Second generation molecules targeting the oncogenic signal mediator, RHOA in gastric cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA780592 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Previously, we designed pharmacologically optimized inhibitor RHOA, a major signaling hub in gastric cancer (GC), the fourth most common cause of death in the world. Here, based on that previous work, we perform the lead optimization and design new RHOA inhibitors for greater anti-GC potency. Two of these compounds, JK-206 and -312 inhibit cell viability and migration of GC cell lines. Furthermore, through our transcriptomics analysis of JK-206 treatment in GC cells, we revealed that pharmacologic inhibition of RHOA was associated with inhibition of mitogenic pathway, including BIRC5. Thus, RHOA→BIRC5 can be regarded as a new therapeutic strategy in GC, possibly regulating proliferation and migration in oncogenic mechanisms.
2022-03-24 | GSE188908 | GEO
Project description:Ras homologous A (RHOA), a signal mediator and a GTPase, is known to be associated with the progression of gastric cancer (GC), which is the fourth most common cause of death in the world. Previously, we designed pharmacologically optimized inhibitors against RHOA, including JK-136 and JK-139. Based on this previous work, we performed lead optimization and designed novel RHOA inhibitors for greater anti-GC potency. Two of these compounds, JK-206 and JK-312, could successfully inhibit the viability and migration of GC cell lines. Furthermore, using transcriptomic analysis of GC cells treated with JK-206, we revealed that the inhibition of RHOA might be associated with the inhibition of the mitogenic pathway. Therefore, JK-206 treatment for RHOA inhibition may be a new therapeutic strategy for regulating GC proliferation and migration.
| S-EPMC8997135 | biostudies-literature
Project description:Oligodendrocyte differentiation and subsequent myelination rely on strict regulatory mechanisms and molecules. Here we aimed at understanding the role of the Rho GTPase RhoA during oligodendrocyte differentiation and myelination in vivo. Using a conditional cell-specific ablation of Rhoa (Rhoa fl/fl mice crossed with Cnp-Cre mice) in oligodendrocytes, we show that RhoA controls the timing and progression differentiation and myelination. To identify putative mechanisms underlying the Rhoa cKO phenotype, we performed quantitative label-free LC-MS/MS proteomics on optic nerves from Rhoa cKO (Rhoa fl/fl Cre+) and control mice (Rhoa fl/fl Cre-) at 30 days post-birth (P30). Manual annotation of the differentially abundant proteins showed a large modulation of several proteins clusters associated with actin cytoskeleton, signal transduction and mitochondria.
2024-11-05 | PXD055052 | Pride
Project description:Gene expression analysis of BJhTERT RhoA-KO and PC3 mRFP was performed before and after six days confrontation in co-cultivation. Analyses of original and control fibroblasts was also performed. To identify molecules that may mediate the tumor promoting effect of RhoA knock out fibroblasts, we performed gene expression analysis of BJhTERT RhoA-KO and PC3 mRFP cells before the confrontation and then after six days after it, using Affymetrix Whole Transcript Assay platform.
2016-07-01 | GSE83913 | GEO
Project description:Gene expression analysis of BJhTERT RhoA-KO and PC3 mRFP was performed before and after six days confrontation in co-cultivation. Analyses of original and control fibroblasts was also performed. To identify molecules that may mediate the tumor promoting effect of RhoA knock out fibroblasts, we performed gene expression analysis of BJhTERT RhoA-KO and PC3 mRFP cells before the confrontation and then after six days after it, using Affymetrix Whole Transcript Assay platform. Four days old fibroblast monolayer was confronted with PC3 mRFP tumor cells, plated in ratio 1:30 to number of plated fibroblasts. After six days of confrontation cells were sorted by FACS (Fluorescence-activated cell sorting). Total RNA was isolated from each confronted and non-confronted cells with kit. Then 150 ng of total RNA were used for transcriptomic analysis.for RNA extraction and hybridization on Affymetrix microarrays
2016-07-01 | E-GEOD-83913 | biostudies-arrayexpress
Project description:Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably utilized immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMECs). We found that ectopic expression of wild-type RhoA as well as a constitutively-active RhoA mutant (G14V) in primary hMEC strains led to their immortalization and preneoplastic transformation. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well known Rho-effectors ,was also capable of immortalizing hMECs.Our results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked cellular transformation and breast cancer. Through microarray analysis, we want to identify genes and pathways linked to RhoA induced hMECs immortalization. Experiment Overall Design: 4 samples, in triplicate analyses per sample.
2008-10-26 | E-GEOD-12917 | biostudies-arrayexpress
Project description:Using mice with a keratinocyte-restricted deletion of the RhoA gene, we explored its role in the regulation of gene expression in vivo and in vitro RNA was isolated from RhoA-null or wildtype keratinocytes, in two different conditions, freshly isolated (in vivo) or cultured (in vitro), using the RNeasy kit (Qiagen, Germany). Hybridization to GeneChip Mouse Genome 430 2.0 Array (Affymetrix, Santa Clara, CA) was carried out at the Copenhagen University Hospital Microarray Center using standard protocols. 2 biological replicates were analyzed for each in vivo genotype (2 samples from RhoA-null, 2 from wildtype), while 3 replicates for each in vitro genotype.
2015-01-07 | E-GEOD-64714 | biostudies-arrayexpress
Project description:The small GTPase RhoA regulates a variety of cellular processes, including cell motility, proliferation, survival and permeability. In addition, there are reports suggesting that the RhoA-ROCK axis plays a role in VEGF-mediated angiogenesis, whereas other work has shown opposite effects. To elucidate this conflicting data, we examined HUVEC and HCAEC after stable overexpression (lentiviral transduction) of constitutively active (G14V/Q63L), dominant-negative (T19N), or wild-type RhoA using a variety of in vitro angiogenesis assays (proliferation, migration, tube formation, angiogenic sprouting, endothelial cell viability) and a HUVEC xenograft assay in immune incompetent NSGTM mice in vivo. We observed that expression of active as well as wild-type RhoA but not expression of dominant-negative RhoA significantly increased endothelial cell death as well as inhibited endothelial cell proliferation, migration, tube formation and angiogenic sprouting of endothelial cells in vitro and reduced HUVEC-related angiogenesis in vivo. Inhibition of RhoA by C3 transferase antagonized inhibitory RhoA effects and strongly enhanced VEGF-induced angiogenic sprouting in control-treated cells. In contrast, inhibition of RhoA effectors ROCK1/2 and LIMK1/2 had no significant effect on RhoA-related effects, but again increased angiogenic sprouting and migration of control-treated cells. In line with these data, VEGF did not activate RhoA in HUVEC as measured by a FRET-based biosensor. Furthermore, global transcriptome and subsequent bioinformatic gene ontology (GO) enrichment analyses revealed that constitutively active RhoA induces a differentially expressed gene pattern that is enriched for GO biological process terms such as mitotic nuclear division, cell proliferation, cell motility and cell adhesion and includes a significant decrease in VEGFR-2 and NOS3 expression. Thus, our data demonstrate that increased RhoA activity has the potential to trigger endothelial dysfunction and anti-angiogenic effects independently of its well-characterized downstream effectors ROCK and LIMK.
2022-07-06 | GSE182806 | GEO
Project description:Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably utilized immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMECs). We found that ectopic expression of wild-type RhoA as well as a constitutively-active RhoA mutant (G14V) in primary hMEC strains led to their immortalization and preneoplastic transformation. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well known Rho-effectors ,was also capable of immortalizing hMECs.Our results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked cellular transformation and breast cancer. Through microarray analysis, we want to identify genes and pathways linked to RhoA induced hMECs immortalization.
2008-09-26 | GSE12917 | GEO
Project description:RHOA is a recurrently mutated gene in diffuse-type gastric cancer, whose molecular influence in gastric cancer has not been well uncovered. We aimed to clarify the contribution of RHOA to pro-oncogenesis to improve the understanding of the role of RHOA as a therapeutic target. We performed microarray analysis after RHOA knockdown for HGC-27, AGS, CCK-81, and SW948.
2021-02-01 | GSE110237 | GEO