Clinical and Prognostic Significance of RhoA and RhoC Gene Expression in Esophageal Squamous Cell Carcinoma
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Objective:To detect Rho family(RhoA,RhoB,RhoC) mRNA expression and study the role of Rho family in endometriosis.Method: Quantified RT-PCR technique was used in the detection.Result: RhoA and RhoC mRNA expression in endometriosis was lower than that in normal endometrium markedly(P0.05,vs normal).RhoB mRNA expression didn't show any distinction between the groups.Conclusion: Endometriosis may be related to the low expression of RhoA and RhoC.
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Objective To investigate changes of expressions of RhoA and RhoB and RhoC in lung cancertissues to explore the relationship of Rho subfamily with development,migration,and metastasis of lung carcinoma.MethodsThe expressions of RhoA,RhoB and RhoC mRNA and protein in four different lung cancer cell lines(LTEP-a-2,SK-MES-1,NCI-H446,and NCI-H292)were detected by real-time quantitative reverse transcriptionpolymerase chain reaction(QRT-PCR) and Western blotting, and were compared with MRC-5(control group). Theexpressions of RhoA,RhoB and RhoC protein in 45 cases of lung cancer tissue by immunocytochemistry.Results The expressions of RhoA and RhoB mRNA and protein in lung cancer cell line LTEP-a-2,SK-MES-1,NCI-H446,and NCI-H292 were significantly higher than those in control group(allP0.05),while no statisticaldifference was found among four lung cancer cell lines(allP0.05). The expressions of RhoA and RhoB protein inhuman lung cancer tissue were positive,but the levels of them were not statistically different between moderatelydifferentiated squamous carcinoma group and non-moderately differentiated squamous carcinoma group(allP0.05).The expression of RhoC protein was negative.ConclusionThe expressions of RhoA and RhoB were elevated inlung cancer,which indicates that Rho subfamily involve in the development,migration and metastasis of lungcancer.
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Endothelial cells line the vasculature and are important for the regulation of blood pressure, vascular permeability, clotting and transendothelial migration of leukocytes and tumor cells. A group of proteins that that control the endothelial barrier function are the RhoGTPases. This study focuses on three homologous (>88%) RhoGTPases: RhoA, RhoB, RhoC of which RhoB and RhoC have been poorly characterized. Using a RhoGTPase mRNA expression analysis we identified RhoC as the highest expressed in primary human endothelial cells. Based on an existing RhoA FRET sensor we developed new RhoB/C FRET sensors to characterize their spatiotemporal activation properties. We found all these RhoGTPase sensors to respond to physiologically relevant agonists (e.g. Thrombin), reaching transient, localized FRET ratio changes up to 200%. These RhoA/B/C FRET sensors show localized GEF and GAP activity and reveal spatial activation differences between RhoA/C and RhoB. Finally, we used these sensors to monitor GEF-specific differential activation of RhoA/B/C. In summary, this study adds high-contrast RhoB/C FRET sensors to the currently available FRET sensor toolkit and uncover new insights in endothelial and RhoGTPase cell biology. This allows us to study activation and signaling by these closely related RhoGTPases with high spatiotemporal resolution in primary human cells.
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Summary Rho GTPases are well known to regulate cell motility through activation of a variety of downstream effector proteins, including enzymes, adaptor proteins and actin nucleators. The three closely related Rho GTPases RhoA, RhoB and RhoC all have the potential to interact with the same downstream effectors, yet they have substantially different effects on cell shape and migratory properties. Here I review the different ways in which RhoA, RhoB and RhoC expression is regulated in cancer and how they play distinct roles in cancer progression. I describe their main effectors known to contribute to cell motility. Recent results from our laboratory and others indicate that RhoA, RhoB and RhoC can be activated by specific stimuli and act through different effectors to control distinct aspects of cancer cell migration and invasion. This suggests that they each make unique contributions to cancer by participating in different protein complexes.
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A number of small GTPases are involved in cancer cell proliferation, migration and invasion, acting as molecular switches that cycle between GTP‐ and GDP‐bound states. GTPase‐activating proteins (GAPs) have been established as a major class of negative regulators of Rho GTPase signaling. To investigate the biological function of p190 RhoGAP toward RhoA in cancer cell invasion and metastasis, we generated a chimera made of the RhoGAP domain of p190 and the C‐terminus of RhoA (p190‐RhoA chimera), and transfected it into human pancreatic cancer cells, AsPC‐1. Epidermal growth factor (EGF)‐induced activation of RhoA, as well as RhoB and RhoC, to a lesser extent, was significantly inhibited in p190‐RhoA chimera‐transfected AsPC‐1 cells compared with that of control cells (mock‐infected), when assessed by pull‐down assay for GTP‐bound RhoA, RhoB, and RhoC, respectively. EGF‐induced invasion of p190‐RhoA chimera transfectants was significantly inhibited compared with that of mock‐infected cells in a modified Boyden chamber assay. Furthermore, the mice injected intrasplenically with AsPC‐1 cells that overexpressed the p190‐RhoA chimera had a marked reduction in the number and size of metastatic nodules in the liver. These data suggest that the inhibitory action of p190 RhoGAP toward RhoA offers a novel approach to the treatment of invasion and metastasis of cancer cells. ( Cancer Sci 2006; 97: 848–853)
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The three Rho subfamily members, RhoA, RhoB, and RhoC, share 85% sequence identity, yet display opposite phenotypes. Whereas RhoA and RhoC proteins promote cellular proliferation, invasion, metastasis, and human cancers, RhoB hinders oncogenesis. How such similar proteins can have such opposing functions is not clearly defined. HMG-CoA reductase inhibitors (statins), typically prescribed for their cholesterol-lowering properties, were additionally found to lower rates of various cancers. Rho proteins were hypothesized to contribute to this anti- tumorigenic effect given that one of the pleiotropic effects of statins is inhibition of Rho prenylation. In our experiments, we found that RhoA and RhoC were more sensitive to the statin-induced decline in prenylation than RhoB, likely due to the ability of RhoB to be additionally farnesylated. In addition, we found that RhoA, RhoB, and RhoC activation and expression were greatly increased in lovastatin-treated cells. An increase in activated, GTP-bound Rho occurred even when RhoA and RhoC were completely unprenylated. This increase in Rho activation was at least partly explained by the decreased ability of unprenylated Rho to associate with its Rho- dissociation inhibitor, RhoGDI\[alpha\]. An increase in activated, yet unprenylated, Rho in response to statins could lead to a potential gain-of-function or a loss-of- function for Rho, and we hypothesized that this might explain how statins provide their anti-oncogenic properties. However, many statin-induced effects on proliferation, transcription, apoptosis, and polyploidy could not be explained by a change in Rho function and we found no evidence that the lovastatin-induced increase in RhoB contributed significantly to the anti-proliferative and pro-apoptotic effects of lovastatin in human leukemia cells. We used a proteomics approach to search for Rho interacting factors with differential binding affinity for RhoA/C and RhoB. Through the use of affinity chromatography and mass spectrometry, we identified a novel RhoA and RhoC isoform-specific interacting protein, IQGAP1. The binding to IQGAP1 was found to be dependent on the activation and prenylation state of Rho. Like RhoA and RhoC, IQGAP1 has many pro-proliferative, pro-invasion, and pro-oncogenesis properties. The lack of RhoB association with IQGAP1 may explain in part how this Rho isoform differs so dramatically in its function from RhoA and C.
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