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Vishal Sahu, Abhishek Gupta, Rahul Kumar, Tarang Gupta, Anant Mohan, Sharmistha Dey
BACKGROUND: Rac proteins play a major role in tumorogenesis. We quantified Rac1 and Rac1b in serum of non small cell lung cancer (NSCLC) patients. METHODS: The blood of 77 NSCLC patients and 52 healthy controls were collected and quantified the concentration of Rac1 and Rac1b mainly by surface plasmon resonance and it was verify by Western blot analysis. RESULTS: Rac1 and Rac1b were found to be significantly over expressed in serum of NSCLC patients compare to healthy controls...
September 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
Paulo Matos, Vânia Gonçalves, Peter Jordan
A recently acknowledged morphological pathway to colorectal cancer originates from precursor polyps with a serrated appearance due to branching and folding of the colon epithelium. This serrated origin accounts for up to 30% of all colorectal tumors but these are heterogeneous regarding molecular characteristics and patient outcome. Here we review the current knowledge about the classification of this tumor subtype and its association with five key features: mutation status of the BRAF or KRAS genes, the CpG island methylation phenotype, microsatellite instability, immune cell infiltration, and overexpression of GTPase RAC1b...
August 2016: Biochimica et Biophysica Acta
Márcia Faria, Liliana Capinha, Joana Simões-Pereira, Maria João Bugalho, Ana Luísa Silva
RAC1b is a hyperactive variant of the small GTPase RAC1 known to be a relevant molecular player in different cancers. Previous studies from our group lead to the evidence that its overexpression in papillary thyroid carcinoma (PTC) is associated with an unfavorable prognosis. In the present study, we intended to extend the analysis of RAC1b expression to thyroid follicular neoplasms and to seek for clinical correlations. RAC1b expression levels were determined by RT-qPCR in thyroid follicular tumor samples comprising 23 follicular thyroid carcinomas (FTCs) and 33 follicular thyroid adenomas (FTAs)...
2016: International Journal of Endocrinology
Gang Li, Li Ying, Hong Wang, Si-Si Wei, Jie Chen, Yi-He Chen, Wei-Ping Xu, Qi-Qiang Jie, Qing Zhou, Yi-Gang Li, Yi-Dong Wei, Yue-Peng Wang
Rac1b is a constitutively activated, alternatively spliced form of the small GTPase Rac1. Previous studies showed that Rac1b promotes cell proliferation and inhibits apoptosis. In the present study, we used microarray analysis to detect genes differentially expressed in HEK293T cells and SW480 human colon cancer cells stably overexpressing Rac1b. We found that the pro-proliferation genes JNK2, c-JUN and cyclin-D1 as well as anti-apoptotic AKT2 and MCL1 were all upregulated in both lines. Rac1b promoted cell proliferation and inhibited apoptosis by activating the JNK2/c-JUN/cyclin-D1 and AKT2/MCL1 pathways, respectively...
April 5, 2016: Oncotarget
Christine Mehner, Erin Miller, Aziza Nassar, William R Bamlet, Evette S Radisky, Derek C Radisky
Breast, lung, and pancreatic cancers collectively represent one third of all diagnosed tumors and are responsible for almost 40% of overall cancer mortality. Despite improvements in current treatments, efforts to develop more specific therapeutic options are warranted. Here we identify matrix metalloproteinase 3 (MMP3) as a potential target within all three of these tumor types. MMP3 has previously been shown to induce expression of Rac1b, a tumorigenic splice isoform of Rac1. In this study we find that MMP3 and Rac1b proteins are both strongly expressed by the tumor cells of all three tumor types and that expression of MMP3 protein is prognostic of poor survival in pancreatic cancer patients...
November 2015: Genes & Cancer
Vânia Gonçalves, Andreia F A Henriques, Joana F S Pereira, Ana Neves Costa, Mary Pat Moyer, Luís Ferreira Moita, Margarida Gama-Carvalho, Paulo Matos, Peter Jordan
No abstract text is available yet for this article.
January 2016: RNA
Eglė Jakubauskienė, Inga Peciuliene, Laurynas Vilys, Paulius Mocevicius, Giedrius Vilkaitis, Arvydas Kanopka
BACKGROUND: Cell lines derived from human tumors have been extensively used as experimental models of neoplastic disease. Although such cell lines differ from both normal and cancerous tissue. OBJECTIVE: The data obtained used DNA and RNA microarray systems does not give full information about protein expression levels in cells and tissues. We present experimental evidence that splicing factor SRSF1, SRSF2, U2AF35, U2AF65 and KHSRP expression levels in gastrointestinal tract (colon, gastric and pancreatic) tumors differ compare to healthy tissues and in cell lines, derived from corresponding organs...
2015: Cancer Biomarkers: Section A of Disease Markers
Andreia F A Henriques, Patrícia Barros, Mary Pat Moyer, Paulo Matos, Peter Jordan
Mutations in the BRAF oncogene have been identified as a tumor-initiating genetic event in mainly melanoma, thyroid and colon cancer, resulting in an initial proliferative stimulus that is followed by a growth arrest period known as oncogene-induced senescence (OIS). It remains unknown what triggers subsequent escape from OIS to allow further tumor progression. A previous analysis revealed that around 80% of colorectal tumors carrying a mutation in BRAF also overexpress splice variant Rac1b. We used normal NCM460 colonocytes as a model to express oncogenic B-Raf-V600E in the presence or absence of co-transfected Rac1b and then analyzed the effect on expression of senescence markers...
December 28, 2015: Cancer Letters
Yuna Guo, S Ray Kenney, Carolyn Y Muller, Sarah Adams, Teresa Rutledge, Elsa Romero, Cristina Murray-Krezan, Rytis Prekeris, Larry A Sklar, Laurie G Hudson, Angela Wandinger-Ness
Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum toxin substrate 1) are attractive therapeutic targets in ovarian cancer based on established importance in tumor cell migration, adhesion, and invasion. Despite a predicted benefit, targeting GTPases has not yet been translated to clinical practice. We previously established that Cdc42 and constitutively active Rac1b are overexpressed in primary ovarian tumor tissues. Through high-throughput screening and computational shape homology approaches, we identified R-ketorolac as a Cdc42 and Rac1 inhibitor, distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac...
October 2015: Molecular Cancer Therapeutics
Magdalena A Cichon, Celeste M Nelson, Derek C Radisky
Epithelial-mesenchymal transition (EMT) is a physiological program that is activated during cancer cell invasion and metastasis. We show here that EMT-related processes are linked to a broad and conserved program of transcriptional alterations that are influenced by cell contact and adhesion. Using cultured human breast cancer and mouse mammary epithelial cells, we find that reduced cell density, conditions under which cell contact is reduced, leads to reduced expression of genes associated with mammary epithelial cell differentiation and increased expression of genes associated with breast cancer...
2015: Cancer Informatics
Li Ying, Gang Li, Si-si Wei, Hong Wang, Pei An, Xun Wang, Kai Guo, Xian-jin Luo, Ji-min Gao, Qing Zhou, Wei Li, Ying Yu, Yi-gang Li, Jun-li Duan, Yue-peng Wang
AIM: Small GTPase Rac1 is a member of the Ras superfamily, which plays important roles in regulation of cytoskeleton reorganization, cell growth, proliferation, migration, etc. The aim of this study was to determine how a constitutively active Rac1b regulated cell proliferation and to investigate the effects of the Rac1b inhibitor sanguinarine. METHODS: Three HEK293T cell lines stably overexpressing GFP, Rac1-GFP or Rac1b-GFP were constructed by lentiviral infection...
February 2015: Acta Pharmacologica Sinica
Hiroki Ishii, Masao Saitoh, Kei Sakamoto, Tetsuo Kondo, Ryohei Katoh, Shota Tanaka, Mitsuyoshi Motizuki, Keisuke Masuyama, Keiji Miyazawa
ESRP1 (epithelial splicing regulatory protein 1) and ESRP2 regulate alternative splicing events associated with epithelial phenotypes of cells, and both are down-regulated during the epithelial-mesenchymal transition. However, little is known about their expression and functions during carcinogenesis. In this study, we found that expression of both ESRP1 and ESRP2 is plastic: during oral squamous cell carcinogenesis, these proteins are up-regulated relative to their levels in normal epithelium but down-regulated in invasive fronts...
October 3, 2014: Journal of Biological Chemistry
Christine Mehner, Erin Miller, Davitte Khauv, Aziza Nassar, Ann L Oberg, William R Bamlet, Lizhi Zhang, Jens Waldmann, Evette S Radisky, Howard C Crawford, Derek C Radisky
UNLABELLED: Pancreatic ductal adenocarcinoma (PDA) arises at the convergence of genetic alterations in KRAS with a fostering microenvironment shaped by immune cell influx and fibrotic changes; identification of the earliest tumorigenic molecular mediators evokes the proverbial chicken and egg problem. Matrix metalloproteinases (MMP) are key drivers of tumor progression that originate primarily from stromal cells activated by the developing tumor. Here, MMP3, known to be expressed in PDA, was found to be associated with expression of Rac1b, a tumorigenic splice isoform of Rac1, in all stages of pancreatic cancer...
October 2014: Molecular Cancer Research: MCR
Virginia Alonso-Espinaco, Miriam Cuatrecasas, Vicente Alonso, Pilar Escudero, Maribel Marmol, Carlos Horndler, Javier Ortego, Rosa Gallego, Jordi Codony-Servat, Xabier Garcia-Albeniz, Pedro Jares, Antoni Castells, Juan José Lozano, Rafael Rosell, Joan Maurel
INTRODUCTION: Chemotherapy is the principal treatment in metastatic colorectal cancer (mCRC) patients. RAC1b, a RAC1 spliced variant, is over-expressed in colorectal cancer (CRC), and impairs apoptosis by activation of nuclear-factor-KB. Since RAC1b has been associated with the BRAF(V600E) mutation, associated with poor prognosis in CRC, we evaluated the role of RAC1b expression as a predictor of chemotherapy efficacy in mCRC. METHODS: We analysed KRAS and BRAF mutation, microsatellite instability and RAC1b expression in 157 mCRC patients treated with FOLFOX/XELOX in first-line therapy...
July 2014: European Journal of Cancer
Vânia Gonçalves, Andreia F A Henriques, Andreia Henriques, Joana F S Pereira, Joana Pereira, Ana Neves Costa, Mary Pat Moyer, Luís Ferreira Moita, Margarida Gama-Carvalho, Paulo Matos, Peter Jordan
The premessenger RNA of the majority of human genes can generate various transcripts through alternative splicing, and different tissues or disease states show specific patterns of splicing variants. These patterns depend on the relative concentrations of the splicing factors present in the cell nucleus, either as a consequence of their expression levels or of post-translational modifications, such as protein phosphorylation, which are determined by signal transduction pathways. Here, we analyzed the contribution of protein kinases to the regulation of alternative splicing variant Rac1b that is overexpressed in certain tumor types...
April 2014: RNA
Hendrik Ungefroren, Susanne Sebens, Klaudia Giehl, Ole Helm, Stephanie Groth, Fred Fändrich, Christoph Röcken, Bence Sipos, Hendrik Lehnert, Frank Gieseler
Transforming growth factor (TGF)-β1 promotes progression of pancreatic ductal adenocarcinoma (PDAC) by enhancing epithelial-mesenchymal transition, cell migration/invasion, and metastasis, in part by cooperating with the small GTPase Rac1. Prompted by the observation of higher expression of Rac1b, an alternatively spliced Rac1 isoform, in pancreatic ductal epithelial cells and in patients with chronic pancreatitis vs. PDAC, as well as in long-time vs. short-time survivors among PDAC patients, we asked whether Rac1b might negatively affect TGF-β1 prometastatic function...
January 15, 2014: Oncotarget
Qike K Chen, KangAe Lee, Derek C Radisky, Celeste M Nelson
Mouse mammary epithelial cells undergo transdifferentiation via epithelial-mesenchymal transition (EMT) upon treatment with matrix metalloproteinase-3 (MMP3). In rigid microenvironments, MMP3 upregulates expression of Rac1b, which translocates to the cell membrane to promote induction of reactive oxygen species and EMT. Here we examine the role of the extracellular matrix (ECM) in this process. Our data show that the basement membrane protein laminin suppresses the EMT response in MMP3-treated cells, whereas fibronectin promotes EMT...
October 2013: Differentiation; Research in Biological Diversity
Ana Luísa Silva, Francisca Carmo, Maria João Bugalho
CONTEXT: The BRAF V600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). In colorectal cancer, BRAF V600E was described to functionally cooperate with RAC1b, a hyperactive splice variant of the small GTPase RAC1, to sustain cell survival. This interplay has never been investigated in PTCs. OBJECTIVE: We aimed to analyze the expression of RAC1b in PTC and correlate its expression with BRAF V600E mutational status, histopathological features, and clinical outcome...
June 2013: European Journal of Endocrinology
Yoshifumi Mori, Shunsuke Yagi, Atsuro Sakurai, Michiyuki Matsuda, Etsuko Kiyokawa
Rac1b is frequently expressed in a number of human cancer cells. It is still unclear, however, whether Rac1b causes morphological abnormalities in epithelial tissues. To investigate whether Rac1b induces morphological changes in 3-dimensional epithelial structures, we utilized an auxin-dependent protein expression system, which enabled us to rapidly induce and evaluate Rac1b function in MDCK (Madin-Darby Canine Kidney) cysts, a model for polarized epithelial structure. Cells carrying the wild-type Rac1, Rac1b and constitutively active Rac1V12 gene were morphologically indistinguishable from normal, when their coding proteins were not expressed...
January 2013: Small GTPases
Michael Bordonaro
RNA processing involves a variety of processes affecting gene expression, including the removal of introns through RNA splicing, as well as 3' end processing (cleavage and polyadenylation). Alternative RNA processing is fundamentally important for gene regulation, and aberrant processing is associated with the initiation and progression of cancer. Deregulated Wnt signaling, which is the initiating event in the development of most cases of human colorectal cancer (CRC), has been linked to modified RNA processing, which may contribute to Wnt-mediated colonic carcinogenesis...
2013: Journal of Cancer
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