubMed] Free Access to Full Article Related Publications
Chromatin readers decipher the functional readouts of histone modifications by recruiting specific effector complexes for subsequent epigenetic reprogramming. The LSD1 (also known as KDM1A) histone demethylase complex modifies chromatin and represses transcription in part by catalyzing demethylation of dimethylated histone H3 lysine 4 (H3K4me2), a mark for active transcription. However, none of its currently known subunits recognizes methylated histones. The Snai1 family transcription factors are central drivers of epithelial-to-mesenchymal transition (EMT) by which epithelial cells acquire enhanced invasiveness. Snai1-mediated transcriptional repression of epithelial genes depends on its recruitment of the LSD1 complex and ensuing demethylation of H3K4me2 at its target genes. Through biochemical purification, we identified the MBT domain-containing protein SFMBT1 as a novel component of the LSD1 complex associated with Snai1. Unlike other mammalian MBT domain proteins characterized to date that selectively recognize mono- and dimethylated lysines, SFMBT1 binds di- and trimethyl H3K4, both of which are enriched at active promoters. We show that SFMBT1 is essential for Snai1-dependent recruitment of LSD1 to chromatin, demethylation of H3K4me2, transcriptional repression of epithelial markers, and induction of EMT by TGFβ. Carcinogenic metal nickel is a widespread environmental and occupational pollutant. Nickel alters gene expression and induces EMT. We demonstrate the nickel-initiated effects are dependent on LSD1-SFMBT1-mediated chromatin modification. Furthermore, in human cancer, expression of SFMBT1 is associated with mesenchymal markers and unfavorable prognosis. These results highlight a critical role of SFMBT1 in epigenetic regulation, EMT, and cancer.

Yen MC, Weng TY, Chen YL, et al.
An HDAC inhibitor enhances cancer therapeutic efficiency of RNA polymerase III promoter-driven IDO shRNA.
Cancer Gene Ther. 2013; 20(6):351-7 [PubMed] Related Publications
Histone deacetylase (HDAC) inhibitors are used in treating certain human malignancies. Our laboratories demonstrated their capability in enhancing antitumor effect of DNA vaccine driven by an RNA polymerase II (RNA pol II) promoter. However, it is unknown whether HDAC inhibitors enhance the therapeutic short hairpin RNA (shRNA) expressed by an RNA polymerase III (RNA pol III) promoter. We investigated whether HDAC inhibitors augmented antitumor effect of indoleamine 2,3 dioxygenase (IDO) shRNA. HDAC inhibitor OSU-HDAC42 and suberoylanilide hydroxamic acid enhanced RNA pol III-driven U6 and H1 promoter activity in three different cell types in vitro: 293, NIH3T3 and dendritic cell line DC2.4. Subcutaneous injection of OSU-HDAC42 enhanced U6 and H1 promoter activity on abdominal skin of mice in vivo. Combination of IDO shRNA and OSU-HDAC42 increased antitumor effect of IDO shRNA in MBT-2 murine bladder tumor model. IDO shRNA induced tumor-infiltrating CD8⁺ and CD4⁺ T cells, whereas OSU-HDAC42 treatment induced tumor-infiltrating CD4⁺ T cells. Combination of OSU-HDAC42 and IDO shRNA further induced tumor-infiltrating natural killer cells and enhanced interferon-γ in lymphocytes, but suppressed interleukin (IL)-4 expression of lymphocytes. In addition, OSU-HDAC42 treatment did not alter mRNA expression of IL-12 and tumor necrosis factor-α. In conclusion, HDAC inhibitor OSU-HDAC42 may serve as adjuvant of the therapeutic shRNA expressed by an RNA pol III promoter.

Weber G, Gerdemann U, Caruana I, et al.
Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant.
Leukemia. 2013; 27(7):1538-47 [PubMed] Free Access to Full Article Related Publications
Adoptive immunotherapy with ex vivo expanded T cells is a promising approach to prevent or treat leukemia. Myeloid leukemias express tumor-associated antigens (TAA) that induce antigen-specific cytotoxic T lymphocyte (CTL) responses in healthy individuals. We explored the feasibility of generating TAA-specific CTLs from stem cell donors of patients with myeloid leukemia to enhance the graft-versus-leukemia effect after stem cell transplantation. CTL lines were manufactured from peripheral blood of 10 healthy donors by stimulation with 15mer peptide libraries of five TAA (proteinase 3 (Pr3), preferentially expressed antigen in melanoma, Wilms tumor gene 1 (WT1), human neutrophil elastase (NE) and melanoma-associated antigen A3) known to be expressed in myeloid leukemias. All CTL lines responded to the mix of five TAA and were multi-specific as assessed by interferon-γ enzyme-linked immunospot. Although donors showed individual patterns of antigen recognition, all responded comparably to the TAAmix. Immunogenic peptides of WT1, Pr3 or NE could be identified by epitope mapping in all donor CTL lines. In vitro experiments showed recognition of partially human leukocyte antigen (HLA)-matched myeloid leukemia blasts. These findings support the development of a single clinical grade multi-tumor antigen-specific T-cell product from the stem cell source, capable of broad reactivity against myeloid malignancies for use in donor-recipient pairs without limitation to a certain HLA-type.

Johnson NM, Lemmens BB, Tijsterman M
A role for the malignant brain tumour (MBT) domain protein LIN-61 in DNA double-strand break repair by homologous recombination.
PLoS Genet. 2013; 9(3):e1003339 [PubMed] Free Access to Full Article Related Publications
Malignant brain tumour (MBT) domain proteins are transcriptional repressors that function within Polycomb complexes. Some MBT genes are tumour suppressors, but how they prevent tumourigenesis is unknown. The Caenorhabditis elegans MBT protein LIN-61 is a member of the synMuvB chromatin-remodelling proteins that control vulval development. Here we report a new role for LIN-61: it protects the genome by promoting homologous recombination (HR) for the repair of DNA double-strand breaks (DSBs). lin-61 mutants manifest numerous problems associated with defective HR in germ and somatic cells but remain proficient in meiotic recombination. They are hypersensitive to ionizing radiation and interstrand crosslinks but not UV light. Using a novel reporter system that monitors repair of a defined DSB in C. elegans somatic cells, we show that LIN-61 contributes to HR. The involvement of this MBT protein in HR raises the possibility that MBT-deficient tumours may also have defective DSB repair.

Han C, Ihara M, Ueda H
Expression of an antibody-enzyme complex by the L-chain fusion method.
J Biosci Bioeng. 2013; 116(1):17-21 [PubMed] Related Publications
In this report, we describe a novel method for directly preparing enzyme-labeled antibodies harvested from IgM-producing hybridoma cells. We constructed expression vectors for antibody light (L) chain-enzyme fusion proteins by linking either the genes for the murine lambda L chain or its constant region (C(L)) with one of two proteins, either the secreted placental alkaline phosphatase or Gaussia luciferase (Gluc). When the vectors were transfected into anti-NP (4-hydroxy-3-nitrophacetyl) IgM-producing myeloma cells, secretion of the IgM-enzyme complex from the gene-transfected cells was confirmed by a direct enzyme-linked immunosorbent assay with an immobilized antigen. Furthermore, when human hybridoma HF10B4, a cell line that produces anti-human lung cancer IgM, was transfected with the vector containing L-Gluc, a significantly stronger signal was obtained for the human lung carcinoma SBC-1 cells than for cervical HeLa cells. Because successful production of an active IgM-enzyme complex containing a heterologous L chain-enzyme fusion was observed, the L-chain fusion method will be a generally applicable method for preparing various IgM-enzyme complexes.

Lee K, Na W, Maeng JH, et al.
Regulation of DU145 prostate cancer cell growth by Scm-like with four mbt domains 2.
J Biosci. 2013; 38(1):105-12 [PubMed] Related Publications
Mammalian SFMBTs have been considered to be polycomb group repressors. However, molecular mechanisms underlying mammalian SFMBTs-mediated gene regulation and their biological function have not been characterized. In the present study, we identified YY1 and methylated histones as interacting proteins of human SFMBT2. We also found that human SFMBT2 binds preferentially to methylated histone H3 and H4 that are associated with transcriptional repression. Using DU145 prostate cancer cells as a model, we showed that SFMBT2 has a transcriptional repression activity on HOXB13 gene expression. In addition, occupancy of SFMBT2 coincided with enrichment of diand tri-methylated H3K9 and H4K20 as well as tri-methylated H3K27 at the HOXB13 gene promoter. When SFMBT2 was depleted by siRNA in DU145 prostate cancer cells, significant up-regulation of HOXB13 gene expression and decreased cell growth were observed. Collectively, our findings indicate that human SFMBT2 may regulate cell growth via epigenetic regulation of HOXB13 gene expression in DU145 prostate cancer cells.

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