TTPA

Gene Summary

Gene:TTPA; alpha tocopherol transfer protein
Aliases: ATTP, AVED, TTP1, alphaTTP
Location:8q12.3
Summary:This gene encodes a soluble protein that binds alpha-trocopherol, a form of vitamin E, with high selectivity and affinity. This protein plays an important role in regulating vitamin E levels in the body by transporting vitamin E between membrane vesicles and facilitating the secretion of vitamin E from hepatocytes to circulating lipoproteins. Mutations in this gene cause hereditary vitamin E deficiency (ataxia with vitamin E deficiency, AVED) and retinitis pigmentosa. [provided by RefSeq, Nov 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:alpha-tocopherol transfer protein
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 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.

  • Adenocarcinoma
  • Receptors, Urokinase Plasminogen Activator
  • beta Catenin
  • MMP2
  • Breast Cancer
  • Chromosome 8
  • TGFB1
  • Transcription
  • Risk Factors
  • Promoter Regions
  • Neoplasm Proteins
  • Transfection
  • Plasminogen Activator Inhibitor 1
  • Reproducibility of Results
  • Biomarkers, Tumor
  • Urokinase-Type Plasminogen Activator
  • Neoplasm Invasiveness
  • Signal Transduction
  • Prostate Cancer
  • Lung Cancer
  • Plasminogen Activators
  • Gene Expression Profiling
  • Uterine Cancer
  • Thromboplastin
  • rab GTP-Binding Proteins
  • Cancer Gene Expression Regulation
  • Gene Expression
  • Receptor, erbB-2
  • Stomach Cancer
  • TIMP2
  • gamma Catenin
  • Immunohistochemistry
  • Vitronectin
  • Cell Surface Receptors
  • Transforming Growth Factor beta
  • Urothelium
  • Cell Movement
  • U937 Cells
  • Neoplasm Metastasis
  • Cell Proliferation
Tag cloud generated 31 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: TTPA (cancer-related)

Jevrić M, Matić IZ, Krivokuća A, et al.
Association of uPA and PAI-1 tumor levels and 4G/5G variants of PAI-1 gene with disease outcome in luminal HER2-negative node-negative breast cancer patients treated with adjuvant endocrine therapy.
BMC Cancer. 2019; 19(1):71 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The aim of this study was to evaluate the prognostic potential of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) tumor tissue levels and examine the association between these biomarkers and classical prognostic factors in early node-negative luminal breast cancer patients. The clinical value of 4G/5G variants of PAI-1 gene was evaluated.
PATIENTS AND METHODS: This study involved 81 node-negative, estrogen receptor-positive and/or progesterone receptor-positive and human epidermal growth factor receptor 2-negative operable breast cancer patients who underwent radical surgical resection and received adjuvant endocrine therapy. Determination of uPA and PAI-1 concentrations in the breast cancer tissue extracts was performed using FEMTELLE® uPA/PAI-1 ELISA. An insertion (5G)/deletion (4G) polymorphism at position - 675 of the PAI-1 gene was detected by PCR-RFLP analysis.
RESULTS: Our research showed that patients with uPA tumor tissue levels higher than 3 ng/mg of protein had significantly reduced disease-free survival (DFS) and overall survival (OS) when compared to patients with uPA tumor tissue levels lower or equal to 3 ng/mg of protein. Patients with PAI-1 tumor tissue levels higher than 14 ng/mg of protein had significantly decreased OS in comparison with patients with PAI-1 tumor tissue levels lower or equal to 14 ng/mg of protein. ROC analysis confirmed the uPA and PAI-1 discriminative potential for the presence/absence of relevant events in these patients and resulted in higher cut-off values (5.65 ng/mg of protein for uPA and 27.10 ng/mg of protein for PAI-1) than standard reference cut-off values for both biomarkers. The prognostic importance of uPA and PAI-1 ROC cut-off values was confirmed by the impact of uPA higher than 5.65 ng/mg of protein and PAI-1 higher than 27.10 ng/mg of protein on poorer DFS, OS and event-free survival (EFS). We observed that patients with dominant allele in PAI-1 genotype (heterozygote and dominant homozygote, - 675 4G/5G and - 675 5G/5G) had significantly increased DFS, OS and EFS when compared with patients with recessive homozygote genotype (- 675 4G/4G).
CONCLUSION: Our study indicates that uPA and PAI-1 tumor tissue levels and 4G/5G variants of PAI-1 gene might be of prognostic significance in early node-negative luminal HER2-negative breast cancer patients treated with adjuvant endocrine therapy.

Jin Y, Liang ZY, Zhou WX, Zhou L
Plasminogen activator inhibitor 2 (PAI2) inhibits invasive potential of hepatocellular carcinoma cells in vitro via uPA- and RB/E2F1-related mechanisms.
Hepatol Int. 2019; 13(2):180-189 [PubMed] Related Publications
BACKGROUND: Plasminogen activator inhibitor 2 (PAI2) has been shown to be associated with invasive phenotypes and prognosis in hepatocellular carcinoma (HCC). However, its biological roles and underlying mechanisms in invasion of HCC have not been explored. The present study aimed to address the issues.
METHODS: First, sub-lines in that PAI2 was stably overexpressed and silenced were established based on MHCC97H and BEL7402 cell lines, respectively. Wound-healing and transwell assays were applied to evaluate cell migration and invasion. Urokinase-type plasminogen activator (uPA) activity was measured using an ELISA kit. Real-time RT-PCR and western blotting were used to show gene expression at mRNA and protein levels. E2F1 expression in human specimens was determined by tissue microarray-based immunohistochemical staining.
RESULTS: The sub-lines, MHCC97H-PAI2 and BEL7402-siPAI2, were successfully established. The two sub-lines carried much lower and higher migration and invasion powers, respectively, in contrast to the controls. In MHCC97H-PAI2 sub-line, intra-medium uPA activity was significantly decreased, while RB expression was obviously elevated, compared with the controls. The BEL7402-siPAI2 sub-line presented the opposite trend. To identify the role of RB/E2F1 pathway, we transiently overexpressed E2F1 in MHCC97H-PAI2 sub-line, and largely reversed the inhibitory effects of PAI2 on cell migration and invasion, through regulating multiple matrix metalloproteinases and epithelial-mesenchymal transition. In HCC specimens, E2F1 expression was much higher in tumor than in non-tumor tissues, and was significantly related to Edmondson-Steiner grade, overall as well as tumor-free survival.
CONCLUSIONS: Our data suggest that PAI2 inhibits invasive potential of HCC cells via uPA- and RB/E2F1-related mechanisms.

Tian YS, Chen KC, Zulkefli ND, et al.
Evaluation of the Inhibitory Effects of Genipin on the Fluoxetine-Induced Invasive and Metastatic Model in Human HepG2 Cells.
Molecules. 2018; 23(12) [PubMed] Free Access to Full Article Related Publications
Metastasis of hepatocellular carcinoma (HCC) is usually unrecognized before any pathological examination, resulting in time-taking treatment and poor prognosis. As a consequence, HCC patients usually show symptoms of depression. In order to suppress such psychiatric disorders and to facilitate better treatment outcome, antidepressants are prescribed. Up to present, information about the effect of antidepressants on HCC is still lacking. Therefore, we chose fluoxetine (FXT), one of the top five psychiatric prescriptions in the United States, together with the HepG2 cell model to explore its effect on HCC. Our study found that FXT (5 µM) increased the migratory distance of HepG2 cells by a factor of nearly 1.7 compared to control. In addition, our study also investigated the effect of genipin (GNP), which is an active compound from Gardenia jasminoides Ellis fruit (family Rubiaceae), on the FXT-induced HepG2 cells. Our study found that 30 and 60 µM GNP reduced the migratory distance by 42% and 74% respectively, compared to FXT treatment alone. Furthermore, we also found that FXT upregulated matrix metalloproteinases (MMPs) genes, increased the protein expression of MMPs, urokinase-type plasminogen activator (uPA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), activator protein 1 (AP-1), phosphorylated mitogen-activated protein kinase (P-p38), phosphorylated protein kinase B (P-Akt), downregulated tissue inhibitor metalloproteinases (TIMPs) genes and decreased the TIMPs proteins expression whereas, GNP fully counteracted the action of FXT. Conclusively, this study has provided valuable information regarding the possible molecular mechanisms through which FXT affects the metastatic invasiveness of HepG2 cells and evidences to support that GNP counteracts such effect via the same molecular mechanisms.

Eriksson BO, Gahm C, Halle M
Upregulation of Plasminogen Activator Inhibitor-1 in Irradiated Recipient Arteries and Veins from Free Tissue Transfer Reconstruction in Cancer Patients.
Mediators Inflamm. 2018; 2018:4058986 [PubMed] Free Access to Full Article Related Publications
Background: Clinical studies have shown that radiotherapy can induce vascular disease at the site of exposure but is usually not clinically evident until years after treatment. We have studied irradiated human arteries and veins to better understand the underlying biology in search of future treatments. The aim was to investigate whether radiotherapy contributed to a sustained expression of plasminogen activator inhibitor-1 (PAI-1) in human arteries and veins.
Methods: Irradiated arteries and veins were harvested, together with unirradiated control vessels, from patients undergoing free tissue transfer reconstruction at a median time of 90 weeks [5-650] following radiation exposure. Differential gene expression of PAI-1 was analysed, together with immunohistochemistry (IHC) and immunofluorescence (IF).
Results: PAI-1 gene expression was increased in both arteries (
Conclusion: The current study shows a sustained upregulation of PAI-1 in both arteries and veins after exposure to ionizing radiation, indicating a chronic inflammation mainly in the adventitia. We believe that the results contribute to further understanding of radiation-induced vascular disease, where targeting PAI-1 may be a potential treatment.

Völker HU, Weigel M, Strehl A, Frey L
Levels of uPA and PAI-1 in breast cancer and its correlation to Ki67-index and results of a 21-multigene-array.
Diagn Pathol. 2018; 13(1):67 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Conventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX®, a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction. The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test.
METHODS: The results of Ki67, uPA/PAI-1 and OncotypeDX® were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed.
RESULTS: With a proliferation index Ki67 of < 14%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9%); p = 0.054, Student's t-test. When Ki67 was > 14% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14% with non-raised uPA/PAI-1 (p < 0.03, Student's t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values.
CONCLUSION: A combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised).

Sharma MC
Annexin A2 (ANX A2): An emerging biomarker and potential therapeutic target for aggressive cancers.
Int J Cancer. 2019; 144(9):2074-2081 [PubMed] Related Publications
ANX A2 is an important member of annexin family of proteins expressed on surface of endothelial cells (ECs), macrophages, mononuclear cells and various types of cancer cells. It exhibits high affinity binding for calcium (Ca

Xu J, Zhang W, Tang L, et al.
Epithelial-mesenchymal transition induced PAI-1 is associated with prognosis of triple-negative breast cancer patients.
Gene. 2018; 670:7-14 [PubMed] Related Publications
Epithelial-mesenchymal transition (EMT) is a key developmental program in which epithelial cells lose polarity and become mesenchymal cells, and that is often activated during cancer invasion and metastasis. Triple negative breast cancer (TNBC) patients have a relatively aggressive biological behavior with a high risk of distant recurrence and metastasis. Here, we stimulated TNBC cells to undergo EMT, and detected the protein expression profiles of the protein secretion. High-throughput data showed that EMT could promote TNBC cells to secret PAI-1. We found that TNBC-secreted PAI-1 could increase cell growth, migration and invasion, and the expression of EMT markers in the TNBC cell lines and xenograft PAI-1-/- mice model. Using a tissues microarray of 165 TNBC patients and published breast cancer database, we found PAI-1 expression was significantly elevated in the breast cancer tissues, comparing with the normal adjacent tissues and was associated with prognosis of patients with TNBC. Taken together, our results suggests an important role of PAI-1 in the EMT process of TNBC cells and illustrates the great potential of developing PAI-1-targeting therapy for clinical TNBC patients.

Kisanga EP, Tang Z, Guller S, Whirledge S
Glucocorticoid signaling regulates cell invasion and migration in the human first-trimester trophoblast cell line Sw.71.
Am J Reprod Immunol. 2018; 80(1):e12974 [PubMed] Related Publications
PROBLEM: The development of the placenta and its functions are sensitive to infection and stress, which can activate the hypothalamic-pituitary-adrenal axis. Adrenally produced glucocorticoids are the body's primary mediators of the inflammatory and stress response. Although the glucocorticoid receptor (GR) is expressed in all human villous trophoblast tissue, the effect of glucocorticoids on placentation is not well understood.
METHOD OF STUDY: Using microarray analysis, we identified the glucocorticoid-regulated transcriptional profile in the immortalized first-trimester extravillous trophoblast cell line Swan.71 (Sw.71).
RESULTS: The synthetic glucocorticoid dexamethasone significantly regulated 3829 genes, including genes associated with cell movement, growth, and survival. SERPINE1, an inhibitor of trophoblast invasion, was induced by glucocorticoids in Sw.71 cells and is associated with the pathogenesis of preeclampsia. Glucocorticoid treatment induced recruitment of activated polymerase II and GR to the SERPINE1 promoter, suggesting a mechanism for transcriptional regulation. Functionally, glucocorticoid treatment inhibited cell proliferation, migration, and invasion.
CONCLUSION: These findings suggest that glucocorticoids regulate extravillous trophoblast functions by altering the gene expression profile, which may contribute to the pathogenesis of reproductive disorders such as preeclampsia and IUGR.

Peterle GT, Maia LL, Trivilin LO, et al.
PAI-1, CAIX, and VEGFA expressions as prognosis markers in oral squamous cell carcinoma.
J Oral Pathol Med. 2018; 47(6):566-574 [PubMed] Related Publications
BACKGROUND: In oral squamous cell carcinoma (OSCC), the HIF-1 complex promotes the expression of genes involved in specific mechanisms of cell survival under hypoxic conditions, such as plasminogen activator inhibitor-1 (PAI-1), carbonic anhydrase 9 (CAIX), and vascular endothelial growth factor A (VEGFA). The study aimed to investigate the presence and prognostic value of PAI-1, CAIX, and VEGFA in OSCC.
MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expressions of these proteins in 52 tumoral tissue samples of patients with OSCC, surgically treated and followed by a minimum of 24 months after surgery. The correlations between protein expressions and clinicopathological parameters and prognosis were analyzed.
RESULTS: Positive PAI-1 membrane expression was significantly associated with local disease relapse (P = .027). Multivariate analysis revealed that the positive PAI-1 membrane expression is an independent marker for local disease relapse, with approximately 14-fold increased risk when compared to negative expression (OR = 14.49; CI = 1.40-150.01, P = .025). Strong PAI-1 cytoplasmic expression was significantly associated with the less differentiation grade (P = .027). Strong CAIX membrane expression was significantly associated with local disease-free survival (P = .038). Positive CAIX cytoplasmic expression was significantly associated with lymph node affected (P = .025) and with disease-specific survival (P = .022). Multivariate analysis revealed that the positive CAIX cytoplasmic expression is an independent risk factor for disease-related death, increasing their risk approximately 3-fold when compared to negative expression (HR = 2.84; CI = 1.02-7.87, P = .045). Positive VEGFA cytoplasmic expression was significantly associated with less differentiation grade (P = .035).
CONCLUSION: Our results suggest a potential role for these expressions profiles as tumor prognostic markers in OSCC patients.

Samuelson Bannow BT, Konkle BA
Laboratory biomarkers for venous thromboembolism risk in patients with hematologic malignancies: A review.
Thromb Res. 2018; 163:138-145 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Despite high rates of venous thromboembolism (VTE) among patients with hematologic malignancies, few tools exist to assist providers in identifying those patients at highest risk for this potentially fatal complication. Laboratory biomarkers, such as d-dimer, have demonstrated utility in some clinical settings to distinguish patients at increased risk.
MATERIALS AND METHODS: We performed a systematic review of the literature utilizing search terms including "biomarker", "venous thromboembolism", "hematologic malignancy", "lymphoma", "myeloma" and "leukemia" in the Medline database. A total of 25 studies investigating laboratory biomarkers of increased thrombotic risk in the setting of hematologic malignancy were identified and included in this review.
RESULTS AND CONCLUSIONS: The most studied biomarkers, d-dimer and fibrinogen, demonstrated some degree of efficacy in identifying high-risk patients at levels >4.0 mg/L or <1.0 g/L respectively. Additional markers which demonstrated promise included thrombin generation, mean platelet volume, soluble VEGF, soluble P-selectin and extracellular vesicles. Other biomarkers reviewed, which did not consistently demonstrate significant associations with VTE included prothrombin fragments F1 + 2, factor VIII, protein C, protein S, von Willebrand antigen and activity, antithrombin, thrombin antithrombin complex, antiphospholopid antibody, plasminogen activator inhibitor, tissue factor pathway inhibitor and several variants associated with known hypercoagulable states (factor V Leiden, prothrombin gene variant, methylenetetrahydrofolate reductase variant). Data to support any of the biomarkers discussed here in routine clinical decision-making are currently lacking, but additional investigation in clinical studies, ideally in combination with clinical factors known to be associated with increased thrombotic risk, is warranted.

Neoh CA, Wu WT, Dai GF, et al.
Flaccidoxide-13-Acetate Extracted from the Soft Coral Cladiella kashmani Reduces Human Bladder Cancer Cell Migration and Invasion through Reducing Activation of the FAK/PI3K/AKT/mTOR Signaling Pathway.
Molecules. 2017; 23(1) [PubMed] Free Access to Full Article Related Publications
Metastasis of cancer is the cause of the majority of cancer deaths. Active compound flaccidoxide-13-acetate, isolated from the soft coral

Lin CY, Cho CF, Bai ST, et al.
ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.
Sci Rep. 2017; 7(1):15108 [PubMed] Free Access to Full Article Related Publications
Lung cancer has a very high prevalence of brain metastasis, which results in a poor clinical outcome. Up-regulation of a disintegrin and metalloproteinase 9 (ADAM9) in lung cancer cells is correlated with metastasis to the brain. However, the molecular mechanism underlying this correlation remains to be elucidated. Since angiogenesis is an essential step for brain metastasis, microarray experiments were used to explore ADAM9-regulated genes that function in vascular remodeling. The results showed that the expression levels of vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANGPT2), and tissue plasminogen activator (PLAT) were suppressed in ADAM9-silenced cells, which in turn leads to decreases in angiogenesis, vascular remodeling, and tumor growth in vivo. Furthermore, simultaneous high expression of ADAM9 and VEGFA or of ADAM9 and ANGPT2 was correlated with poor prognosis in a clinical dataset. These findings suggest that ADAM9 promotes tumorigenesis through vascular remodeling, particularly by increasing the function of VEGFA, ANGPT2, and PLAT.

van Veen M, Matas-Rico E, van de Wetering K, et al.
Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells.
Elife. 2017; 6 [PubMed] Free Access to Full Article Related Publications
The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior.

Christensen A, Kiss K, Lelkaitis G, et al.
Urokinase-type plasminogen activator receptor (uPAR), tissue factor (TF) and epidermal growth factor receptor (EGFR): tumor expression patterns and prognostic value in oral cancer.
BMC Cancer. 2017; 17(1):572 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumor-specific biomarkers are a prerequisite for the development of targeted imaging and therapy in oral squamous cell carcinoma (OSCC). urokinase-type Plasminogen Activator Receptor (uPAR), Tissue Factor (TF) and Epidermal Growth Factor Receptor (EGFR) are three biomarkers that exhibit enhanced expression in many types of cancers, and have been investigated as potential biomarkers for targeted strategies and prognostication. The aim of the study was to investigate the expression patterns of uPAR, TF and EGFR and their potential prognostic value in OSCC.
METHODS: Immunohistochemical expression of uPAR, TF and EGFR in tumor resection specimens from 191 patients with primary OSCC was analyzed. Overall (OS) and disease-free survival (DFS) was calculated. Associations between biomarker expression, clinicopathological factors and patient survival was analyzed using the Cox proportional hazards model for univariate and multivariate analysis, log rank and Kaplan-Meier statistics.
RESULTS: uPAR and TF exhibited a highly tumor-specific expression pattern while EGFR also showed expression in normal tissues outside the tumor compartment. The overall positive expression rate of uPAR, TF and EGFR was 95%, 58% and 98%, respectively. High uPAR expression across the entire cohort was negatively associated with OS (p = 0.031, HR = 1.595 (95%CI 1.044-2.439)) in univariate analysis. The 5-year OS for high and low uPAR expression was 39% and 56%, respectively. The expression of TF and EGFR was not associated with survival outcome.
CONCLUSIONS: This study may suggest that uPAR and TF could potentially be attractive targets for molecular imaging and therapy in OSCC due to high positive expression rates and tumor-specific expression patterns. High uPAR expression was significantly associated with a reduced survival. uPAR seems to be a prognostic biomarker in oral cancer.

Mauro CD, Pesapane A, Formisano L, et al.
Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors.
Sci Rep. 2017; 7(1):9388 [PubMed] Free Access to Full Article Related Publications
The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell membrane receptor that focuses urokinase (uPA) proteolytic activity on the cell surface. Its expression is increased in many human cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), and correlates with a poor prognosis and early invasion and metastasis. uPAR is able to control, through a cross-talk with tyrosine kinase receptors, the shift between tumor dormancy and proliferation, that usually precedes metastasis formation. Therefore, we investigated the role of uPAR expression in RAS mutated NSCLC and CRC cells. In this study we provided evidence, for the first time, that RAS mutational condition is functionally correlated to uPAR overexpression in NSCLC and CRC cancer cell lines and patient-derived tissue samples. Moreover, oncogenic features related to uPAR overexpression in RAS mutated NSCLC and CRC, such as adhesion, migration and metastatic process may be targeted, in vitro and in vivo, by new anti-uPAR small molecules, specific inhibitors of uPAR-vitronectin interaction. Therefore, anti-uPAR drugs could represent an effective pharmacological strategy for NSCLC and CRC patients carrying RAS mutations.

Sameni M, Cavallo-Medved D, Franco OE, et al.
Pathomimetic avatars reveal divergent roles of microenvironment in invasive transition of ductal carcinoma in situ.
Breast Cancer Res. 2017; 19(1):56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The breast tumor microenvironment regulates progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). However, it is unclear how interactions between breast epithelial and stromal cells can drive this progression and whether there are reliable microenvironmental biomarkers to predict transition of DCIS to IDC.
METHODS: We used xenograft mouse models and a 3D pathomimetic model termed mammary architecture and microenvironment engineering (MAME) to study the interplay between human breast myoepithelial cells (MEPs) and cancer-associated fibroblasts (CAFs) on DCIS progression.
RESULTS: Our results show that MEPs suppress tumor formation by DCIS cells in vivo even in the presence of CAFs. In the in vitro MAME model, MEPs reduce the size of 3D DCIS structures and their degradation of extracellular matrix. We further show that the tumor-suppressive effects of MEPs on DCIS are linked to inhibition of urokinase plasminogen activator (uPA)/urokinase plasminogen activator receptor (uPAR)-mediated proteolysis by plasminogen activator inhibitor 1 (PAI-1) and that they can lessen the tumor-promoting effects of CAFs by attenuating interleukin 6 (IL-6) signaling pathways.
CONCLUSIONS: Our studies using MAME are, to our knowledge, the first to demonstrate a divergent interplay between MEPs and CAFs within the DCIS tumor microenvironment. We show that the tumor-suppressive actions of MEPs are mediated by PAI-1, uPA and its receptor, uPAR, and are sustained even in the presence of the CAFs, which themselves enhance DCIS tumorigenesis via IL-6 signaling. Identifying tumor microenvironmental regulators of DCIS progression will be critical for defining a robust and predictive molecular signature for clinical use.

Bystricky B, Jurisova S, Karaba M, et al.
Relationship Between Circulating Tumor Cells and Tissue Plasminogen Activator in Patients with Early Breast Cancer.
Anticancer Res. 2017; 37(4):1787-1791 [PubMed] Related Publications
AIM: Cancer increases the risk of venous thromboembolism (VTE) and circulating tumor cells (CTCs) are associated with an increased risk of VTE and, thus, with increased D-dimers as a product of fibrinolysis. Tissue plasminogen activator (tPA) is one of the key enzymes in the fibrinolytic pathway. Its activity is crucial in maintaining the balance between blood coagulation and fibrinolysis. This study aimed to analyze the association between CTCs and tPA in patients with primary breast cancer before surgery.
PATIENTS AND METHODS: This prospective study included 110 patients in whom CTCs were detected by quantitative reverse transcription polymerase chain reaction targeted at epithelial (CK19) or epithelial-mesenchymal transition (EMT)-associated genes[TWIST1, SNAI1, SNAI2, zinc finger E-box-binding homeobox 1 (ZEB1), forkhead box protein C2 (FOXC2)]. Plasma tPA protein was detected using enzyme-linked immunosorbent assay (ELISA).
RESULTS: CTCs were detected in 31 (28.2%) patients. There was no association between plasma tPA and CTCs. Although on average, higher levels of tPA were detected in patients with CTCs expressing EMT-associated genes, this difference did not reach statistical significance. There was no association of plasma tPA with any of the observed patient or tumor characteristics.
CONCLUSION: Even though the blood coagulation pathway may be activated in more aggressive disease related to an elevated CTC count, in this study, we did not find any association between CTCs and plasma concentrations of tPA.

Skrypnik K, Suliburska J, Skrypnik D, et al.
The genetic basis of obesity complications.
Acta Sci Pol Technol Aliment. 2017 Jan-Mar; 16(1):83-91 [PubMed] Related Publications
Intensive research is currently being performed into the genetic background of excess body mass compli- cations such as diabetes, cardiovascular disorders, especially atherosclerosis and coronary heart disease. Chronic inflammation is an important process in the pathogenesis of obesity, wherein there is an aberrant ex- pression of genes encoding adipokines. Visceral tissue is characterized by a higher expression and secretion of interleukin-8, interleukin-1ß and plasminogen activator inhibitor 1 in the subcutaneous tissue secretion of leptin prevails. An important complication of obesity is obstructive sleep apnea, often observed in Prader- Willi syndrome. The genetic background of sleep apnea may be a polymorphism of the SREBF1 gene. The consequence of excess body mass is metabolic syndrome, which may be related to the occurrence of the rs926198 variant of gene encoding caveolin-1. The genes of transcription factor TCF7L2 and PPAR-γ2 take part in the pathogenesis of diabetes development. It has been demonstrated that oncogenes FOS, FOSB, and JUN may be co-responsible not only for obesity but also for osteoporosis and colorectal cancer. It has been shown that weight loss causes a modification in the expression of about 100 genes involvedt in the production of substances such as cytokines and other responsible for chronic inflammation in obesity. In future studies on the complications of obesity, such scientific disciplines as proteomics, peptidomics, metabolomics and transcriptomics should be used. The aim of this study is to present the current state of knowledge about the genetic basis of obesity complications.

Yıldırım ME, Karakuş S, Kurtulgan HK, et al.
The Association of Plasminogen Activator Inhibitor Type 1 (PAI-1) Level and PAI-1 4G/5G Gene Polymorphism with the Formation and the Grade of Endometrial Cancer.
Biochem Genet. 2017; 55(4):314-321 [PubMed] Related Publications
Plasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor (Serpine 1), and it inhibits both tissue plasminogen activator and urokinase plasminogen activator which are important in fibrinolysis. We aimed to find whether there is a possible association between PAI-1 level, PAI-1 4G/5G polymorphism, and endometrial cancer. PAI-1 levels in peripheral blood were determined in 82 patients with endometrial carcinoma and 76 female healthy controls using an enzyme-linked immunoassay (ELISA). Then, the genomic DNA was extracted and screened by reverse hybridization procedure (Strip assay) to detect PAI 1 4G/5G polymorphism. The levels of PAI-1 in the patients were higher statistically in comparison to controls (P < 0.001). The distribution of PAI-1 4G/5G polymorphism was quite different between patients and controls (P = 0.008), and 4G allelic frequency was significantly higher in the patients of endometrial cancer than in controls (P = 0.026). We found significant difference between Grade 1 and Grade 2+3 patients in terms of the PAI-1 levels (P = 0.047). There was no association between PAI-1 4G/5G polymorphism and the grades of endometrial cancer (P = 0.993). Our data suggest that the level of PAI-1 and PAI-1 4G/5G gene polymorphism are effective in the formation of endometrial cancer. PAI-1 levels are also associated with the grades of endometrial cancer.

Arosarena OA, Barr EW, Thorpe R, et al.
Osteoactivin regulates head and neck squamous cell carcinoma invasion by modulating matrix metalloproteases.
J Cell Physiol. 2018; 233(1):409-421 [PubMed] Free Access to Full Article Related Publications
Nearly 60% of patients with head and neck squamous cell carcinoma (HNSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell migration and invasion, which are in part dependent on extracellular matrix degradation by matrix metalloproteinases. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies, and has been shown to upregulate matrix metalloproteinase (MMP) expression and activity. To determine how OA modulates MMP expression and activity in HNSCC, and to investigate OA effects on cell invasion, we assessed effects of OA treatment on MMP mRNA and protein expression, as well as gelatinase and caseinolytic activity in HNSCC cell lines. We assessed the effects of OA gene silencing on MMP expression, gelatinase and caseinolytic activity, and cell invasion. OA treatment had differential effects on MMP mRNA expression. OA treatment upregulated MMP-10 expression in UMSCC14a (p = 0.0431) and SCC15 (p < 0.0001) cells, but decreased MMP-9 expression in UMSCC14a cells (p = 0.0002). OA gene silencing decreased MMP-10 expression in UMSCC12 cells (p = 0.0001), and MMP-3 (p = 0.0005) and -9 (p = 0.0036) expression in SCC25 cells. In SCC15 and SCC25 cells, OA treatment increased MMP-2 (p = 0.0408) and MMP-9 gelatinase activity (p < 0.0001), respectively. OA depletion decreased MMP-2 (p = 0.0023) and -9 (p < 0.0001) activity in SCC25 cells. OA treatment increased 70 kDa caseinolytic activity in UMSCC12 cells consistent with tissue type plasminogen activator (p = 0.0078). OA depletion decreased invasive capacity of UMSCC12 cells (p < 0.0001). OA's effects on MMP expression in HNSCC are variable, and may promote cancer cell invasion.

Claro F, Moreira LR, Morari J, et al.
Assessment of the Cancer Risk of the Fat-Grafted Breast in a Murine Model.
Aesthet Surg J. 2017; 37(5):603-613 [PubMed] Related Publications
Background: The results of experimental studies indicate that grafting of autologous adipose tissue may induce tumorigenesis at the recipient site, but clinical results do not support a carcinogenic effect of fat grafting to the breast.
Objectives: The authors assessed cancer risk following transplantation of autologous fat into murine mammary tissue.
Methods: In this animal study, mammary tissues from 54 breasts of 9 female rats were either grafted with autologous subcutaneous fat, grafted with autologous omental fat, or unmanipulated. Tissues were harvested and processed for histologic and immunohistochemical analyses, and the mRNA expression levels of specific genes were determined.
Results: No atypia or changes in lobular structures were observed in lipofilled breasts compared with controls. The numbers of ductal cell layers and terminal ductal units were similar for lipofilled and control breasts. Macrophage concentrations also were similar for the 3 groups. The localization and magnitude of plasminogen activator inhibitor 1 were similar for lipofilled and unmanipulated breast tissue. The percentages of cells expressing Ki67 or estrogen receptor (ER) and the ER/Ki67 balance were similar for the 3 groups. Gene expression was not altered in lipofilled breasts, compared with controls.
Conclusions: No theoretical risk of cancer was detected in the microenvironment of the lipofilled rat breast.

Bosse K, Haneder S, Arlt C, et al.
Mass spectrometry-based secretome analysis of non-small cell lung cancer cell lines.
Proteomics. 2016; 16(21):2801-2814 [PubMed] Related Publications
Tyrosine kinase inhibitors, such as erlotinib, display reliable responses and survival benefits for the treatment of human non-small cell lung cancer (NSCLC) patients. However, primary or acquired resistance limits their therapeutic success. In this study, we conducted in-depth mass spectrometric analyses of NSCLC cell secretomes. To identify secreted proteins that are differentially regulated in erlotinib-sensitive (PC-9) and -resistant (PC-9ER) NSCLC cell lines, SILAC experiments were performed. On average, 900 proteins were identified in each sample with low variations in the numbers of identified proteins. Fourteen proteins were found to be differently regulated among erlotinib-sensitive and -resistant NSCLC cell lines, with five proteins (tissue-type plasminogen activator, epidermal growth factor receptor, urokinase-type plasminogen activator, platelet-derived growth factor D, and myeloid-derived growth factor) showing the most prominent regulation. Tissue-type plasminogen activator (t-PA) was up to 10-times upregulated in erlotinib-resistant NSCLC cells compared with erlotinib-sensitive cells. T-PA is an established tumor marker for various cancer types and seems to be a promising prognostic marker to differentiate erlotinib-sensitive from erlotinib-resistant NSCLC cells. To gain further insights into t-PA-regulated pathways, a t-PA variant was expressed in E. coli cells and its interactions with proteins secreted from erlotinib-sensitive and -resistant NCSLC cells were studied by a combined affinity enrichment chemical cross-linking/mass spectrometry (MS) approach. Fourteen proteins were identified as potential t-PA interaction partners, deserving a closer inspection to unravel the mechanisms underlying erlotinib resistance in NSCLC cells.

Huber MC, Mall R, Braselmann H, et al.
uPAR enhances malignant potential of triple-negative breast cancer by directly interacting with uPA and IGF1R.
BMC Cancer. 2016; 16:615 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. TNBC is defined negative for the protein expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). One prominent feature of this cancer type is the frequent overexpression of major components of the urokinase-type plasminogen activator system (uPAS) including uPA, its receptor uPAR and the inhibitor PAI-1, which may be valuable as therapeutic targets.
METHODS: Direct interactions of uPAR with interactors were demonstrated by immunoprecipitations and proximity ligation assays. For stable knockdowns of target proteins, lentiviral vectors were used and the effects were analysed by immunoblottings and using in vitro cell viability, migration and invasion assays. Immunohistochemical and statistical analyses of biomarkers and clinical parameters were conducted in a TNBC cohort (n = 174).
RESULTS: Direct tumour-promoting interactions of uPAR with uPA and the insulin-like growth factor receptor 1 (IGF1R) were shown in TNBC cells and these interactions were significantly reduced (p = 0.001) when uPAR was downregulated. The combined knockdown of uPAR and uPA or IGF1R additively and significantly reduced cell viability, migration and invasion of the model cell lines. In TNBC tissue, the complexes formed by uPAR with uPA or with IGF1R significantly correlated with the histological grade (p = 0.0019) as well as with cathepsin B and D (p ≤ 0.0001) that are implicated in cell invasion and metastasis.
CONCLUSIONS: Our outcomes show that not only overexpressed biomarkers promote tumourigenesis, but rather their interactions further potentiate tumour progression. This study emphasises the potential of combined approaches targeting uPAR and its interactors with regard to an improved therapy of TNBC.

Matheis F, Heppt MV, Graf SA, et al.
A Bifunctional Approach of Immunostimulation and uPAR Inhibition Shows Potent Antitumor Activity in Melanoma.
J Invest Dermatol. 2016; 136(12):2475-2484 [PubMed] Related Publications
Significant advancements of mutation-based targeted therapy and immune checkpoint blockade have been achieved in melanoma. Nevertheless, acquired resistance and nonresponders to therapy require different strategies. An innovative approach is presented here that is based on the combination of innate immune system activation and simultaneous targeting of the oncogene urokinase-type plasminogen activator receptor (uPAR). We generated two triphosphate-conjugated siRNAs targeting uPAR (ppp-uPAR) by in vitro transcription. Specific uPAR knockdown and simultaneous activation of the retinoic acid-inducible gene 1 (RIG-I) was shown in different human melanoma cells, fibroblasts, and melanocytes. The compounds induced massive apoptosis in melanoma cells, whereas fibroblasts and melanocytes were less sensitive. The effects were less pronounced when the IFN receptor was blocked. Treatment with ppp-uPAR led to accumulation of p53 and induction of RIG-I-dependent proapoptotic signaling. The apoptotic effects induced by ppp-uPAR were maintained in melanoma cell lines that had acquired double resistance to B-RAF and MEK/extracellular signal-regulated kinase inhibition. Systemic intraperitoneal application of ppp-uPAR in nude mice significantly reduced growth of human melanoma xenografts and elicited a systemic innate immune response with increased serum cytokine levels. Our data suggest that ppp-uPAR represents a therapeutically attractive compound that may help overcome the strong therapy resistance of melanoma.

Pei H, Yang Y, Cui L, et al.
Bisdemethoxycurcumin inhibits ovarian cancer via reducing oxidative stress mediated MMPs expressions.
Sci Rep. 2016; 6:28773 [PubMed] Free Access to Full Article Related Publications
As one main active compound of curcuminoids, Bisdemethoxycurcumin (BDMC) possesses several biological activities, such as anti-inflammation and anti-cancer activities. However, the detailed mechanism of BDMC's anti-metastasis activity in ovarian cancer has not been clearly elucidated yet. In the present study, cell proliferation, wound healing motility, cell adhesion and invasion with or without BDMC were determined. In addition, western blot was used to examine proteins expressions. The lucigenin-enhanced luminescence was introduced to assess cellular oxidative stress. The luciferase reporter gene assay was introduced to evaluate the transcriptional activity of NF-κB. Finally, BDMC significantly inhibited the adhesion, migration, invasion and metastasis of SKOV-3 cells. Moreover, BDMC inhibited expressions of several degradation-associated proteins, such as matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), CD147, urokinase plasminogen activator (uPA), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), whereas increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), in a dose-dependent manner. In addition, BDMC reduced generation of cellular superoxide in a dose-dependent manner. Furthermore, BDMC inhibited the phosphorylation levels of NF-κB p65 and IκB-α, and consequently reduced NF-κB-driven luciferase expression. Collectively, BDMC serves as a therapeutic medicine to suppress ovarian cancer, perhaps via inhibiting cellular oxidative stress and subsequently inactivating NF-κB pathway.

Svalina MN, Kikuchi K, Abraham J, et al.
IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma.
Sci Rep. 2016; 6:27012 [PubMed] Free Access to Full Article Related Publications
Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma.

Chan JM, Darke AK, Penney KL, et al.
Selenium- or Vitamin E-Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT.
Cancer Epidemiol Biomarkers Prev. 2016; 25(7):1050-1058 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epidemiologic studies and secondary analyses of randomized trials supported the hypothesis that selenium and vitamin E lower prostate cancer risk. However, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no benefit of either supplement. Genetic variants involved in selenium or vitamin E metabolism or transport may underlie the complex associations of selenium and vitamin E.
METHODS: We undertook a case-cohort study of SELECT participants randomized to placebo, selenium, or vitamin E. The subcohort included 1,434 men; our primary outcome was high-grade prostate cancer (N = 278 cases, Gleason 7 or higher cancer). We used weighted Cox regression to examine the association between SNPs and high-grade prostate cancer risk. To assess effect modification, we created interaction terms between randomization arm and genotype and calculated log likelihood statistics.
RESULTS: We noted statistically significant (P < 0.05) interactions between selenium assignment, SNPs in CAT, SOD2, PRDX6, SOD3, and TXNRD2, and high-grade prostate cancer risk. Statistically significant SNPs that modified the association of vitamin E assignment and high-grade prostate cancer included SEC14L2, SOD1, and TTPA In the placebo arm, several SNPs, hypothesized to interact with supplement assignment and risk of high-grade prostate cancer, were also directly associated with outcome.
CONCLUSION: Variants in selenium and vitamin E metabolism/transport genes may influence risk of overall and high-grade prostate cancer, and may modify an individual man's response to vitamin E or selenium supplementation with regards to these risks.
IMPACT: The effect of selenium or vitamin E supplementation on high-grade prostate cancer risk may vary by genotype. Cancer Epidemiol Biomarkers Prev; 25(7); 1050-8. ©2016 AACR.

Park GT, Kim SU, Choi KC
Anti-proliferative Effect of Engineered Neural Stem Cells Expressing Cytosine Deaminase and Interferon-β against Lymph Node-Derived Metastatic Colorectal Adenocarcinoma in Cellular and Xenograft Mouse Models.
Cancer Res Treat. 2017; 49(1):79-91 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Genetically engineered stem cells may be advantageous for gene therapy against various human cancers due to their inherent tumor-tropic properties. In this study, genetically engineered human neural stem cells (HB1.F3) expressing
MATERIALS AND METHODS: CD can convert a prodrug, 5-fluorocytosine (5-FC), to active 5-fluorouracil, which inhibits tumor growth through the inhibition of DNA synthesis,while IFN-β also strongly inhibits tumor growth by inducing the apoptotic process. In reverse transcription polymerase chain reaction analysis, we confirmed that HB1.F3.CD cells expressed the CD gene and HB1.F3.CD.IFN-β cells expressed both CD and IFN-β genes.
RESULTS: In results of a modified trans-well migration assay, HB1.F3.CD and HB1.F3.CD.IFN-β cells selectively migrated toward SW-620, human lymph node-derived metastatic colorectal adenocarcinoma cells. The viability of SW-620 cells was significantly reduced when co-cultured with HB1.F3.CD or HB1.F3.CD.IFN-β cells in the presence of 5-FC. In addition, it was found that the tumor-tropic properties of these engineered human neural stem cells (hNSCs) were attributed to chemoattractant molecules including stromal cell-derived factor 1, c-Kit, urokinase receptor, urokinase-type plasminogen activator, and C-C chemokine receptor type 2 secreted by SW-620 cells. In a xenograft mouse model, treatment with hNSC resulted in significantly inhibited growth of the tumor mass without virulent effects on the animals.
CONCLUSION: The current results indicate that engineered hNSCs and a prodrug treatment inhibited the growth of SW-620 cells. Therefore, hNSC therapy may be a clinically effective tool for the treatment of lymph node metastatic colorectal cancer.

Yang SH, Li CF, Chu PY, et al.
Overexpression of regulator of G protein signaling 11 promotes cell migration and associates with advanced stages and aggressiveness of lung adenocarcinoma.
Oncotarget. 2016; 7(21):31122-36 [PubMed] Free Access to Full Article Related Publications
Regulator of G protein signaling 11 (RGS11), a member of the R7 subfamily of RGS proteins, is a well-characterized GTPase-accelerating protein that is involved in the heterotrimeric G protein regulation of the amplitude and kinetics of receptor-promoted signaling in retinal bipolar and nerve cells. However, the role of RGS11 in cancer is completely unclear. Using subtractive hybridization analysis, we found that RGS11 was highly expressed in the lymph-node metastatic tissues and bone-metastatic tumors obtained from patients with lung adenocarcinoma. Characterization of the clinicopathological features of 91 patients showed that around 57.1% of the tumor samples displayed RGS11 overexpression that was associated with primary tumor status, nodal metastasis and increased disease stages. Its high expression was an independent predictive factor for poor prognosis of these patients. Cotransfection of guanine nucleotide-binding protein beta-5 (GNB5) markedly increased RGS11 expression. Enhancement or attenuation of RGS11 expression pinpointed its specific role in cell migration, but not in cell invasion and proliferation. Signaling events initiated by the RGS11-GNB5 coexpression activated the c-Raf/ERK/FAK-mediated pathway through upregulation of the Rac1 activity. Consistently, increasing the cell invasiveness of the transfectants by additional cotransfection of the exogenous urokinase-plasminogen activator gene caused a significant promotion in cell invasion in vitro and in vivo, confirming that RGS11 functions in cell migration, but requires additional proteolytic activity for cell and tissue invasion. Collectively, overexpression of RGS11 promotes cell migration, participates in tumor metastasis, and correlates the clinicopathological conditions of patients with lung adenocarcinoma.

Flemer B, Lynch DB, Brown JM, et al.
Tumour-associated and non-tumour-associated microbiota in colorectal cancer.
Gut. 2017; 66(4):633-643 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: A signature that unifies the colorectal cancer (CRC) microbiota across multiple studies has not been identified. In addition to methodological variance, heterogeneity may be caused by both microbial and host response differences, which was addressed in this study.
DESIGN: We prospectively studied the colonic microbiota and the expression of specific host response genes using faecal and mucosal samples ('ON' and 'OFF' the tumour, proximal and distal) from 59 patients undergoing surgery for CRC, 21 individuals with polyps and 56 healthy controls. Microbiota composition was determined by 16S rRNA amplicon sequencing; expression of host genes involved in CRC progression and immune response was quantified by real-time quantitative PCR.
RESULTS: The microbiota of patients with CRC differed from that of controls, but alterations were not restricted to the cancerous tissue. Differences between distal and proximal cancers were detected and faecal microbiota only partially reflected mucosal microbiota in CRC. Patients with CRC can be stratified based on higher level structures of mucosal-associated bacterial co-abundance groups (CAGs) that resemble the previously formulated concept of enterotypes. Of these, Bacteroidetes Cluster 1 and Firmicutes Cluster 1 were in decreased abundance in CRC mucosa, whereas Bacteroidetes Cluster 2, Firmicutes Cluster 2, Pathogen Cluster and Prevotella Cluster showed increased abundance in CRC mucosa. CRC-associated CAGs were differentially correlated with the expression of host immunoinflammatory response genes.
CONCLUSIONS: CRC-associated microbiota profiles differ from those in healthy subjects and are linked with distinct mucosal gene-expression profiles. Compositional alterations in the microbiota are not restricted to cancerous tissue and differ between distal and proximal cancers.

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