TFF2

Gene Summary

Gene:TFF2; trefoil factor 2
Aliases: SP, SML1
Location:21q22.3
Summary:Members of the trefoil family are characterized by having at least one copy of the trefoil motif, a 40-amino acid domain that contains three conserved disulfides. They are stable secretory proteins expressed in gastrointestinal mucosa. Their functions are not defined, but they may protect the mucosa from insults, stabilize the mucus layer and affect healing of the epithelium. The encoded protein inhibits gastric acid secretion. This gene and two other related trefoil family member genes are found in a cluster on chromosome 21. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:trefoil factor 2
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
Show (12)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 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.

  • Transfection
  • Growth Substances
  • Neoplasm Proteins
  • Signal Transduction
  • Promoter Regions
  • Adenoma
  • Adenocarcinoma
  • Gene Expression Profiling
  • Pancreatic Cancer
  • Cancer Gene Expression Regulation
  • Gene Expression
  • Proteins
  • Up-Regulation
  • Cancer RNA
  • Amino Acid Sequence
  • Molecular Sequence Data
  • Gastric Mucosa
  • Neuropeptides
  • RTPCR
  • DNA Methylation
  • Messenger RNA
  • Young Adult
  • Metaplasia
  • Immunohistochemistry
  • Polymerase Chain Reaction
  • Peptides
  • Trefoil Factor-1
  • Chromosome 21
  • Biomarkers, Tumor
  • Trefoil Factor-2
  • Single Nucleotide Polymorphism
  • Bile Duct Cancer
  • Upstream Stimulatory Factors
  • Muscle Proteins
  • Stomach Cancer
  • Neoplastic Cell Transformation
  • Precancerous Conditions
  • Disease Progression
  • Breast Cancer
  • Case-Control Studies
  • Mucins
Tag cloud generated 13 March, 2017 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: TFF2 (cancer-related)

Klinger PH, Andrade AF, Delsin LE, et al.
Inhibition of SHH pathway mechanisms by arsenic trioxide in pediatric medulloblastomas: a comprehensive literature review.
Genet Mol Res. 2017; 16(1) [PubMed] Related Publications
Recent innovations in the genomic understanding of medulloblastomas have provided new ways to explore this highly invasive malignant brain cancer arising from the cerebellum. Among the four different medulloblastoma subgroups described to date, the sonic hedgehog (SHH) genetic pathway is the pathway activated in the tumorigenesis of medulloblastoma. SHH-related medulloblastomas are usually of nodular/desmoplastic histology and frequently occur in children under the age of three, an age group highly susceptible to the acute and long-term effects of treatment. Several new drugs aimed at SHH modulation are currently under development. This review focuses on the role of arsenic trioxide, a drug well established in clinical practice and probably an under-explored agent in medulloblastoma management, in the SHH pathway.

Campregher PV, Petroni RC, Muto NH, et al.
A Novel Assay for the Identification of NOTCH1 PEST Domain Mutations in Chronic Lymphocytic Leukemia.
Biomed Res Int. 2016; 2016:4247908 [PubMed] Free Access to Full Article Related Publications
Aims. To develop a fast and robust DNA-based assay to detect insertions and deletions mutations in exon 34 that encodes the PEST domain of NOTCH1 in order to evaluate patients with chronic lymphocytic leukemia (CLL). Methods. We designed a multiplexed allele-specific polymerase chain reaction (PCR) combined with a fragment analysis assay to detect specifically the mutation c.7544_7545delCT and possibly other insertions and deletions in exon 34 of NOTCH1. Results. We evaluated our assay in peripheral blood samples from two cohorts of patients with CLL. The frequency of NOTCH1 mutations was 8.4% in the first cohort of 71 unselected CLL patients. We then evaluated a second cohort of 26 CLL patients with known cytogenetic abnormalities that were enriched for patients with trisomy 12. NOTCH1 mutations were detected in 43.7% of the patients with trisomy 12. Conclusions. We have developed a fast and robust assay combining allele-specific PCR and fragment analysis able to detect NOTCH1 PEST domain insertions and deletions.

Oliveira CC, Maciel-Guerra H, Kucko L, et al.
Double-hit lymphomas: clinical, morphological, immunohistochemical and cytogenetic study in a series of Brazilian patients with high-grade non-Hodgkin lymphoma.
Diagn Pathol. 2017; 12(1):3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Double-hit lymphomas (DHL) are rare high-grade neoplasms characterized by two translocations: one involving the gene MYC and another involving genes BCL2 or BCL6, whose diagnosis depends on cytogenetic examination. This research studied DHL and morphological and/or immunophenotypic factors associated with the detection of these translocations in a group of high-grade non-Hodgkin lymphoma cases.
METHOD: Clinical and morphological reviews of 120 cases diagnosed with diffuse large B-cell lymphoma and Burkitt lymphoma were conducted. Immunohistochemistry (CD20, CD79a, PAX5, CD10, Bcl6, Bcl2, MUM1, TDT and Myc) and fluorescence in situ hybridization for detection of MYC, BCL2 and BCL6 gene translocations were performed in a tissue microarray platform.
RESULTS: Three cases of DHL were detected: two with translocations of MYC and BCL2 and one with translocations of MYC and BCL6, all leading to death in less than six months. Among 90 cytogenetically evaluable biopsies, associations were determined between immunohistochemistry and fluorescence in situ hybridization for MYC (p = 0.036) and BCL2 (p = 0.001). However, these showed only regular agreement, indicated by Kappa values of 0.23 [0.0;0.49] and 0.35 [0.13;0.56], respectively. "Starry sky" morphology was strongly associated with MYC positivity (p = 0.01). The detection of three cases of DHL, all resulting in death, confirms the rarity and aggressiveness of this neoplasm.
CONCLUSIONS: The "starry sky" morphological pattern and immunohistochemical expression of Myc and Bcl2 represent possible selection factors for additional cytogenetic diagnostic testing.

Mihara N, Chiba T, Yamaguchi K, et al.
Minimal essential region for krüppel-like factor 5 expression and the regulation by specificity protein 3-GC box binding.
Gene. 2017; 601:36-43 [PubMed] Related Publications
Krüppel-like factor 5 (KLF5) transcriptionally controls the proliferation-differentiation balance of epithelium and is overexpressed in carcinomas. Although genomic region modifying KLF5 expression is widespread in different types of cells, the region that commonly regulates basal expression of the genes across cell-types is uncertain. In this study we determined the minimal essential region for the expression and its regulatory transcription factors using oral carcinoma cells. A reporter assay defined a 186bp region downstream of the transcription start site and a cluster of six GC boxes (GC1-GC6) as the minimal essential region. Mutation in the GC1 or GC6 regions but not other GC boxes significantly decreased the reporter expression. The decrease by the GC1 mutation was reproduced in the 2kbp full-length promoter, but not by the GC6 mutation. Additionally, specificity proteins (Sp) that can be expressed in epithelial cells and bind GC box, Sp3 co-localized with KLF5 in oral epithelium and carcinomas and chromatin immunoprecipitation analyses showed Sp3 as the prime GC1-binding protein. Inhibition of Sp-GC box binding by mithramycin A and knockdown of Sp3 by the short interfering RNA decreased expression of the reporter gene and endogenous KLF5. These data demonstrate that a 186bp region is the minimal essential region and that Sp3-GC1 binding is essential to the basal expression of KLF5.

Bortolotto LF, Barbosa FR, Silva G, et al.
Cytotoxicity of trans-chalcone and licochalcone A against breast cancer cells is due to apoptosis induction and cell cycle arrest.
Biomed Pharmacother. 2017; 85:425-433 [PubMed] Related Publications
Chalcones are precursors of flavonoids that exhibit structural heterogeneity and potential antitumor activity. The objective of this study was to characterize the cytotoxicity of trans-chalcone and licochalcone A (LicoA(1)) against a breast cancer cell line (MCF-7) and normal murine fibroblasts (3T3). Also the mechanisms of the anti-cancer activity of these two compounds were studied. The alkaline comet assay revealed dose-dependent genotoxicity, which was more responsive against the tumor cell line, compared to the 3T3 mouse fibroblast cell line. Flow cytometry showed that the two chalcones caused the cell cycle arrest in the G1 phase and induced apoptosis in MCF-7 cells. Using PCR Array, we found that trans-chalcone and LicoA trigger apoptosis mediated by the intrinsic pathway as demonstrated by the inhibition of Bcl-2 and induction of Bax. In western blot assay, the two chalcones reduced the expression of cell death-related proteins such as Bcl-2 and cyclin D1 and promoted the cleavage of PARP. However, only trans-chalcone induced the expression of the CIDEA gene and protein in these two experiments. Furthermore, transient transfections of MCF-7 using a construction of a promoter-luciferase vector showed that trans-chalcone induced the expression of the CIDEA promoter activity in 24 and 48h. In conclusion, the results showed that trans-chalcone promoted high induction of the CIDEA promoter gene and protein, which is related to DNA fragmentation during apoptosis.

Oliveira JS, Ferreira RS, Santos LM, et al.
Self-declared ethnicity and genomic ancestry in prostate cancer patients from Brazil.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Some studies of polymorphisms in prostate cancer (PCa) analyze individuals in a uniform manner, regardless of genetic ancestry. However, PCa aggressiveness differs between subjects of African descent and those of European extraction. Thus, genetic ancestry analysis may be used to detect population stratification in case-control association studies. We genotyped 11 ancestry informative markers to estimate the contributions of African, European, and Amerindian ancestries in a case-control sample of 213 individuals from Bahia State, Northeast Brazil, including 104 PCa patients. We compared this data with self-reported ancestry and the stratification of cases by PCa aggressiveness according to Gleason score. A larger African genetic contribution (44%) was detected among cases, and a greater European contribution (61%) among controls. Self-declaration data revealed that 74% of PCa patients considered themselves non-white (black and brown), and 41.3% of controls viewed themselves as white. Our data showed a higher degree of European ancestry among fast-growing cancer cases than those of intermediate and slow development. This differs from many previous studies, in which the prevalence of African ancestry has been reported for all grades. Differences were observed between degrees of PCa aggressiveness in terms of genetic ancestry. In particular, the greater European contribution among patients with high-grade PCa indicates that a population's genetic structure can influence case-control studies. This investigation contributes to our understanding of the genetic basis of tumor aggressiveness among groups of different genetic ancestries, especially admixed populations, and has significant implications for the assessment of inter-population heterogeneity in drug treatment effects.

Zhang Y, Huang Y, Jin Z, et al.
A convenient and effective strategy for the enrichment of tumor-initiating cell properties in prostate cancer cells.
Tumour Biol. 2016; 37(9):11973-11981 [PubMed] Related Publications
Stem-like prostate cancer (PrCa) cells, also called PrCa stem cells (PrCSCs) or PrCa tumor-initiating cells (PrTICs), are considered to be involved in the mediation of tumor metastasis and may be responsible for the poor prognosis of PrCa patients. Currently, the methods for PrTIC sorting are mainly based on cell surface marker or side population (SP). However, the rarity of these sorted cells limits the investigation of the molecular mechanisms and therapeutic strategies targeting PrTICs. For PrTIC enrichment, we induced cancer stem cell (CSC) properties in PrCa cells by transducing three defined factors (OCT3/4, SOX2, and KLF4), followed by culture with conventional serum-containing medium. The CSC properties in the transduced cells were evaluated by proliferation, cell cycle, SP assay, drug sensitivity technology, in vivo tumorigenicity, and molecular marker analysis of PrCSCs compared with parental cells and spheroids. After culture with serum-containing medium for 8 days, the PrCa cells transduced with the three factors showed significantly enhanced CSC properties in terms of marker gene expression, sphere formation, chemoresistance to docetaxel, and tumorigenicity. The percentage of CD133(+)/CD44(+) cells was ninefold higher in the transduced cell population than in the adherent PC3 cell population (2.25 ± 0.62 vs. 0.25 ± 0.12 %, respectively), and the SP increased to 1.22 ± 0.18 % in the transduced cell population, but was undetectable in the adherent population. This method can be used to obtain abundant PrTIC material and enables a complete understanding of PrTIC biology and development of novel therapeutic agents targeting PrTICs.

Chen Y, Zhao J, Luo Y, et al.
Downregulated expression of miRNA-149 promotes apoptosis in side population cells sorted from the TSU prostate cancer cell line.
Oncol Rep. 2016; 36(5):2587-2600 [PubMed] Related Publications
The objective of the present study was to identify prostate cancer stem cells and determine the effects of modulating specific miRNAs on prostate CSC proliferation and apoptosis. We applied flow cytometry sorting of side population cells to cultures of prostate cancer cell lines (TSU, DU145, PC-3 and LNCaP). The proportion of SP cells in the TSU line was 1.60±0.40% (mean ± SD), while that of the DU145, PC-3 and LNCaP lines was 0.60±0.05, 0.80±0.05 and 0.60±0.20%, respectively. Because the proportion of SP cells derived from TSU cells is greater, these cells were selected to sort side population cells and non-side population cells. The stem-like properties of SP cells had been identified by in vivo and in vitro experiments, and the related study was published. RNA was extracted from the SP cells and non-SP cells and analyzed using miRNA microarray technology. Fifty-three miRNAs with significant differences in their expression were detected in total. Furthermore, 20 of these miRNAs were validated by qPCR. We found that hsa-miR‑149 expression in SP cells and non-SP cells was significantly different; hsa-miR-149 was significantly upregulated in SP cells. By constructing a vector for lentiviral infection, we found that the downregulation of hsa-miR-149 leads to a reduction in proliferation, an increase in apoptosis, and a significant reduction in the colony formation potential, thus, inhibiting tumor growth in vivo of SP cells from the TSU cell line. The present study will provide new avenues toward understanding the function of prostate cancer stem cells (PCSCs) in tumorigenicity and metastasis.

Freitas VG, Focchi GR, Pereira ER, et al.
HPV genotyping and p16 expression in Xingu Indigenous Park, Brazil.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
The association between high-risk human papillomavirus (HPV) genotypes and p16 expression in indigenous women from the Xingu Indigenous Park, Brazil, was unknown. This study evaluated p16 expression in women with a histological diagnosis of cervical intraepithelial neoplasia (CIN) 3 or higher and correlated this expression with HPV genotypes to determine possible discrepancies in the expression of this marker. We evaluated 37 previously collected samples with different HPV genotypes and high-grade lesions diagnosed based on cytology, histology, and colposcopy. Immunohistochemical analysis was performed using paraffin-embedded tissue sections and the CINtec® Histology Kit. p16 protein expression was investigated by immunostaining with an anti-p16 antibody. HPV genotyping was performed by reverse hybridization. The age of the study population ranged from 22-75 years (43.81 ± 15.89 years) and parity ranged from 1-11 (5.92 ± 2.58). Thirteen different HPV genotypes were found using the INNO-LiPA kit. Single and multiple infections by HPV were found with prevalence of single infections (P = 0.029). Comparison between HPV genotype and simple or multiple infections was highly significant; it was observed more HPV 52 followed by HPV 16 in single infections (P < 0.001). p16 expression was predominantly diffuse, which was observed in 91.7% of lesions, whereas 8.3% were focal (P < 0.001). HPV 52, HPV 16 and 31 were the most prevalent HPV types in high-grade CIN in these indigenous women. Diffuse p16 expression in high-grade CIN was not influenced by the viral genotype; however, more studies are necessary to further our understanding of this restricted group.

Wang JB, Ma DL, Li JY, et al.
Association between expression of DNA mismatch repair genes and clinical features and prognosis of patients with radical resection of colon cancer.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
The aim of this study was to investigate the clinical significance of the expression of DNA mismatch repair (MMR) genes in patients subjected to radical surgical removal of colon cancer, as well as their correlation with disease prognosis. Ninety stage II and III colon cancer patients who received laparoscopic radical resection of colon cancer at our hospital were recruited in this study. The expression of hMLH1, hMSH2, hMSH6, and hPMS2 in the resected tumor tissues was examined by SP immunohistochemistry, in order to analyze the relationship between defective DNA MMR (dMMR) and the clinico-pathological features and prognosis of colon cancer. Patients were followed up over a period of 5-35 months, and the Kaplan-Meier survival curve was plotted. dMMR was confirmed in 27 subjects (30.0%), among whom recurrence with metastasis and death was reported in 5 (18.5%) and 2 (7.4%) patients, respectively. The remaining 63 subjects displayed proficient DNA MMR (pMMR); among these, 19 (30.2%) and 7 (11.1%) recurrences with metastasis and death were reported, respectively. dMMR showed no significant correlation with gender, age, or therapeutic modality (P > 0.05), but was significantly correlated with the degree of differentiation, tumor location, number of resected lymph nodes, presence of ileus, and TNM stage (P < 0.05). The prognosis of patients with dMMR was better than that of patients with pMMR. dMMR serves as a biomarker for the prognosis of stage II/III colon cancers.

de Barros E Lima Bueno R, Ramão A, Pinheiro DG, et al.
HOX genes: potential candidates for the progression of laryngeal squamous cell carcinoma.
Tumour Biol. 2016; 37(11):15087-15096 [PubMed] Related Publications
Laryngeal squamous cell carcinoma (LSCC) is a very aggressive cancer, considered to be a subtype of the head and neck squamous cell carcinoma (HNSCC). Despite significant advances in the understanding and treatment of cancer, prognosis of patients with LSCC has not improved recently. In the present study, we sought to understand better the genetic mechanisms underlying LSCC development. Thirty-two tumor samples were collected from patients undergoing surgical resection of LSCC. The samples were submitted to whole-genome cDNA microarray analysis aiming to identify genetic targets in LSCC. We also employed bioinformatic approaches to expand our findings using the TCGA database and further performed functional assays, using human HNSCC cell lines, to evaluate viability, cell proliferation, and cell migration after silencing of selected genes. Eight members of the homeobox gene family (HOX) were identified to be overexpressed in LSCC samples when compared to normal larynx tissue. Quantitative RT-PCR analysis validated the overexpression of HOX gene family members in LSCC. Receiver operating characteristic (ROC) statistical method curve showed that the expression level of seven members of HOX gene family can distinguish tumor from nontumor tissue. Correlation analysis of clinical and gene expression data revealed that HOXC8 and HOXD11 genes were associated with the differentiation degree of tumors and regional lymph node metastases, respectively. Additionally, siRNA assays confirmed that HOXC8, HOXD10, and HOXD11 genes might be critical for cell colony proliferation and cell migration. According to our findings, several members of the HOX genes were overexpressed in LSCC samples and seem to be required in biological processes involved in tumor development. This suggests that HOX genes might play a critical role in the physiopathology of LSCC tumors.

Palaska I, Gagari E, Theoharides TC
The effects of P. gingivalis and E. coli LPS on the expression of proinflammatory mediators in human mast cells and their relevance to periodontal disease.
J Biol Regul Homeost Agents. 2016 Jul-Sep; 30(3):655-664 [PubMed] Related Publications
Mast cells (MCs) are tissue-resident immune cells that participate in a variety of allergic and inflammatory conditions, including periodontal disease, through the release of cytokines, chemokines and proteolytic enzymes. Porhyromonas gingivalis (P. g) is widely recognized as a major pathogen in the development and progression of periodontitis. Here we compared the differential effects of lipopolysaccharides (LPS) from P. g and E. coli on the expression and production of tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein (MCP-1) by human MCs. Human LAD2 MCs were stimulated with LPS from either P. g or E. coli (1-1000 ng/ml). MCs were also stimulated with SP (2μM) serving as the positive control or media alone as the negative control. After 24 h, the cells and supernatant fluids were collected and analyzed for β-Hexosaminidase (β-hex) spectrophotometrically, TNF, VEGF and MCP-1 release by ELISA and real-time polymerase chain reaction (PCR) for mediator gene expression, respectively. To assess the functional role of tolllike receptors (TRL) in mediator release, MCs were pre-incubated with either anti-TLR2 or anti- TLR4 (2 μg/ml) polyclonal antibody for 1 h before stimulation with LPS. When MCs were stimulated with SP (2 μM), there was a statistically significant β-hex release as well as release of TNF, VEGF and MCP-1. Stimulation of MCs with either type of LPS did not induce degranulation based on the lack of β-hex release. However, both types of LPS stimulated expression and release of TNF, VEGF and MCP-1. Although, P. g LPS induced significant release of TNF, VEGF and MCP-1, the effect was not concentration-dependent. There was no statistically significant difference between the effects of P. g and E. coli LPS. P. g LPS stimulated TNF through TLR-2 while E. coli utilized TRL-4 instead. In contrast, VEGF release by P. g LPS required both TRL-2 and TRL-4 while E. coli LPS required TLR-4. Release of MCP-1 was independent of TLR-2 or TLR-4. P. g LPS activates human MCs to generate and release TNF, VEGF and MCP-1 through different TLRs than E. coli LPS. MCs may, therefore, be involved in the inflammatory processes responsible for periodontal disease.

Dasgupta H, Mukherjee N, Islam S, et al.
Frequent alterations of homologous recombination repair pathway in primary and chemotolerant breast carcinomas: clinical importance.
Future Oncol. 2017; 13(2):159-174 [PubMed] Related Publications
AIM: To understand the importance of homologous recombination repair pathway in development of breast carcinoma (BC), alterations of some key regulatory genes like BRCA1, BRCA2, FANCC and FANCD2 were analyzed in pretherapeutic/neoadjuvant chemotherapy (NACT)-treated BC samples.
MATERIALS & METHODS: Alterations (deletion/methylation/expression) of the genes were analyzed in 118 pretherapeutic and 41 NACT-treated BC samples.
RESULTS: High deletion/methylation (29-68%) and 64-78% overall alterations of the genes were found in the samples. Concordance was evident between alteration and protein expression of the genes. Estrogen/progesterone receptor-negative tumors showed significantly high alterations even in NACT-treated samples having low CD44 and proliferating cell nuclear antigen expression. Pretherapeutic patients with alterations showed poor prognosis.
CONCLUSION: Alterations of homologous recombination repair pathway genes are needed for the development of BC.

DO Carmo NG, Sakamoto LH, Pogue R, et al.
Altered Expression of PRKX, WNT3 and WNT16 in Human Nodular Basal Cell Carcinoma.
Anticancer Res. 2016; 36(9):4545-51 [PubMed] Related Publications
BACKGROUND/AIM: Nodular and superficial are the most common subtypes of basal cell carcinoma (BCC). Signaling pathways such as Hedgehog (HH) and Wingless (WNT) signaling are associated with BCC phenotypic variation. The aim of the study was to evaluate of the expression profiles of 84 genes related to the WNT and HH signaling pathways in patients with nodular and superficial BCC.
MATERIALS AND METHODS: A total of 58 BCCs and 13 samples of normal skin were evaluated by quantitative real-time polymerase chain reaction (qPCR) to detect the gene-expression profile.
RESULTS: qPCR array showed segregation in BCC subtypes compared to healthy skin. PRKX, WNT3 and WNT16 were significantly (p<0.05) altered: PRKX was up-regulated, and WNT3 and WNT16 were down-regulated in nodular BCC.
CONCLUSION: PRKX, WNT3 and WNT16 genes, belonging to the WNT signaling pathway, are involved in the tumorigenic process of nodular BCC.

Guo XQ, Li XY
The expression and clinical significance of metastasis suppressor gene and matrix metalloproteinase-2 in esophageal squamous cell of carcinoma.
Pak J Pharm Sci. 2016; 29(4 Suppl):1339-42 [PubMed] Related Publications
To investigate the expression and clinical significance of metastasis suppressor gene and matrix metalloproteinase-2 in esophageal squamous cell of carcinoma. choose 30 cases of specimens of esophageal squamous cell carcinoma which are removed in surgery and confirmed by pathology and 30 cases of specimens of normal esophageal mucosa. Use immunohistochemistry SP method to detect the expression of nm23-H1, MMP-2 protein in esophageal squamous cell carcinoma and normal esophageal mucosal. The positive rate of nm23-H1 protein in esophageal squamous cell carcinoma was 43.3% (13/30), while that in normal esophageal mucosa was 100% (30/30), which has a significant difference between them (χ2=22. 083, P<0.05). The positive rate of MMP-2 protein in esophageal squamous cell carcinoma was 90.0% (27/30), while that in normal esophageal mucosa was 33.3% (10/30), and there is a significant difference between them (χ2=28. 370, P<0.05); For the expression of nm23-H1 and MMP-2 in esophageal squamous cell carcinoma, there was nothing to do with sex, age and tumor size (P>0.05), but it was related to the degree of tumor differentiation, depth of invasion and lymph node metastasis (P<0.05); The expression of nm23-H1 is related to the cut end of residual cancer (P<0.05), while the expression of MMP-2 has nothing to do with the cut end of residual cancer (P>0.05); The expression of nm23-H1 and MMP-2 in esophageal squamous cell carcinoma was negatively correlated. nm23-H1 and MMP-2 have played a role in the development of esophageal cancer, which can promote the occurence of distant metastasis; The loss of expression of nm23-H1 may be related to cut end residual cancer; nm23-H1 and MMP-2 may be as an indicator for esophageal cancer metastasis and prognosis.

Shin SS, Park SS, Hwang B, et al.
MicroRNA-892b influences proliferation, migration and invasion of bladder cancer cells by mediating the p19ARF/cyclin D1/CDK6 and Sp-1/MMP-9 pathways.
Oncol Rep. 2016; 36(4):2313-20 [PubMed] Related Publications
Cancers often utilize microRNAs to suppress tumor suppressor genes, thus facilitating their potential for growth and invasion. In the present study, we report the novel findings that miR-892b inhibits proliferation, migration and invasion of bladder cancer cells. The basal expression level of miR‑892b was significantly lower in 3 different bladder cancer cell lines than in normal human urothelial cells. Transfection of miR-892b mimics to bladder cancer cells resulted in dose‑dependent growth arrest. Flow cytometric analysis of the cell cycle showed that miR-892b-transfected bladder cancer cells were subject to arrest in the G1 phase, which was due to the downregulation of cyclin D1 and CDK6 followed by upregulation of p19ARF. In addition, overexpression of miR-892b impeded the migration and invasion of EJ cells. Expression of MMP-9 in EJ cells was blocked by transfection of miR-892b; the effect was regulated, at least in part, by activation of the Sp-1 transcription factor. Overall, we verified that miR-892b regulates the p19ARF/cyclin D1/CDK6 and Sp-1/MMP-9 signaling networks in bladder cancer cells and may provide a treatment option for advanced-stage bladder cancers.

Micocci KC, Moritz MN, Lino RL, et al.
ADAM9 silencing inhibits breast tumor cells transmigration through blood and lymphatic endothelial cells.
Biochimie. 2016 Sep-Oct; 128-129:174-82 [PubMed] Related Publications
ADAMs are transmembrane multifunctional proteins that contain disintegrin and metalloprotease domains. ADAMs act in a diverse set of biological processes, including fertilization, inflammatory responses, myogenesis, cell migration, cell proliferation and ectodomain cleavage of membrane proteins. These proteins also have additional functions in pathological processes as cancer and metastasis development. ADAM9 is a member of ADAM protein family that is overexpressed in several types of human carcinomas. The aim of this study was to investigate the role of ADAM9 in hematogenous and lymphatic tumor cell dissemination assisting the development of new therapeutic tools. The role of ADAM9 in the interaction of breast tumor cells (MDA-MB-231) and endothelial cells was studied through RNA silencing. ADAM9 silencing in MDA-MB-231 cells had no influence in expression of several genes related to the metastatic process such as ADAM10, ADAM12, ADAM17, cMYC, MMP9, VEGF-A, VEGF-C, osteopontin and collagen XVII. However, there was a minor decrease in ADAM15 expression but an increase in that of MMP2. Moreover, ADAM9 silencing had no effect in the adhesion of MDA-MB-231 cells to vascular (HMEC-1 and HUVEC) and lymphatic cells (HMVEC-dLyNeo) under flow condition. Nevertheless, siADAM9 in MDA-MB-231 decreased transendothelial cell migration in vitro through HUVEC, HMEC-1 and HMVEC-dLyNeo (50%, 40% and 32% respectively). These results suggest a role for ADAM9 on the extravasation step of the metastatic cascade through both blood and lymph vessels.

Canevari RA, Marchi FA, Domingues MA, et al.
Identification of novel biomarkers associated with poor patient outcomes in invasive breast carcinoma.
Tumour Biol. 2016; 37(10):13855-13870 [PubMed] Related Publications
Breast carcinoma (BC) corresponds to 23 % of all cancers in women, with 1.38 million new cases and 460,000 deaths worldwide annually. Despite the significant advances in the identification of molecular markers and different modalities of treatment for primary BC, the ability to predict its metastatic behavior is still limited. The purpose of this study was to identify novel molecular markers associated with distinct clinical outcomes in a Brazilian cohort of BC patients. We generated global gene expression profiles using tumor samples from 24 patients with invasive ductal BC who were followed for at least 5 years, including a group of 15 patients with favorable outcomes and another with nine patients who developed metastasis. We identified a set of 58 differentially expressed genes (p ≤ 0.01) between the two groups. The prognostic value of this metastasis signature was corroborated by its ability to stratify independent BC patient datasets according to disease-free survival and overall survival. The upregulation of B3GNT7, PPM1D, TNKS2, PHB, and GTSE1 in patients with poor outcomes was confirmed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in an independent sample of patients with BC (47 with good outcomes and eight that presented metastasis). The expression of BCL2-associated agonist of cell death (BAD) protein was determined in 1276 BC tissue samples by immunohistochemistry and was consistent with the reduced BAD mRNA expression levels in metastatic cases, as observed in the oligoarray data. These findings point to novel prognostic markers that can distinguish breast carcinomas with metastatic potential from those with favorable outcomes.

Wätjen W, Ebada SS, Bergermann A, et al.
Cytotoxic effects of the anthraquinone derivatives 1'-deoxyrhodoptilometrin and (S)-(-)-rhodoptilometrin isolated from the marine echinoderm Comanthus sp.
Arch Toxicol. 2017; 91(3):1485-1495 [PubMed] Related Publications
We investigated cytotoxic effects of the anthraquinone derivatives 1'-deoxyrhodoptilometrin (SE11) and (S)-(-)-rhodoptilometrin (SE16) isolated from the marine echinoderm Comanthus sp. in two tumor cell lines (C6 glioma, Hct116 colon carcinoma). Both compounds showed cytotoxic effects, with SE11 [IC50-value (MTT assay): 13.1 µM in Hct116 cells] showing a higher potency to induce apoptotic and necrotic cell death. No generation of oxidative stress was detectable (DCF assay), and also no modulation of Nrf2/ARE and NFκB signaling could be shown. Investigation of 23 protein kinases associated with cell proliferation, survival, metastasis, and angiogenesis showed that both compounds were potent inhibitors of distinct kinases, e.g., IGF1-receptor kinase, focal adhesion kinase, and EGF receptor kinase with SE11 being a more potent compound (IC50 values: 5, 18.4 and 4 µM, respectively). SE11 caused a decrease in ERK phosphorylation which may be a consequence of the inhibition of EGF receptor kinase by this compound. Since an inhibition of the EGF receptor/MAPK pathway is an important target for diverse cytostatic drugs, we suggest that the anthraquinone derivative 1'-deoxyrhodoptilometrin (SE11) may be an interesting lead structure for the development of new anticancer drugs.

Michna A, Schötz U, Selmansberger M, et al.
Transcriptomic analyses of the radiation response in head and neck squamous cell carcinoma subclones with different radiation sensitivity: time-course gene expression profiles and gene association networks.
Radiat Oncol. 2016; 11:94 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Acquired and inherent radioresistance of tumor cells is related to tumor relapse and poor prognosis - not only in head and neck squamous cell carcinoma (HNSCC). The underlying molecular mechanisms are largely unknown. Therefore, systemic in-depth analyses are needed to identify key regulators of radioresistance. In the present study, subclones of the CAL-33 HNSCC cell line with different radiosensitivity were analyzed to identify signaling pathways related to the different phenotypes.
METHODS: Subclones with altered radiosensitivity were generated by fractionated irradiation of the parental CAL-33 cells. Differences in radiosensitivity were confirmed in colony formation assays. Selected subclones were characterized at the genomic and transcriptomic level by SKY, array CGH, and mRNA-microarray analyses. Time-course gene expression analyses upon irradiation using a natural cubic spline regression model identified temporally differentially expressed genes. Moreover, early and late responding genes were identified. Gene association networks were reconstructed using partial correlation. The Reactome pathway database was employed to conduct pathway enrichment analyses.
RESULTS: The characterization of two subclones with enhanced radiation resistance (RP) and enhanced radiosensitivity (SP) revealed distinct genomic and transcriptomic changes compared to the parental cells. Differentially expressed genes after irradiation shared by both subclones pointed to important pathways of the early and late radiation response, including senescence, apoptosis, DNA repair, Wnt, PI3K/AKT, and Rho GTPase signaling. The analysis of the most important nodes of the gene association networks revealed pathways specific to the radiation response in different phenotypes of radiosensitivity. Exemplarily, for the RP subclone the senescence-associated secretory phenotype (SASP) together with GPCR ligand binding were considered as crucial. Also, the expression of endogenous retrovirus ERV3-1in response to irradiation has been observed, and the related gene association networks have been identified.
CONCLUSIONS: Our study presents comprehensive gene expression data of CAL-33 subclones with different radiation sensitivity. The resulting networks and pathways associated with the resistant phenotype are of special interest and include the SASP. The radiation-associated expression of ERV3-1 also appears highly attractive for further studies of the molecular mechanisms underlying acquired radioresistance. The identified pathways may represent key players of radioresistance, which could serve as potential targets for molecularly designed, therapeutical intervention.

de Brito BS, Gaspar NG, Egal ES, et al.
PLAG1 expression is maintained in recurrent pleomorphic adenoma.
Virchows Arch. 2016; 469(4):477-81 [PubMed] Related Publications
The proto-oncogene (pleomorphic adenoma gene 1 (PLAG1)) is immunohistochemically overexpressed in pleomorphic adenoma (PA). Its expression in recurrent pleomorphic adenoma (RPA), however, has not been investigated. Since complex mechanisms are involved in tumor recurrence, the aim of this study was to investigate whether PLAG1 overexpression occurs in RPA. We studied PLAG1 protein expression in 40 PAs and 36 RPAs by immunohistochemistry. Cases with immunopositive cells were classified into two categories, between 10 and 50 % and >50 %. In both groups, PLAG1 expression was observed in both epithelial and myoepithelial cells. Of PAs, 37 cases (93 %) were positive, while this was the case in 34 RPA cases (94 %). Our findings suggest that in addition to morphological similarity, PA and RPA express PLAG1, which might play a role in tumor recurrence. Furthermore, as for PA, expression of PLAG1 can be considered a valuable diagnostic marker for RPA.

Ignarro RS, Facchini G, Vieira AS, et al.
Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells.
Mol Cell Biochem. 2016; 418(1-2):167-78 [PubMed] Related Publications
Temozolomide (TMZ) is an alkylating agent used to treat glioblastoma. This tumor type synthesizes the antioxidant glutathione through system X c (-) , which is inhibited by sulfasalazine (SAS). We exposed A172 and T98G human glioblastoma cells to a presumably clinically relevant concentration of TMZ (25 µM) and/or 0.5 mM SAS for 1, 3, or 5 days and assessed cell viability. For both cell lines, TMZ alone did not alter viability at any time point, while the coadministration of TMZ and SAS significantly reduced cell viability after 5 days. The drug combination exerted a synergistic effect on A172 cells after 3 and 5 days. Therefore, this particular lineage was subjected to complementary analyses on the genetic (transcriptome) and functional (glutathione and proliferating cell nuclear antigen (PCNA) protein) levels. Cellular pathways containing differentially expressed genes related to the cell cycle were modified by TMZ alone. On the other hand, SAS regulated pathways associated with glutathione metabolism and synthesis, irrespective of TMZ. Moreover, SAS, but not TMZ, depleted the total glutathione level. Compared with the vehicle-treated cells, the level of PCNA protein was lower in cells treated with TMZ alone or in combination with SAS. In conclusion, our data showed that the association of TMZ and SAS is cytotoxic to T98G and A172 cells, thus providing useful insights for improving TMZ clinical efficacy through testing this novel drug combination. Moreover, the present study not only reports original information on differential gene expression in glioblastoma cells exposed to TMZ and/or SAS but also describes an antiproliferative effect of TMZ, which has not yet been observed in A172 cells.

Hirsch Werle C, Damiani I, Paier Milanez G, et al.
Antimelanoma effect of Salmonella Typhimurium integration host factor mutant in murine model.
Future Oncol. 2016; 12(20):2367-78 [PubMed] Related Publications
AIM: This study aimed to evaluate an attenuated Salmonella ihfA-null mutant strain as therapeutic agent to control tumor growth.
MATERIALS & METHODS: After bacterial toxicity evaluation, C57BL/6JUnib mice were inoculated with B16F10 cells and treated with two Salmonella strains (LGBM 1.1 and LGBM 1.41).
RESULTS: LGBM 1.1 can reduce tumor mass, but it exerts some toxic effects. Although LGBM 1.41 is less toxic than LGBM 1.1, it does not reduce tumor mass significantly. Indeed, animals treated with LGBM 1.41 present only slightly initial delay in tumor progression and increased survival rate as compared with the control.
CONCLUSION: The null-mutants of ihfA gene of Salmonella Typhimurium could be a promising candidate for melanoma treatment.

Vega-Benedetti AF, Saucedo C, Zavattari P, et al.
PLAGL1: an important player in diverse pathological processes.
J Appl Genet. 2017; 58(1):71-78 [PubMed] Related Publications
The PLAGL1 gene encodes a homonymous zinc finger protein that promotes cell cycle arrest and apoptosis through multiple pathways. The protein has been implicated in metabolic, genetic, and neoplastic illnesses, but the molecular mechanisms by which the protein PLAGL1 participates in such diverse processes remains to be elucidated. In this review, we focus mainly on the molecular biology of PLAGL1 and the relevance of its abnormalities to several pathological processes.

Shan GP, Zhang P, Li P, et al.
Numb Gene Enhances Radiation Sensitivity of Nonsmall Cell Lung Cancer Stem Cells.
Cancer Biother Radiopharm. 2016; 31(5):180-8 [PubMed] Related Publications
OBJECTIVE: To study the effects of Numb gene expression on radiation sensitivity of nonsmall cell lung cancer (NSCLC) stem cells.
MATERIALS AND METHODS: The side population (SP) cells A549-SP were transfected with pcDNA3.1 (pcDNA3.1 group), pcDNA-Numb (pcDNA-Numb group) and shRNA-Numb (shRNA-Numb group). Real-time quantitative polymerase chain reaction and Western blot were performed to determine Numb expression; MTT method was used to measure the proliferation activity change of the NSCLC stem cells both before and after irradiation with different doses of 60Coγ ray; Hoechst staining and Annexin V-FITC/PI were used to detect the apoptosis of the NSCLC stem cells; and colony-forming assay was used to determine the effect of Numb expression on radiation sensitivity of the NSCLC stem cells.
RESULTS: Increased mRNA and protein expressions of the A549-SP cells were found in the pcDNA-Numb group, and decreased mRNA and protein expressions were found in the shRNA-Numb group. The optical density value of the cells decreased in the pcDNA-Numb group but increased in the shRNA-Numb group. The cells with over-expressed Numb showed obvious nuclear condensation and fragmentation; the apoptosis rate increased significantly. The cells with knockdown Numb showed less nuclear damage; the apoptosis rate significantly decreased. After irradiation, the cells in the pcDNA-Numb group showed decreased survival rate, clonality, and the values of D0, Dq, N, and SF2; whereas the cells in the shRNA-Numb group showed the opposite trend.
CONCLUSIONS: Radiation sensitivity of NSCLC stem cells was enhanced with the increase of Numb expression. Determination of Numb expression helped to evaluate the response of lung cancer to radiotherapy, which was important for guiding tumor treatment clinically.

Shang HG, Yu HL, Ma XN, Xu X
Multidrug resistance and tumor-initiating capacity of oral cancer stem cells.
J BUON. 2016 Mar-Apr; 21(2):461-5 [PubMed] Related Publications
PURPOSE: Recent studies in several tumors showed that presence of cancer stem like side population (SP) cells are responsible for chemotherapeutic drugs resistance and tumor relapse. In our present study, we have analyzed the role of SP cells in oral squamous cell carcinoma cell (OSCC) line OSCC-77.
METHODS: The oral cancer cell line OSCC-77 was analyzed for the presence of SP cells by FACS using Hoechst 33342 dye exclusion method. Further the FACS-sorted SP and non-SP cells were subjected to drug resistance and sphere formation assays.
RESULTS: We identified that the presence of SP cells in OSCC-77 cell line was 3.4%, which was reduced to 0.6% in the presence of verapamil, an inhibitor of ABC transporter. Furthermore, we showed that these SP cells were highly drug-resistant, had increased survival and were highly potent for self-renewal. Also, the clone formation efficiency of SP cells was significantly higher compared to non-SP cells (p<0.01).
CONCLUSION: Our data suggest that cancer stem-like SP cells of OSCC-77 cell line contribute to multidrug resistance and are highly involved in tumor relapse. However, further characterization of SP cells at gene expression level and their signaling pathways might provide new insights into the development of novel anticancer drugs.

Šemeláková M, Jendželovský R, Fedoročko P
Drug membrane transporters and CYP3A4 are affected by hypericin, hyperforin or aristoforin in colon adenocarcinoma cells.
Biomed Pharmacother. 2016; 81:38-47 [PubMed] Related Publications
Our previous results have shown that the combination of hypericin-mediated photodynamic therapy (HY-PDT) at sub-optimal dose with hyperforin (HP) (compounds of Hypericum sp.), or its stable derivative aristoforin (AR) stimulates generation of reactive oxygen species (ROS) leading to antitumour activity. This enhanced oxidative stress evoked the need for an explanation for HY accumulation in colon cancer cells pretreated with HP or AR. Generally, the therapeutic efficacy of chemotherapeutics is limited by drug resistance related to the overexpression of drug efflux transporters in tumour cells. Therefore, the impact of non-activated hypericin (HY), HY-PDT, HP and AR on cell membrane transporter systems (Multidrug resistance-associated protein 1-MRP1/ABCC1, Multidrug resistance-associated protein 2-MRP2/ABCC2, Breast cancer resistance protein - BCRP/ABCG2, P-glycoprotein-P-gp/ABCC1) and cytochrome P450 3A4 (CYP3A4) was evaluated. The different effects of the three compounds on their expression, protein level and activity was determined under specific PDT light (T0+, T6+) or dark conditions (T0- T6-). We found that HP or AR treatment affected the protein levels of MRP2 and P-gp, whereas HP decreased MRP2 and P-gp expression mostly in the T0+ and T6+ conditions, while AR decreased MRP2 in T0- and T6+. Moreover, HY-PDT treatment induced the expression of MRP1. Our data demonstrate that HP or AR treatment in light or dark PDT conditions had an inhibitory effect on the activity of individual membrane transport proteins and significantly decreased CYP3A4 activity in HT-29 cells. We found that HP or AR significantly affected intracellular accumulation of HY in HT-29 colon adenocarcinoma cells. These results suggest that HY, HP and AR might affect the efficiency of anti-cancer drugs, through interaction with membrane transporters and CYP3A4.

Franco-Salla GB, Prates J, Cardin LT, et al.
Euphorbia tirucalli modulates gene expression in larynx squamous cell carcinoma.
BMC Complement Altern Med. 2016; 16:136 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Some plants had been used in the treatment of cancer and one of these has attracted scientific interest, the Euphorbia tirucalli (E. tirucalli), used in the treatment of asthma, ulcers, warts has active components with activities scientifically proven as antimutagenic, anti-inflammatory and anticancer.
METHODS: We evaluate the influence of the antitumoral fraction of the E. tirucalli latex in the larynx squamous cell carcinoma (Hep-2), on the morphology, cell proliferation and gene expression. The Hep-2 cells were cultivated in complete medium (MEM 10 %) and treated with E. tirucalli latex for 1, 3, 5 and 7 days. After statistically analyzing the proliferation of the tested cells, the cells were cultivated again for RNA extraction and the Rapid Subtractive Hybridization (RaSH) technique was used to identify genes with altered expression. The genes found using the RaSH technique were analyzed by Gene Ontology (GO) using Ingenuity Systems.
RESULTS: The five genes found to have differential expression were validated by real-time quantitative PCR. Though treatment with E. tirucalli latex did not change the cell morphology in comparison to control samples, but the cell growth was significantly decreased. The RaSH showed change in the expression of some genes, including ANXA1, TCEA1, NGFRAP1, ITPR1 and CD55, which are associated with inflammatory response, transcriptional regulation, apoptosis, calcium ion transport regulation and complement system, respectively. The E. tirucalli latex treatment down-regulated ITPR1 and up-regulated ANXA1 and CD55 genes, and was validated by real-time quantitative PCR.
CONCLUSIONS: The data indicate the involvement of E. tirucalli latex in the altered expression of genes involved in tumorigenic processes, which could potentially be applied as a therapeutic indicator of larynx cancer.

Danella Polli C, Pereira Ruas L, Chain Veronez L, et al.
Jacalin-Activated Macrophages Exhibit an Antitumor Phenotype.
Biomed Res Int. 2016; 2016:2925657 [PubMed] Free Access to Full Article Related Publications
Tumor-associated macrophages (TAMs) have an ambiguous and complex role in the carcinogenic process, since these cells can be polarized into different phenotypes (proinflammatory, antitumor cells or anti-inflammatory, protumor cells) by the tumor microenvironment. Given that the interactions between tumor cells and TAMs involve several players, a better understanding of the function and regulation of TAMs is crucial to interfere with their differentiation in attempts to skew TAM polarization into cells with a proinflammatory antitumor phenotype. In this study, we investigated the modulation of macrophage tumoricidal activities by the lectin jacalin. Jacalin bound to macrophage surface and induced the expression and/or release of mainly proinflammatory cytokines via NF-κB signaling, as well as increased iNOS mRNA expression, suggesting that the lectin polarizes macrophages toward the antitumor phenotype. Therefore, tumoricidal activities of jacalin-stimulated macrophages were evaluated. High rates of tumor cell (human colon, HT-29, and breast, MCF-7, cells) apoptosis were observed upon incubation with supernatants from jacalin-stimulated macrophages. Taken together, these results indicate that jacalin, by exerting a proinflammatory activity, can direct macrophages to an antitumor phenotype. Deep knowledge of the regulation of TAM functions is essential for the development of innovative anticancer strategies.

Li Y, Cui W, Woodroof JM, Zhang D
Extranodal B Cell Lymphoma with Prominent Spindle Cell Features Arising in Uterus and in Maxillary Sinus: Report of Two Cases and Literature Review.
Ann Clin Lab Sci. 2016; 46(2):213-8 [PubMed] Related Publications
Primary B-cell lymphoma exhibiting a spindle dominant pattern is extremely rare and represents a potential diagnostic pitfall. Here we report two cases of extranodal B cell lymphoma with spindle cell dominant morphology (sp-BCL) of uterus and maxillary sinus. Case 1 was a 54-year-old female with a large mass in the lower uterine segment, inseparable from the wall of the rectum and the urinary bladder. This is the first report of primary sp-BCL arising in the lower uterine segment. Case 2 was a 54-year-old male with a permeative mass involving the maxillary sinus wall with extension into the premaxillary soft tissues. Biopsies of both cases revealed a diffuse infiltration by medium to large atypical spindle cells. A panel of immunohistochemical stains was performed to rule out the possibilities of sarcoma, carcinoma, or melanoma. The final diagnosis was diffuse large B cell lymphoma, germinal center type. This is the first report of sp-BCL incorporating molecular genetic studies and the next-generation sequencing analysis performed on the maxillary lymphoma revealed three genomic alterations in genes of EZH2 (Y646N), IRF8 (S55A), and TNFRSF14 (splice site 304+2T>C). These genes were reported to play important roles in the pathogenesis of diffuse large B cell lymphoma. Both patients achieved complete remission after excision and chemo-radiation therapy despite the extensive local involvement.

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