Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The GTPases of the Rho family are molecular switches that play an important role in a wide range of cellular processes and are increasingly implicated in tumourigenesis. Unlike what was found for the Ras oncogenes in tumours, hardly any activating mutations have been found in the genes encoding Rho proteins. In the past, we have identified Tiam1 (T-lymphoma invasion and metastasis) as a specific activator for the Rho-like GTPase Rac. In vivo, Tiam1 deficiency protects against Ras-induced skin carcinogenesis, underscoring the consequences of deregulated signalling for the onset and progression of tumours. Thus, an important level of regulation of signalling via the Rho-like GTPases comes from the specific control of their activators. In this paper, we review what is known on the specific regulation of Tiam1 signalling towards Rac.
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PMID:Regulation of Tiam1-Rac signalling. 1282 30

Intracellular signaling through Rho-associated coiled-coil forming kinase (ROCK) is a target of antimetastatic therapy and is proposed to be involved in carcinogenesis. Focal adhesion kinase (FAK) functions downstream of ROCK and participates in anti-apoptotic signaling. We hypothesized that a specific ROCK inhibitor, Y-27632, may exert a pro-apoptotic effect in combination with anticancer agents through the suppression of FAK. A549 lung carcinoma cells were treated with Y-27632 and cisplatin. The simultaneous combination did not exert any additional effect, whereas sequential treatment, in which cisplatin followed Y-27632, enhanced cytotoxicity in concentration- and time-dependent manner. Y-27632 did not suppress tyrosine phosphorylation of FAK in A549-FAK, the active form of FAK expressing A549 cells, as observed in parental cells. Nevertheless, the pretreatment of A549-FAK cells with Y-27632 still enhanced cisplatin-induced cytotoxicity. It was concluded that the ROCK inhibitor enhances cisplatin-induced cytotoxicity through FAK suppression-independent mechanism(s). These observations raise the possibility that the inhibition of the ROCK-mediated signal enhances the effect of anti-cancer agents in addition to its antimetastatic property.
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PMID:Enhancement of cisplatin-induced cytotoxicity by ROCK inhibitor through suppression of focal adhesion kinase-independent mechanism in lung carcinoma cells. 1296 88

Rho GTPases were previously shown to have an important role in cancer development and progression, including cell transformation, proliferation, invasion, metastasis, and angiogenesis. However, there is still little information available on the clinical significance of Rho GTPases expression in human cancer specimens. In the present study, we systemically investigated the mRNA expression levels of seven main members RhoA, RhoB, RhoC, Rac1, Rac2, Rac3, and Cdc42 of Rho family using semi-quantitative reverse transcription-PCR in 53 patients with gastric carcinoma and 7 gastric cancer cell lines. The total and activities of RhoA, Rac1 and Cdc42 in 5 gastric cancer cell lines were also examined. The mean mRNA expression levels of RhoA and Rac1 in gastric cancer tissue specimens were significantly higher than those in the adjacent non-tumorous tissue specimens (p < 0.01). The higher expression of RhoA was significantly correlated with higher TNM stage (p < 0.05) as well as with pooly differentiated histological type (p < 0.05) of gastric carcinoma. The increased expression of Rac1 was related to higher TNM stages of gastric carcinoma (p < 0.05). The expression levels of mRNA, total protein and activities of RhoA and Rac1 in 7 gastric cancer cell lines were all higher than that in gastric mucosal epithelial cell line GES-1. These findings indicate that RhoA and Rac1 may play important roles in the carcinogenesis and progression of gastric carcinoma.
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PMID:Expression of seven main Rho family members in gastric carcinoma. 1497 55

E-selectin mediated tumor cell adhesion plays an important role in metastasis. Here we show that ionizing radiation (IR) induces E-selectin gene and protein expression in human endothelial cells at therapeutically relevant dose level. E-selectin expression is accompanied by an increase in the adhesion of human colon carcinoma cells to primary human umbilical vein endothelial cells (HUVEC). The HMG-CoA reductase inhibitor lovastatin impairs IR-stimulated E-selectin expression as analyzed at the level of the protein, mRNA and promoter. Inactivation of Rho GTPases either by use of Clostridium difficile toxin A or by co-expression of dominant-negative Rho blocked IR-induced E-selectin gene induction, indicating Rho GTPases to be essential. Radiation-induced expression of E-selectin was also blocked by all-trans retinoic acid (at-RA), whereas 9-cis retinoic acid was ineffective. Abrogation of IR-stimulated E-selectin expression by lovastatin and at-RA reduced tumor cell adhesion in a dose-dependent manner. Combined treatment with lovastatin and at-RA exerted additive inhibitory effects on radiation-induced E-selectin expression and tumor cell adhesion. Therefore, application of statins and at-RA might have clinical impact in protecting against E-selectin-promoted metastasis, which might arise as an unwanted side effect from radiation treatment.
Carcinogenesis 2004 Aug
PMID:Ionizing radiation-induced E-selectin gene expression and tumor cell adhesion is inhibited by lovastatin and all-trans retinoic acid. 1498 23

Mitogenic growth factor- and integrin-dependent signaling pathways cooperate to control the proliferation of nontransformed cells. As integral mediators of these networks, the Rho family of GTPases play a pivotal role in G1 cell cycle progression, primarily through regulation of cyclin D1 expression, as well as the levels of the cyclin-dependent kinase inhibitors p21cip1 and p27kip1. Such dual control of both the critical positive and negative regulators of G1 progression make the Rho GTPases prime candidates to target the autonomous proliferation which typifies cancer cells. Cyclin D1 has been identified as an important oncogene and the cdk inhibitors as tumor suppressors in human breast carcinogenesis. Evidence pointing to the potential role of Rho-dependent pathways and their interaction with oncogenic Ras in contributing to such cell cycle abnormalities that characterize human breast cancer is also presented.
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PMID:Rho GTPases as key transducers of proliferative signals in g1 cell cycle regulation. 1499 52

The Rho family of GTPases are involved in actin cytoskeleton organization and associated with carcinogenesis and progression of human cancers. We investigated the roles of Rho family GTPases, prototypes RhoA, Rac1, and Cdc42, and the major downstream targets of RhoA, ROCK-I, and ROCK-II in testicular cancer. We quantified protein expression in paired tumor and nontumor samples from surgical specimens from 57 consecutive patients with testicular germ cell tumors using Western blotting. Protein expression of RhoA, ROCK-I, ROCK-II, Rac1, and Cdc42 was significantly higher in tumor tissue than in nontumor tissue (P < 0.0001). Expression of protein for RhoA, ROCK-I, ROCK-II, Rac1, and Cdc42 was greater in tumors of higher stages than lower stages (P < 0.0001, P < 0.001, P < 0.001, P < 0.0001, P < 0.0001, respectively). Within stage II nonseminoma (31 patients), protein levels of RhoA, ROCK-I, ROCK-II, Rac1, and Cdc42 in the primary tumor were lower in the group of 24 patients with no evidence of disease after therapy compared with 7 patients with disease that was refractory/recurrent (P < 0.05). Rho family GTPases may be involved in the progression of testicular germ cell tumors.
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PMID:Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. 1526 55

Dissemination of neoplastic cells from the primary tumor (invasion and metastasis) is a fundamentally dangerous step in multistage carcinogenesis. Recent evidence suggests that Rho GTPase-mediated signaling is linked to dissemination of cells from several different types of human tumors. The Rho family of proteins is typically associated with the regulation of cytoskeletal activity, including actin assembly, microtubule dynamics, and myosin II-dependent contractility of the actin-rich cortex. We examined the effect of overexpression of constitutively active RhoA on islands and monolayers of epithelial cells. Although newly plated cells initially formed small spread islands, there was also a significant population of cells that detached from the substrate, floated in the medium, and then could reattach to the substrate to form new colonies. Detachment of cells from transfected epithelial islands or monolayers occurred in correlation to the plane of cytokinesis after misorientation of the mitotic spindle axis. We suggest that these alterations result from Rho-induced increase of contractility of the cortex of dividing cells, which, during cytokinesis, produces a cell that has budded out of an existing layer of cells. Cell division-mediated detachment of cells from tissue structures may be an important mechanism of tumor dissemination and metastasis.
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PMID:Rho overexpression leads to mitosis-associated detachment of cells from epithelial sheets: a link to the mechanism of cancer dissemination. 1530 43

The rearrangement of the actin cytoskeleton has been shown to play a critical role in the development of transformation and malignant phenotype of cancer cells. Rho family GTPases regulate the arrangement of the actin cytoskeleton. By wound-healing assay, we have found that NIH 3T3 fibroblast cells move towards the wound- gaps by extending filopodial and lamellipdial structures at the leading edge of the moving cells. We have inactivated the function of Rho GTPases of v-Ras transformed NIH 3T3 cells by overexpressing Rho GTPase-activating (RhoGAP) domain of RhoGAP of p190. We have observed that inactivation of Rho, Rac and Cdc42 GTPases by overexpressing RHG causes inhibition of: (i) polymerization of actin to form filaments, (ii) formation of lamellipodia, filopodia and stress fibres, (iii) cell motility, (iv) cell spreading and (v) cell-to-cell adhesions. These results further strengthen the current knowledge on the role of Rho, Rac and Cdc42 GTPases in the regulation of the rearrangement of actin cytoskeleton. Our results, for the first time, demonstrate that RhoGAP domain of RhoGAP could be used to study the molecular mechanism of Ras-mediated signalling in growth, differentiation and carcinogenesis.
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PMID:The role of Rho GTPases in the regulation of the rearrangement of actin cytoskeleton and cell movement. 1536 55

ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with RhoGAP domain. Here, we characterized human ARHGAP10 gene by using bioinformatics. Complete coding sequence of ARHGAP10 isoform A was determined by assembling nucleotide position 1-725 of FLJ41791 cDNA (AK123785.1) and 5'-truncated IMAGE4310652 cDNA (BC011920.2). Nucleotide position 240-2600 of ARHGAP10 isoform A was identical to GRAF2 cDNA (AB050785.1). Complete coding sequence of ARHGAP10 isoform B was derived from FLJ41791 cDNA. ARHGAP10 isoform A, consisting of exons 1-23, encoded full-length protein (786 aa). ARHGAP10 isoform B, consisting of exons 1-5 and intron 5, encoded C-terminally truncated protein (163 aa). ARHGAP10 gene was found encoding two isoforms due to alternative splicing. ARHGAP10 mRNA was expressed in chondrosarcoma, breast cancer, kidney tumors, and brain tumors. ARHGAP10 and ARHGAP26 (GRAF), showing 57.9% total amino-acid identity, shared the common-domain structure with BAR, PH, RhoGAP and SH3 domains. ARHGAP10-NR3C2 locus at human chromosome 4q31.23 and ARHGAP26-NR3C1 locus at human chromosome 5q31 were paralogous regions (paralogons) within the human genome. ARHGAP gene family was found consisting of at least 32 members, including ARHGAP1, ARHGAP2 (CHN1), ARHGAP3, (CHN2), ARHGAP4, ARHGAP5, ARHGAP6 (STARD8), ARHGAP7 (STARD12 or DLC1), ARHGAP8, ARHGAP9, ARHGAP10, ARHGAP12, ARHGAP13 (SRGAP1), ARHGAP14 (SRGAP2), ARHGAP15, ARHGAP17 (RICH1), ARHGAP18, ARHGAP19, ARHGAP20, ARHGAP21, ARHGAP22, ARHGAP23, ARHGAP24, ARHGAP25, ARHGAP26, STRAD13 (DLC2), HA-1, GMIP, PARG1, PIK3R1, PIK3R2, RACGAP1, and FNBP2. Genetic alterations of ARHGAP family genes lead to carcinogenesis through the dysregulation of Rho/Rac/Cdc42-like GTPases.
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PMID:Characterization of human ARHGAP10 gene in silico. 1537 73

ARHGAP1, ARHGAP2, ARHGAP3, ARHGAP4, ARHGAP5, ARHGAP6, ARHGAP7 (DLC1), ARHGAP8, ARHGAP9, ARHGAP10, ARHGAP12, ARHGAP13 (SRGAP1), ARHGAP14 (SRGAP2), ARHGAP15, ARHGAP17 (RICH1), ARHGAP18, ARHGAP19, ARHGAP20, ARHGAP21, ARHGAP22, ARHGAP23, ARHGAP24, ARHGAP25, ARHGAP26, STARD13 (DLC2), HA-1, GMIP, PARG1, RACGAP1, PIK3R1, PIK3R2, and FNBP2 genes encode Rho/Rac/Cdc42-like GTPase activating (RhoGAP) proteins. Here, we characterized human ARHGAP27 gene by using bioinformatics. Complete coding sequence of ARHGAP27 isoform 1, encoding a full-length 889-aa protein, was determined by assembling exon 1 (nucleotide position 143440-144096 of AC091132.16) and most part of FLJ43547 cDNA (nucleotide position 69-3628 of AK125535.1). Complete coding sequence of ARHGAP27 isoform 2, encoding an N-terminally truncated 548-aa protein, was derived from FLJ43547 cDNA. ARHGAP27 isoform 1 consists of exons 1-17, while ARHGAP27 isoform 2 consists of exons 1B, and 2-17. ARHGAP27 gene encoded two isoforms due to alternative splicing of alternative promoter type. ARHGAP27 mRNA was expressed in germinal center B cell, spleen, chronic lymphocytic leukemia, pancreatic cancer, and lung cancer. LOC303583 (NM_ 198759.1) was the representative rat Arhgap27 cDNA. Human ARHGAP27 showed 84.3% total-amino-acid identity with rat Arhgap27, and 39.0% total-amino-acid identity with human ARHGAP12. ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains. ARHGAP27 gene was located at human chromosome 17q21, while ARHGAP12 gene was located at human chromosome 10p11. ARHGAP family genes are cancer-associated genes, because their genetic alterations lead to carcinogenesis through the dysregulation of Rho/Rac/ Cdc42-like GTPases. This is the first report on identification and characterization of the ARHGAP27 gene.
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PMID:Identification and characterization of ARHGAP27 gene in silico. 1549 70


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