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Mutations of RAS Gene Family in Specimens of Bladder Cancer  [cached]
Navaz Karimianpour,Parisa Mousavi-Shafaei,Abed-Ali Ziaee,Mohammad Taghi Akbari
Urology Journal , 2008,
Abstract: Introduction: Studies have shown different types of RAS mutations in human bladder tumors with a wide range of mutation frequencies in different patient populations. This study aimed to assess the frequency of specific-point mutations in the RAS gene family of a group of Iranian patients with bladder cancer. Materials and Methods: We examined the tumor specimens of 35 consecutive patients with transitional cell carcinoma. The DNA samples were evaluated for the occurrence of HRAS, KRAS, and NRAS activation using a polymerase chain reaction-restriction fragment length polymorphism technique. Results: None of the patients had mutations in the RAS gene family “hot spots” including codons 12, 13, and 61. Conclusion: We failed to find RAS mutations in our bladder tumor samples. These observations may reflect the involvement of different etiological factors in the induction of bladder tumor of which RAS mutation might not be present in all populations.
Genetic Aberrations of the K-ras Proto-oncogene in Bladder Cancer in Kashmiri Population  [cached]
Mahoor S. Nanda,A. Syed Sameer,Nidda Syeed,Zaffar A. Shah
Urology Journal , 2010,
Abstract: PURPOSE: To assess the frequency of specific point mutations in the K-ras gene in a group of Kashmiri patients with bladder cancer. MATERIALS AND METHODS: We analyzed the incidence of K-ras exon 1 gene mutations in tumors and surgical margins in 60 patients with transitional cell carcinoma of varied clinical stages and histological grades using the polymerase chain reaction-single strand conformation polymorphism and DNA sequencing. RESULTS: A significant correlation was found between the K-ras, the lymph node status, and tumor recurrence (P < 0.05). Also, smokers and patients with higher tumor grade showed a significantly higher relative risk of developing K-ras mutations than the normal ones. CONCLUSION: K-ras exon 1 gene mutations were found with low frequency in the bladder cancer tumors from Kashmir valley, which suggests that K-ras gene might be involved in a sub-set of bladder tumors, but it needs further investigation on a larger cohort sample to authenticate the current findings.
Japanese encephalitis virus induces matrix metalloproteinase-9 expression via a ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent AP-1 pathway in rat brain astrocytes
Chuen-Mao Yang, Chih-Chung Lin, I-Ta Lee, Yi-Hsin Lin, Caleb M Yang, Wei-June Chen, Mei-Jie Jou, Li-Der Hsiao
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-12
Abstract: In this study, the effect of JEV on expression of MMP-9 was determined by gelatin zymography, western blot analysis, RT-PCR, and promoter assay. The involvement of AP-1 (c-Jun and c-Fos), c-Src, PDGFR, PI3K/Akt, and MAPKs in these responses were investigated by using the selective pharmacological inhibitors and transfection with siRNAs.Here, we demonstrate that JEV induces expression of pro-form MMP-9 via ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent, AP-1 activation in RBA-1 cells. JEV-induced MMP-9 expression and promoter activity were inhibited by pretreatment with inhibitors of AP-1 (tanshinone), c-Src (PP1), PDGFR (AG1296), and PI3K (LY294002), and by transfection with siRNAs of c-Jun, c-Fos, PDGFR, and Akt. Moreover, JEV-stimulated AP-1 activation was inhibited by pretreatment with the inhibitors of c-Src, PDGFR, PI3K, and MAPKs.From these results, we conclude that JEV activates the ROS/c-Src/PDGFR/PI3K/Akt/MAPKs pathway, which in turn triggers AP-1 activation and ultimately induces MMP-9 expression in RBA-1 cells. These findings concerning JEV-induced MMP-9 expression in RBA-1 cells imply that JEV might play an important role in CNS inflammation and diseases.Japanese encephalitis virus (JEV) is a single-stranded, positive-sense RNA virus belonging to the family flaviviridae. JEV is transmitted between animals and human host by culex mosquitoes [1,2]. After the bite of an infected mosquito, JEV amplifies peripherally producing transient viremia before entering into the central nervous system (CNS) [2]. The principal target cells for JEV are in the CNS, and include neurons and astrocytes [3]. Several lines of evidence suggest that JEV frequently causes severe encephalitic illness, and is one of the most important endemic encephalitides in the world, especially in Eastern and Southeastern Asia, clinically manifesting with fever, headache, vomiting, signs of meningeal irritation and altered consciousness leading to high mortality [1-3]. In CNS injuries and in diseases
Vascular endothelial growth factor, p53, and the H-ras oncogene in Egyptian patients with bladder cancer  [cached]
Farha A El-Chennawi, Fatma A Auf, Shereen S Metwally, Youssef M Mosaad, Atallah A Shaaban, Mahmoud Abdo El-Baz, Ziyad E Tawhid, Zakaria F Lotfy
World Journal of Gastrointestinal Oncology , 2009,
Abstract: AIM: To evaluate the relationship between vascular endothelial growth factor (VEGF), p53, and the H-ras oncogene and different clinicopathological parameters in Egyptian patients with Schistosoma-associated transitional cell carcinoma of the bladder. METHODS: The study included 50 patients with transitional cell carcinoma for whom radical cystectomy and urinary diversions were carried out. VEGF and p53 protein expressions were evaluated with an immunohistochemical staining method, and H-ras oncogene mutations were analyzed with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: High grade tumors revealed higher p53 immunostaining than low grade tumors ( P = 0.016). p53 and VEGF protein expressions, as well as H-ras oncogene mutations, had an insignificant impact on patient outcomes ( P = 0.962, P = 0.791, and P = 967, respectively). Cancer extension to regional lymph nodes was associated with poor outcomes ( P = 0.008). CONCLUSION: VEGF, p53 and the H-ras oncogene have no relation to patient survival and outcome in Schistosoma-associated transitional cell carcinoma.
Fibroblast Growth Factor 2 Causes G2/M Cell Cycle Arrest in Ras-Driven Tumor Cells through a Src-Dependent Pathway  [PDF]
Jacqueline Salotti, Matheus H. Dias, Marianna M. Koga, Hugo A. Armelin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072582
Abstract: We recently reported that paracrine Fibroblast Growth Factor 2 (FGF2) triggers senescence in Ras-driven Y1 and 3T3Ras mouse malignant cell lines. Here, we show that although FGF2 activates mitogenic pathways in these Ras-dependent malignant cells, it can block cell proliferation and cause a G2/M arrest. These cytostatic effects of FGF2 are inhibited by PD173074, an FGF receptor (FGFR) inhibitor. To determine which downstream pathways are induced by FGF2, we tested specific inhibitors targeting mitogen-activated protein kinase (MEK), phosphatidylinositol 3 kinase (PI3K) and protein kinase C (PKC). We show that these classical mitogenic pathways do not mediate the cytostatic activity of FGF2. On the other hand, the inhibition of Src family kinases rescued Ras-dependent malignant cells from the G2/M irreversible arrest induced by FGF2. Taken together, these data indicate a growth factor-sensitive point in G2/M that likely involves FGFR/Ras/Src pathway activation in a MEK, PI3K and PKC independent manner.
SSeCKS/Gravin/AKAP12 attenuates expression of proliferative and angiogenic genes during suppression of v-Src-induced oncogenesis
Yongzhong Liu, Lingqiu Gao, Irwin H Gelman
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-105
Abstract: We use cDNA microarrays and semi-quantitative RT-PCR analysis to identify changes in gene expression correlating with i) SSeCKS expression in the absence of v-Src activity, ii) activation of v-Src activity alone, and iii) SSeCKS re-expression in the presence of active v-Src.SSeCKS re-expression resulted in the attenuation of critical Src-induced proliferative and pro-angiogenic gene expression including Afp, Hif-1α, Cdc20a and Pdgfr-β, and conversely, SSeCKS induced several cell cycle regulatory genes such as Ptpn11, Gadd45a, Ptplad1, Cdkn2d (p19), and Rbbp7.Our data provide further evidence that SSeCKS can suppress Src-induced oncogenesis by modulating gene expression downstream of Src kinase activity.SSeCKS, originally identified as a transcriptionally-suppressed gene in v-src and ras-transformed rodent fibroblast cells [1], is the orthologue of human GRAVIN/AKAP12 gene that encodes a kinase-scaffolding protein [2] that is targeted as an autoantigen in some cases of myasthenia gravis [3]. SSeCKS/Gravin/AKAP12 expression is severely downregulated in human prostate, breast and gastric cancer, partially relating to the mapping of the human gene to 6q24-25.1 [4], a cancer deletion hotspot [5]. Re-expression of SSeCKS to physiologic levels in Src- or Ras-transformed fibroblasts or epithelial prostate cancer cells suppresses morphological transformation, anchorage- and growth factor-independent proliferation, and metastatic potential, while restoring normal actin-based cytoskeletal architecture and cell-cycle controls on cyclin D1 expression [4,6,7]. SSeCKS also seems to control the blood-brain barrier by suppressing astrocyte-expressed vascular endothelial growth factor (VEGF) during the switch to normoxic conditions after birth [8]. A recent study indicates that the ability of SSeCKS to suppress lung metastasis formation by MatLyLu prostate cancer cells correlates with its suppression of VEGF 165 and 121 isoforms [9]. Interestingly, SSeCKS does not grossly alter the S
Ras Isoprenylation and pAkt Inhibition by Zoledronic Acid and Fluvastatin Enhances Paclitaxel Activity in T24 Bladder Cancer Cells  [PDF]
Shaojuan Li,Paul De Souza
Cancers , 2011, DOI: 10.3390/cancers3010662
Abstract: Background: Bisphosphonates interfere with the mevalonate pathway and inhibit the prenylation of small GTP-binding proteins such as ras and rap. We hypothesized that zoledronic acid would synergistically inhibit T24 bladder cancer cell growth in combination with fluvastatin and paclitaxel. Methods: Increasing doses of fluvastatin, zoledronic acid, and paclitaxel were investigated as single agents and in combination, and synergistic interactions were evaluated by the Chou-Talalay method. Western blots were used to assess effects on signal transduction pathways. Results: Growth of T24 was significantly inhibited with IC 50 values of 2.67 ± 0.61 mM for fluvastatin and 5.35 ± 1.35 mM for zoledronic acid after 72 hours treatment. Geranylgeranyl pyrophosphate and farnesyl pyrophosphate was able to block, in part, this inhibitory activity. The combinations of zoledronic acid and paclitaxel, zoledronic acid and fluvastatin, and fluvastatin and paclitaxel were all synergistic. Both fluvastatin and zoledronic acid inhibited Ras and Rap prenylation, and the phosphorylation of ERK1/2 and AKT. The degree of inhibition of phosphorylation of these key signaling transduction pathways appears to closely correlate with their synergistic interactions. Conclusions: Zoledronic acid enhances fluvastatin and paclitaxel activity against T24 in a synergistic manner and this is mediated largely by inhibition of both the Ras/Raf/MEK/ERK and PI3K/AKT signaling pathways via isoprenylation inhibition.
Expression Microarray Meta-Analysis Identifies Genes Associated with Ras/MAPK and Related Pathways in Progression of Muscle-Invasive Bladder Transition Cell Carcinoma  [PDF]
Jonathan A. Ewald, Tracy M. Downs, Jeremy P. Cetnar, William A. Ricke
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055414
Abstract: The effective detection and management of muscle-invasive bladder Transition Cell Carcinoma (TCC) continues to be an urgent clinical challenge. While some differences of gene expression and function in papillary (Ta), superficial (T1) and muscle-invasive (≥T2) bladder cancers have been investigated, the understanding of mechanisms involved in the progression of bladder tumors remains incomplete. Statistical methods of pathway-enrichment, cluster analysis and text-mining can extract and help interpret functional information about gene expression patterns in large sets of genomic data. The public availability of patient-derived expression microarray data allows open access and analysis of large amounts of clinical data. Using these resources, we investigated gene expression differences associated with tumor progression and muscle-invasive TCC. Gene expression was calculated relative to Ta tumors to assess progression-associated differences, revealing a network of genes related to Ras/MAPK and PI3K signaling pathways with increased expression. Further, we identified genes within this network that are similarly expressed in superficial Ta and T1 stages but altered in muscle-invasive T2 tumors, finding 7 genes (COL3A1, COL5A1, COL11A1, FN1, ErbB3, MAPK10 and CDC25C) whose expression patterns in muscle-invasive tumors are consistent in 5 to 7 independent outside microarray studies. Further, we found increased expression of the fibrillar collagen proteins COL3A1 and COL5A1 in muscle-invasive tumor samples and metastatic T24 cells. Our results suggest that increased expression of genes involved in mitogenic signaling may support the progression of muscle-invasive bladder tumors that generally lack activating mutations in these pathways, while expression changes of fibrillar collagens, fibronectin and specific signaling proteins are associated with muscle-invasive disease. These results identify potential biomarkers and targets for TCC treatments, and provide an integrated systems-level perspective of TCC pathobiology to inform future studies.
The Association of RAS Association Domain Family Protein1A (RASSF1A) Methylation States and Bladder Cancer Risk: A Systematic Review and Meta-Analysis  [PDF]
Tianyi Gao, Shukui Wang, Bangshun He, Yuqin Pan, Guoqi Song, Ling Gu, Liping Chen, Zhenling Nie, Yeqiong Xu, Rui Li
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048300
Abstract: RAS association domain family protein 1a (RASSF1A) is a putative tumor suppressor gene located on 3p21, has been regarded playing important roles in the regulation of different types of human tumors. Previous reports demonstrated that the frequency of RASSF1A methylation was significantly higher in patients group compared with controls, but the relationship between RASSF1A promoter methylation and pathological features or the tumor grade of bladder cancer remains controversial. Therefore, A meta-analysis of published studies investigating the effects of RASSF1A methylation status in bladder cancer occurrence and association with both pTNM (p, pathologic stage; T, tumor size; N, node status; M, metastatic status) and tumor grade in bladder cancer was performed in the study. A total of 10 eligible studies involving 543 cases and 217 controls were included in the pooled analyses. Under the fixed-effects model, the OR of RASSF1A methylation in bladder cancer patients, compared to non-cancer controls, was 8. 40 with 95%CI = 4. 96–14. 23. The pooled OR with the random-effects model of pTNM and tumor grade in RASSF1A methylated patients, compared to unmethylated patients, was 0. 75 (95%CI = 0. 28–1. 99) and 0. 39 (95%CI = 0. 14–1. 09). This study showed that RASSF1A methylation appears to be an independent prognostic factor for bladder cancer. The present findings also require confirmation through adequately designed prospective studies.
Areca Nut Components Affect COX-2, Cyclin B1/cdc25C and Keratin Expression, PGE2 Production in Keratinocyte Is Related to Reactive Oxygen Species, CYP1A1, Src, EGFR and Ras Signaling  [PDF]
Mei-Chi Chang, Yi-Jane Chen, Hsiao-Hua Chang, Chiu-Po Chan, Chien-Yang Yeh, Yin-Lin Wang, Ru-Hsiu Cheng, Liang-Jiunn Hahn, Jiiang-Huei Jeng
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101959
Abstract: Aims Chewing of betel quid (BQ) increases the risk of oral cancer and oral submucous fibrosis (OSF), possibly by BQ-induced toxicity and induction of inflammatory response in oral mucosa. Methods Primary gingival keratinocytes (GK cells) were exposed to areca nut (AN) components with/without inhibitors. Cytotoxicity was measured by 3-(4,5-dimethyl- thiazol- 2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. mRNA and protein expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. PGE2/PGF2α production was measured by enzyme-linked immunosorbent assays. Results Areca nut extract (ANE) stimulated PGE2/PGF2α production, and upregulated the expression of cyclooxygenase-2 (COX-2), cytochrome P450 1A1 (CYP1A1) and hemeoxygenase-1 (HO-1), but inhibited expression of keratin 5/14, cyclinB1 and cdc25C in GK cells. ANE also activated epidermal growth factor receptor (EGFR), Src and Ras signaling pathways. ANE-induced COX-2, keratin 5, keratin 14 and cdc25C expression as well as PGE2 production were differentially regulated by α–naphthoflavone (a CYP 1A1/1A2 inhibitor), PD153035 (EGFR inhibitor), pp2 (Src inhibitor), and manumycin A (a Ras inhibitor). ANE-induced PGE2 production was suppressed by piper betle leaf (PBL) extract and hydroxychavicol (two major BQ components), dicoumarol (a NAD(P)H:Quinone Oxidoreductase - NQO1 inhibitor) and curcumin. ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol, suggesting that AN components may contribute to the pathogenesis of OSF and oral cancer via induction of aberrant differentiation, cytotoxicity, COX-2 expression, and PGE2/PGF2αproduction. Conclusions CYP4501A1, reactive oxygen species (ROS), EGFR, Src and Ras signaling pathways could all play a role in ANE-induced pathogenesis of oral cancer. Addition of PBL into BQ and curcumin consumption could inhibit the ANE-induced inflammatory response.
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