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RHOB; ras homolog family member B (2p24)

Gene Summary

Gene:RHOB; ras homolog family member B
Aliases: ARH6, ARHB, RHOH6, MST081, MSTP081
Location:2p24
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:rho-related GTP-binding protein RhoB
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (36)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cell Movement
  • Polymerase Chain Reaction
  • Enzyme Inhibitors
  • Gene Expression
  • Cancer Gene Expression Regulation
  • Signal Transduction
  • Neoplastic Cell Transformation
  • Down-Regulation
  • RAS Genes
  • Base Sequence
  • Western Blotting
  • Farnesyltranstransferase
  • Mutation
  • Protein Binding
  • Vestibular Nerve
  • ras Proteins
  • Transcriptional Activation
  • RHOA
  • Cancer DNA
  • Cell Division
  • rho GTP-Binding Proteins
  • GTP-Binding Proteins
  • Messenger RNA
  • Apoptosis
  • Chromosome 2
  • Pancreatic Cancer
  • Neoplasm Invasiveness
  • Membrane Proteins
  • RHOB
  • DNA Methylation
  • Breast Cancer
  • Up-Regulation
  • Alkyl and Aryl Transferases
  • Cell Survival
  • Lung Cancer
  • Transfection
  • RTPCR
  • siRNA
  • Antineoplastic Agents
  • Proto-Oncogene Proteins
  • Cell Proliferation
  • Promoter Regions
Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (3)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerRHOB and Breast Cancer View Publications13
Lung CancerRHOB and Lung Cancer View Publications12
Pancreatic CancerRHOB and Pancreatic Cancer View Publications6

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: RHOB (cancer-related)

Luis-Ravelo D, Antón I, Zandueta C, et al.
RHOB influences lung adenocarcinoma metastasis and resistance in a host-sensitive manner.
Mol Oncol. 2014; 8(2):196-206 [PubMed] Related Publications
Lung adenocarcinoma (ADC) is the most common lung cancer subtype and presents a high mortality rate. Clinical recurrence is often associated with the emergence of metastasis and treatment resistance. The purpose of this study was to identify genes with high prometastatic activity which could potentially account for treatment resistance. Global transcriptomic profiling was performed by robust microarray analysis in highly metastatic subpopulations. Extensive in vitro and in vivo functional studies were achieved by overexpression and by silencing gene expression. We identified the small GTPase RHOB as a gene that promotes early and late stages of metastasis in ADC. Gene silencing of RHOB prevented metastatic activity in a systemic murine model of bone metastasis. These effects were highly dependent on tumor-host interactions. Clinical analysis revealed a marked association between high RHOB levels and poor survival. Consistently, high RHOB levels promote metastasis progression, taxane-chemoresistance, and contribute to the survival advantage to γ-irradiation. We postulate that RHOB belongs to a novel class of "genes of recurrence" that have a dual role in metastasis and treatment resistance.

Related: Lung Cancer


Liu Y, Song N, Ren K, et al.
Expression loss and revivification of RhoB gene in ovary carcinoma carcinogenesis and development.
PLoS One. 2013; 8(11):e78417 [PubMed] Free Access to Full Article Related Publications
RhoB, a member of small GTPases belonging to the Ras protein superfamily, might have a suppressive activity in cancer progression. Here, expression of RhoB gene was evaluated in human benign, borderline and malignant ovary tumors by immunostaining, with normal ovary tissue as control. Malignant tumors were assessed according to Federation Internationale de Gynecologie Obstetrique (FIGO) guidelines and classified in stage I-IV. Revivification of RhoB gene was investigated by analyzing the effect of histone deacetylase (HDAC) inhibitor trichostatin (TSA) and methyltransferase inhibitor 5-azacytidine (5-Aza) on ovarian cancer cells via RT-PCR and western blot. Apoptosis of ovary cancer cells was detected using flowcytometry and fluorescence microscopy. Subsequently, RhoB expression is detected in normal ovary epithelium, borderline tumors, and decreases significantly or lost in the majority of ovarian cancer specimen (P<0.05). RhoB expression decreases significantly from stage II (71.4%) to stage III (43.5%) to stage IV (18.2%, P<0.05). TSA can both significantly revive the RhoB gene and mediate apoptosis of ovarian cancer cells, but 5-Aza couldn't. Interference into Revivification of RhoB gene results in reduction of ovary carcinoma cell apoptosis. It is proposed that loss of RhoB expression occurs frequently in ovary carcinogenesis and progression and its expression could be regulated by histone deacetylation but not by promoter hypermethylation, which may serve as a prospective gene treatment target for the patients with ovarian malignancy not responding to standard therapies.

Related: Azacitidine Ovarian Cancer


Chung KS, Han G, Kim BK, et al.
A novel antitumor piperazine alkyl compound causes apoptosis by inducing RhoB expression via ROS‑mediated c‑Abl/p38 MAPK signaling.
Cancer Chemother Pharmacol. 2013; 72(6):1315-24 [PubMed] Related Publications
PURPOSE: We investigated the action mechanism of a novel anticancer compound, KR28 (1-allyl-4-dodecanoyl-1-ethyl-piperazin-1-ium; bromide), to induce apoptosis of human prostate carcinoma PC-3 cells.
METHODS: To explore an apoptotic signaling of KR28, we used ROS assay, SRB assay, flow cytometry analysis, reporter assay, xenograft assay, Western blotting, and RT-PCR analysis.
RESULTS: The growth inhibitory action of KR28 is cell line specific, impeding the growth of prostate carcinoma PC-3 and stomach carcinoma NUGC-3 cells. KR28 showed strong antitumor activity in PC-3 mouse xenograft model. KR28 increased ROS production, leading to nuclear c-Abl expression, which in turn activated p38 mitogen-activated protein kinase (MAPK) to enhance the expression of RhoB, an apoptosis inducer. The KR28-induced apoptosis was abrogated by the ROS scavenger N-acetylcysteine and by knockdown of c-Abl, p38 MAPK, or ATF2. Moreover, the p300 binding site and two CCAAT boxes in the RhoB promoter appear to be involved in ROS-mediated RhoB expression in the presence of KR28.
CONCLUSION: The antitumor agent KR28 induces apoptosis of PC-3 cells by ROS-mediated RhoB expression via c-Abl upregulation and activation of p38 MAPK/ATF-2.

Related: Apoptosis Cancer Prevention and Risk Reduction Prostate Cancer Signal Transduction Stomach Cancer Gastric Cancer


Malissein E, Meunier E, Lajoie-Mazenc I, et al.
RhoA and RhoC differentially modulate estrogen receptor α recruitment, transcriptional activities, and expression in breast cancer cells (MCF-7).
J Cancer Res Clin Oncol. 2013; 139(12):2079-88 [PubMed] Related Publications
PURPOSE: RhoA and RhoC are closely related, small GTPases that are clearly involved in breast cancer tumorigenesis. Nonetheless, their specific roles in the control of estrogen receptor alpha (ERα) activities have not been elucidated.
METHODS: We used siRNA sequences to specifically down-regulate RhoA and RhoC expression in ERα-positive breast adenocarcinoma MCF-7 cells. We then analyzed the consequences of down-regulation on ERα expression, ERα recruitment to the promoters of four target genes, and the mRNA levels of those genes.
RESULTS: We demonstrated that RhoA and RhoC clearly and similarly modulated ERα recruitment to the vitellogenin estrogen responsive element (ERE) present in a luciferase reporter gene and to the promoters of progesterone receptor (PR), cathepsin D, and pS2 genes. Besides, RhoA up-regulated the ERE-luciferase reporter gene activity and PR mRNA expression and tended to down-regulate cathepsin D and pS2 mRNA expression. Conversely, RhoC inhibition had no significant effect at the mRNA level. Furthermore, RhoA inhibition, and to a lesser extent RhoC inhibition, increased ERα expression. No alteration in ERα mRNA levels was observed, suggesting potential post-translational control.
CONCLUSIONS: Taken together, our results strongly suggest that RhoA and RhoC play different, but clear, roles in ERα signaling. These GTPases are definitely involved, along with RhoB, in ERα recruitment and, to some extent, ERα cofactor balance. We hypothesize a differential role of RhoA in breast cancer tumors that depend on hormone status.

Related: Breast Cancer Signal Transduction RHOA RHOC


Won KJ, Kim BK, Han G, et al.
NSC126188 induces apoptosis of prostate cancer PC-3 cells through inhibition of Akt membrane translocation, FoxO3a activation, and RhoB transcription.
Apoptosis. 2014; 19(1):179-90 [PubMed] Related Publications
We previously reported that NSC126188 caused apoptosis of cancer cells by inducing expression of RhoB. We here present that NSC126188 induces apoptosis of prostate cancer PC-3 cells by inhibiting Akt/FoxO3 signaling, which mediates RhoB upregulation. The apoptosis and Akt dephosphorylation caused by NSC126188 was not substantially relieved by overexpressing wild-type Akt but was relieved by overexpressing constitutively active Akt (CA-Akt) or myristoylated Akt (myr-Akt). Furthermore, overexpression of CA-Akt or myr-Akt downregulated RhoB expression, indicating that RhoB expression is regulated by Akt signaling. Interestingly, membrane translocation of GFP-Akt by insulin exposure was abolished in the cells pretreated with NSC126188 suggesting that NSC126188 directly interfered with translocation of Akt to the plasma membrane. In addition, NSC126188 activated FoxO3a by dephosphorylating S253 via Akt inhibition. Activated FoxO3a translocated to the nucleus and increased transcription of RhoB and other target genes. PC-3 cells transiently overexpressing FoxO3a exhibited increased RhoB expression and apoptosis in response to NSC126188. Conversely, FoxO3a knockdown reduced NSC126188-induced RhoB expression and cell death. These results suggest that RhoB may be a target gene of FoxO3a and is regulated by Akt signaling. Taken together, NSC126188 induces apoptosis of PC-3 cells by interfering with membrane recruitment of Akt, resulting in Akt dephosphorylation and FoxO3a activation, which leads to transcription of RhoB.

Related: Apoptosis Prostate Cancer AKT1


Meyer N, Peyret-Lacombe A, Canguilhem B, et al.
RhoB promotes cancer initiation by protecting keratinocytes from UVB-induced apoptosis but limits tumor aggressiveness.
J Invest Dermatol. 2014; 134(1):203-12 [PubMed] Related Publications
The role of UVB-induced apoptosis in the formation of squamous cell carcinoma (SCC) is recognized. We previously identified the small RhoB (Ras homolog gene family, member B) GTPase, an early response gene to cellular stress, as a critical protein controlling apoptosis of human keratinocytes after UVB exposure. Here we generated SKH1 (hairless immunocompetent mouse) mice invalidated for RhoB to evaluate its role in UVB-induced skin carcinogenesis in vivo. We show that rhob-/- mice have a lower risk of developing UVB-induced keratotic tumors and actinic keratosis that is associated with a higher sensitivity of UVB-exposed keratinocytes to apoptosis. We extend this observation to primary cultures of normal human keratinocytes in which RhoB was downregulated with small interfering RNA (siRNA) and further show that the hypersensitivity to apoptosis depends on B-cell lymphoma 2 (Bcl-2) downregulation. In rhob-/- mice, the UVB-induced tumors were preferentially undifferentiated and highly proliferative. Finally, we show in humans an almost constant loss of RhoB expression in undifferentiated SCCs. These undifferentiated and RhoB-deficient tumors have elevated phosphorylated histone H2AX (γH2AX) and 53BP1, two markers of DNA double-strand breaks. Together, our results indicate that UVB-induced RhoB expression participates in in vivo SCC initiation by increasing keratinocyte survival. Conversely, RhoB may limit tumor aggressiveness as loss of RhoB expression in tumor cells is associated with tumor progression.

Related: Apoptosis Skin Cancer


Ridley AJ
RhoA, RhoB and RhoC have different roles in cancer cell migration.
J Microsc. 2013; 251(3):242-9 [PubMed] Related Publications
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.

Related: Cancer Prevention and Risk Reduction RHOA RHOC


Leone E, Morelli E, Di Martino MT, et al.
Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth.
Clin Cancer Res. 2013; 19(8):2096-106 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Deregulated expression of miRNAs plays a role in the pathogenesis and progression of multiple myeloma. Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of multiple myeloma.
EXPERIMENTAL DESIGN: Here, we investigated the in vitro and in vivo anti-multiple myeloma activity of miR-21 inhibitors.
RESULTS: Either transient-enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant growth inhibition of primary patient multiple myeloma cells or interleukin-6-dependent/independent multiple myeloma cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 mimics significantly increased proliferation of multiple myeloma cells, showing its tumor-promoting potential in multiple myeloma. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B, and BTG2), together with functional impairment of both AKT and extracellular signal-regulated kinase signaling, were achieved by transfection of miR-21 inhibitors into multiple myeloma cells. In vivo delivery of miR-21 inhibitors in severe combined immunodeficient mice bearing human multiple myeloma xenografts expressing miR-21 induced significant antitumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors.
CONCLUSION: Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-multiple myeloma activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease.

Related: Myeloma Myeloma - Molecular Biology PTEN AKT1 miR-21


Tsai HC, Boucher DL, Martinez A, et al.
Modeling truncated AR expression in a natural androgen responsive environment and identification of RHOB as a direct transcriptional target.
PLoS One. 2012; 7(11):e49887 [PubMed] Free Access to Full Article Related Publications
Recent studies identifying putative truncated androgen receptor isoforms with ligand-independent activity have shed new light on the acquisition of androgen depletion independent (ADI) growth of prostate cancer. In this study, we present a model system in which a C-terminally truncated variant of androgen receptor (TC-AR) is inducibly expressed in LNCaP, an androgen-dependent cell line, which expresses little truncated receptor. We observed that when TC-AR is overexpressed, the endogenous full length receptor (FL-AR) is transcriptionally downmodulated. This in essence allows us to "replace" FL-AR with TC-AR and compare their individual properties in exactly the same genetic and cellular background, which has not been performed before. We show that the TC-AR translocates to the nucleus, activates transcription of AR target genes in the absence of DHT and is sufficient to confer ADI growth to the normally androgen dependent LNCaP line. We also show that while there is significant overlap in the genes regulated by FL- and TC-AR there are also differences in the respective suites of target genes with each AR form regulating genes that the other does not. Among the genes uniquely activated by TC-AR is RHOB which is shown to be involved in the increased migration and morphological changes observed in LN/TC-AR, suggesting a role of RHOB in the regulation of androgen-independent behavior of prostate cancer cells.

Related: Prostate Cancer


Ho HH, Chang CS, Ho WC, et al.
Gallic acid inhibits gastric cancer cells metastasis and invasive growth via increased expression of RhoB, downregulation of AKT/small GTPase signals and inhibition of NF-κB activity.
Toxicol Appl Pharmacol. 2013; 266(1):76-85 [PubMed] Related Publications
Our previous study demonstrated the therapeutic potential of gallic acid (GA) for controlling tumor metastasis through its inhibitory effect on the motility of AGS cells. A noteworthy finding in our previous experiment was increased RhoB expression in GA-treated cells. The aim of this study was to evaluate the role of RhoB expression on the inhibitory effects of GA on AGS cells. By applying the transfection of RhoB siRNA into AGS cells and an animal model, we tested the effect of GA on inhibition of tumor growth and RhoB expression. The results confirmed that RhoB-siRNA transfection induced GA to inhibit AGS cells' invasive growth involving blocking the AKT/small GTPase signals pathway and inhibition of NF-κB activity. Finally, we evaluated the effect of GA on AGS cell metastasis by colonization of tumor cells in nude mice. It showed GA inhibited tumor cells growth via the expression of RhoB. These data support the inhibitory effect of GA which was shown to inhibit gastric cancer cell metastasis and invasive growth via increased expression of RhoB, downregulation of AKT/small GTPase signals and inhibition of NF-κB activity. Thus, GA might be a potential agent in treating gastric cancer.

Related: AKT1 Signal Transduction Stomach Cancer Gastric Cancer


Kazerounian S, Gerald D, Huang M, et al.
RhoB differentially controls Akt function in tumor cells and stromal endothelial cells during breast tumorigenesis.
Cancer Res. 2013; 73(1):50-61 [PubMed] Free Access to Full Article Related Publications
Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target tumors. This oversight potentially confounds proof-of-concept studies and increases drug development risks. Here, we show in established murine and human models of breast cancer how differential regulation of Akt by the small GTPase RhoB in cancer cells or stromal endothelial cells determines their dormancy versus outgrowth when angiogenesis becomes critical. In cancer cells in vitro or in vivo, RhoB functions as a tumor suppressor that restricts EGF receptor (EGFR) cell surface occupancy as well as Akt signaling. However, after activation of the angiogenic switch, RhoB functions as a tumor promoter by sustaining endothelial Akt signaling, growth, and survival of stromal endothelial cells that mediate tumor neoangiogenesis. Altogether, the positive impact of RhoB on angiogenesis and progression supercedes its negative impact in cancer cells themselves. Our findings elucidate the dominant positive role of RhoB in cancer. More generally, they illustrate how differential gene function effects on signaling pathways in the tumor stromal component can complicate the challenge of developing therapeutics to target cancer pathophysiology.

Related: Breast Cancer Angiogenesis and Cancer AKT1


Hu Y, Ou Y, Wu K, et al.
miR-143 inhibits the metastasis of pancreatic cancer and an associated signaling pathway.
Tumour Biol. 2012; 33(6):1863-70 [PubMed] Related Publications
Pancreatic cancer is characterized by early metastasis and high mortality. In this study, the role of miR-143 in invasion and metastasis was investigated in pancreatic cancer cells. miR-143 expression was established by an adenovirus-carried miR-143 expression cassette. mRNA and protein levels of gene expression were examined by RT-PCR and Western blot assay, respectively. Rho GTPases activity was measured by the pull down assay. The role of miR-143 in migration and invasion of Panc-1 cells was tested in vitro. The antimetastatic effect of miR-143 was tested in a liver metastasis model, while its antitumor growth effect was tested in a xenograft Panc-1 tumor model. Results demonstrated that ARHGEF1 (GEF1), ARHGEF2 (GEF2), and K-RAS genes are the targets of miR-143. miR-143 expression significantly decreased mRNA and protein levels of GEF1, GEF2, and K-RAS genes; lowered the constitutive activities of RhoA, Rac1, and Cdc42 GTPases; decreased the protein levels of MMP-2 and MMP-9; but significantly increased the protein level of E-cadherin. miR-143 expression also significantly inhibited the migration and invasion of Panc-1 cells in vitro, liver metastasis, and xenograft tumor growth in vivo. Our study suggested that miR-143 plays a central role in the invasion and metastasis of pancreatic cancer and miR-143 is a potential target for pancreatic cancer therapy.

Related: Apoptosis Cancer of the Pancreas Pancreatic Cancer Signal Transduction CDC42 KRAS gene


Maherally Z, Smith JR, An Q, Pilkington GJ
Receptors for hyaluronic acid and poliovirus: a combinatorial role in glioma invasion?
PLoS One. 2012; 7(2):e30691 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: CD44 has long been associated with glioma invasion while, more recently, CD155 has been implicated in playing a similar role. Notably, these two receptors have been shown closely positioned on monocytes.
METHODS AND FINDINGS: In this study, an up-regulation of CD44 and CD155 was demonstrated in established and early-passage cultures of glioblastoma. Total internal reflected fluorescence (TIRF) microscopy revealed close proximity of CD44 and CD155. CD44 antibody blocking and gene silencing (via siRNA) resulted in greater inhibition of invasion than that for CD155. Combined interference resulted in 86% inhibition of invasion, although in these investigations no obvious evidence of synergy between CD44 and CD155 in curbing invasion was shown. Both siRNA-CD44 and siRNA-CD155 treated cells lacked processes and were rounder, while live cell imaging showed reduced motility rate compared to wild type cells. Adhesion assay demonstrated that wild type cells adhered most efficiently to laminin, whereas siRNA-treated cells (p<0.0001 for both CD44 and CD155 expression) showed decreased adhesion on several ECMs investigated. BrdU assay showed a higher proliferation of siRNA-CD44 and siRNA-CD155 cells, inversely correlated with reduced invasion. Confocal microscopy revealed overlapping of CD155 and integrins (β(1), α(v)β(1) and α(v)β(3)) on glioblastoma cell processes whereas siRNA-transfected cells showed consequent reduction in integrin expression with no specific staining patterns. Reduced expression of Rho GTPases, Cdc42, Rac1/2/3, RhoA and RhoB, was seen in siRNA-CD44 and siRNA-CD155 cells. In contrast to CD44-knockdown and 'double'-knockdown cells, no obvious decrease in RhoC expression was observed in CD155-knockdown cells.
CONCLUSIONS: This investigation has enhanced our understanding of cell invasion and confirmed CD44 to play a more significant role in this biological process than CD155. Joint CD44/CD155 approaches may, however, merit further study in therapeutic targeting of infiltrating glioma cells.

Related: Monoclonal Antibodies Signal Transduction


Suboj P, Babykutty S, Valiyaparambil Gopi DR, et al.
Aloe emodin inhibits colon cancer cell migration/angiogenesis by downregulating MMP-2/9, RhoB and VEGF via reduced DNA binding activity of NF-κB.
Eur J Pharm Sci. 2012; 45(5):581-91 [PubMed] Related Publications
Aloe emodin (AE), a natural anthraquinone, is reported to have antiproliferative activity in various cancer cell lines. In this study we analyzed molecular mechanisms involved in the antimigratory and antiangiogenic activity of this hydroxy anthraquinone in colon cancer cell, WiDr. Our results show that a relatively non toxic concentration of AE suppressed the phorbol-12-myristyl-13-acetate (PMA) induced migration and invasion of tumor cells. On analysis for the molecules involved in the migration/invasion, we found AE downregulated mRNA expression and promoter/gelatinolytic activity of Matrix Metalloproteinase (MMP)-2/9, as well as the RhoB expression at gene and protein level. It was also a strong inhibitor of Vascular Endothelial Growth Factor (VEGF) expression, promoter activity and endothelial cell migration/invasion and in vitro angiogenesis. AE suppressed the nuclear translocation and DNA binding of NF-κB, which is an important transcription factor for controlling MMP-2/9 and VEGF gene expression. Taken together these data indicate that AE target multiple molecules responsible for cellular invasion, migration and angiogenesis. Inhibitory effect on angiogenic and metastatic regulatory processes make AE a sensible candidate as a specific blocker of tumor associated events.

Related: Angiogenesis Inhibitors MMP2 MMP9: matrix metallopeptidase 9 Angiogenesis and Cancer Signal Transduction VEGFA


Volanis D, Zaravinos A, Kadiyska T, et al.
Expression profile of Rho kinases in urinary bladder cancer.
J BUON. 2011 Jul-Sep; 16(3):511-21 [PubMed] Related Publications
PURPOSE: To investigate the expression of RhoA, RhoB, RhoC, Rac1 and Cdc42 kinases in urothelial cell carcinoma (UCC) of the urinary bladder and determine the expression profile of 107 Rho-associated genes, including GTPases, GDIs, GAPs and GEFs.
METHODS: Rho expression was investigated using microarrays, qPCR and Western blotting in 77 UCC specimens with paired normal urothelium. Computational analysis was also performed on Gene Expression Omnibus datasets. Further microarray analysis was carried out for the expression profiling of the Rho-associated genes.
RESULTS: RhoB mRNA and protein levels were significantly lower in UCC, suggesting a tumour-suppressor role. On the contrary, mRNA of RhoC and protein levels of RhoA, RhoC and Cdc42, respectively, were significantly higher in UCC vs. normal tissue. High Cdc42 mRNA levels correlated with worse overall survival (p=0.027), whereas high RhoB mRNA levels correlated both with better overall (p=0.0258) and cancer-specific (p=0.0272) survival. Computational analysis verified the expression profile of Rho kinases among superficial UCCs, muscle-invasive UCCs and normal tissues.
CONCLUSION: The majority of the Rho-related genes showed over-expression in UCC vs. normal tissue. Alterations in RhoA, RhoB, RhoC, Rac1 and Cdc42 expression play a significant role in the genesis and progression of UCC of the urinary bladder.

Related: Bladder Cancer Bladder Cancer - Molecular Biology CDC42


Liu M, Tang Q, Qiu M, et al.
miR-21 targets the tumor suppressor RhoB and regulates proliferation, invasion and apoptosis in colorectal cancer cells.
FEBS Lett. 2011; 585(19):2998-3005 [PubMed] Related Publications
It has become increasingly clear that microRNAs play an important role in many human diseases including cancer. Here, we show that expression of miR-21 in HEK293 and several colorectal cancer cells was found inversely correlated with ras homolog gene family, member B (RhoB) expression. miR-21 expression significantly suppressed RhoB 3' UTR luciferase-reporter activity, but the inhibitory effect was lost when the putative target sites were mutated. Exogenous miR-21 over-expression mimicked the effect of RhoB knockdown in promoting proliferation and invasion and inhibiting apoptosis, whereas anti-miR-21 or RhoB expression yielded opposite effects, in colorectal cancer cells. These results suggest that miR-21 is a regulator of RhoB expression and RhoB could be a useful target in exploring the potential therapeutic benefits of miR-21 mediated tumor cell behaviors in colorectal cancer.

Related: Apoptosis Colorectal (Bowel) Cancer miR-21


Spangler B, Kappelmann M, Schittek B, et al.
ETS-1/RhoC signaling regulates the transcription factor c-Jun in melanoma.
Int J Cancer. 2012; 130(12):2801-11 [PubMed] Related Publications
Recently, we discovered that the loss of E-cadherin induces c-Jun protein expression, which is a member of the AP-1 transcription factor family and a key player in the processes of cell proliferation and tumor development and also found in elevated levels in melanomas. Notably, the mRNA level of c-Jun was not affected, suggesting that c-Jun is regulated at post-transcriptional level. Here, we present data that suggest that the dynamic cytoskeletal network, linked to E-cadherin, is involved in the regulation of the c-Jun protein and transcriptional activity. In a signaling cascade, the loss of E-cadherin activates the transcriptional regulator ETS-1 and consequently leads to the induction of RhoC expression that stabilizes c-Jun in melanoma. The link between RhoC and c-Jun seems to be indirect via the cytoskeleton. We conclude that the loss of E-cadherin mediated cell-adhesion induces c-Jun protein expression in a multistep process, offering several possibilities for therapeutic intervention.

Related: Melanoma Signal Transduction RHOA RHOC


Wang X, Li C, Ju S, et al.
Myeloma cell adhesion to bone marrow stromal cells confers drug resistance by microRNA-21 up-regulation.
Leuk Lymphoma. 2011; 52(10):1991-8 [PubMed] Related Publications
The bone marrow microenvironment plays a role in myeloma cell proliferation and adhesion-mediated drug resistance. In this study, we investigated microRNA-21 (miR-21) expression changes in myeloma cells that adhered to bone marrow stromal cells (BMSCs). In addition, we studied the synergistic effect of miR-21 inhibition with dexamethasone (Dex), doxorubicin (Dox), or bortezomib (Bort) on myeloma cell survival. We found that up-regulation of miR-21 expression was partially driven by nuclear factor-κB (NF-κB) signaling via myeloma cell adhesion to BMSCs. We also confirmed that RhoB is a miR-21 regulation target gene. Moreover, miR-21 inhibition combined with cytotoxic drug Dex or Dox inhibited myeloma cell survival more effectively than either treatment alone. These results suggest that the regulatory mechanisms of miR-21 expression may be a promising target for fine-tuning anti-myeloma therapy.

Related: Doxorubicin Myeloma Myeloma - Molecular Biology miR-21 Bortezomib


Fujita A, Shida A, Fujioka S, et al.
Clinical significance of Rho GDP dissociation inhibitor 2 in colorectal carcinoma.
Int J Clin Oncol. 2012; 17(2):137-42 [PubMed] Related Publications
BACKGROUND: Small GTPase proteins, including RhoA, RhoB, RhoC, Rac1, and cdc42, are important molecules for linking cell shape and cell-cycle progression because of their role in both cytoskeletal arrangements and mitogenic signaling. Over-expression of wild-type or constitutively active forms of RhoA has been shown to induce invasive behavior in non-invasive rat hepatoma cells in vitro. In addition, over-expression of RhoC has been found in melanoma cells with increasing metastatic activity as well as inflammatory breast cancer. These results indicate that overexpression of Rho proteins contributes to cancer cell invasion and metastasis. Rho GDP dissociation inhibitor 2 (RhoGDI2) was recently shown to act as a metastasis suppressor gene in bladder cancer. The purpose of this study was to clarify the clinical significance of this gene expression in patients with colorectal carcinoma.
METHODS: Fifty pairs of normal mucosa and cancer specimens obtained at the time of surgery from patients with colorectal cancer (CRC) were subjected to reverse transcription-polymerase chain reaction for RhoGDI2.
RESULTS: No patients with RhoGDI2-higher expression tumors had liver metastasis (0 in 8 cases); however, 33.3% (14 in 42 cases) of patients with RhoGDI2-lower expression tumors had liver metastasis. With regard to outcome in relation to RhoGDI2-positivity, RhoGDI2-higher expression tumors had a significant correlation with superior relapse-free survival (RFS) time as compared to RhoGDI2-lower expression tumors in stage III CRC (log-rank test, P < 0.05). Moreover, multivariate analysis indicated that RhoGDI2 was an independent prognostic factor for RFS.
CONCLUSION: RhoGDI2 is a novel predictor of RFS in patients with colorectal carcinoma.

Related: Colorectal (Bowel) Cancer


Zhang C, Elkahloun AG, Liao H, et al.
Expression signatures of the lipid-based Akt inhibitors phosphatidylinositol ether lipid analogues in NSCLC cells.
Mol Cancer Ther. 2011; 10(7):1137-48 [PubMed] Free Access to Full Article Related Publications
Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphoinositide-3-kinase (PI3K) that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of five active PIAs and the PI3K inhibitor LY294002 (LY) was conducted in non-small cell lung carcinoma cells using high-density oligonucleotide arrays. Gene ontology analysis revealed that genes involved in apoptosis, wounding response, and angiogenesis were upregulated by PIAs, whereas genes involved in DNA replication, repair, and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3, and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB), and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity.

Related: Non-Small Cell Lung Cancer Lung Cancer AKT1


Srougi MC, Burridge K
The nuclear guanine nucleotide exchange factors Ect2 and Net1 regulate RhoB-mediated cell death after DNA damage.
PLoS One. 2011; 6(2):e17108 [PubMed] Free Access to Full Article Related Publications
Commonly used antitumor treatments, including radiation and chemotherapy, function by damaging the DNA of rapidly proliferating cells. However, resistance to these agents is a predominant clinical problem. A member of the Rho family of small GTPases, RhoB has been shown to be integral in mediating cell death after ionizing radiation (IR) or other DNA damaging agents in Ras-transformed cell lines. In addition, RhoB protein expression increases after genotoxic stress, and loss of RhoB expression causes radio- and chemotherapeutic resistance. However, the signaling pathways that govern RhoB-induced cell death after DNA damage remain enigmatic. Here, we show that RhoB activity increases in human breast and cervical cancer cell lines after treatment with DNA damaging agents. Furthermore, RhoB activity is necessary for DNA damage-induced cell death, as the stable loss of RhoB protein expression using shRNA partially protects cells and prevents the phosphorylation of c-Jun N-terminal kinases (JNKs) and the induction of the pro-apoptotic protein Bim after IR. The increase in RhoB activity after genotoxic stress is associated with increased activity of the nuclear guanine nucleotide exchange factors (GEFs), Ect2 and Net1, but not the cytoplasmic GEFs p115 RhoGEF or Vav2. Importantly, loss of Ect2 and Net1 via siRNA-mediated protein knock-down inhibited IR-induced increases in RhoB activity, reduced apoptotic signaling events, and protected cells from IR-induced cell death. Collectively, these data suggest a mechanism involving the nuclear GEFs Ect2 and Net1 for activating RhoB after genotoxic stress, thereby facilitating cell death after treatment with DNA damaging agents.

Related: Breast Cancer ECT2


Baillo A, Giroux C, Ethier SP
Knock-down of amphiregulin inhibits cellular invasion in inflammatory breast cancer.
J Cell Physiol. 2011; 226(10):2691-701 [PubMed] Free Access to Full Article Related Publications
We have previously shown that SUM-149 human breast cancer cells require an amphiregulin (AREG) autocrine loop for cell proliferation. We also demonstrated that AREG can increase epidermal growth factor receptor (EGFR) stability and promote EGFR localization to the plasma membrane. In the present studies we successfully knocked-down AREG expression in SUM-149 cells by lentiviral infection of AREG shRNA. In the absence of AREG expression, SUM-149 cell growth was slowed, but not completely inhibited. Furthermore, cells infected with AREG shRNA constructs showed an increase in EGFR protein expression by Western blot. Immunofluorescence and confocal microscopy showed that following AREG knock-down, EGFR continued to localize to the cell surface. Soft agar assays demonstrated that AREG knock-down cells retain anchorage-independent growth capacity. Additionally mammosphere forming assays and Adefluor staining analysis showed that knock-down of AREG expression did not affect the expression of stem cell phenotypes. However, following AREG knock-down, SUM-149 cells demonstrated a dramatic decrease in their ability to invade a Matrigel matrix. Consistent with this observation, microarray analysis comparing cells infected with a non-silencing vector to the AREG knock-down cells, identified genes associated with the invasive phenotype such as RHOB and DKK1, and networks associated with cell motility such as integrin-linked kinase signaling, and focal adhesion kinase signaling. AREG was also found to modulate WNT and Notch signaling in these cells. Thus, AREG functions in regulating the invasive phenotype, and we propose that this regulation may be through altered signaling that occurs when AREG activates plasma membrane localized EGFR.

Related: Signal Transduction


Kim BK, Kim HM, Chung KS, et al.
Upregulation of RhoB via c-Jun N-terminal kinase signaling induces apoptosis of the human gastric carcinoma NUGC-3 cells treated with NSC12618.
Carcinogenesis. 2011; 32(3):254-61 [PubMed] Related Publications
RhoB expression is reduced in most invasive tumors, with loss of RhoB expression correlating significantly with tumor stage. Here, we demonstrate that upregulation of RhoB by the potent anticancer agent NSC126188 induces apoptosis of NUGC-3 human gastric carcinoma cells. The crucial role of RhoB in NSC126188-induced apoptosis is indicated by the rescue of NUGC-3 cells from apoptosis by knockdown of RhoB. In the presence of NSC126188, c-Jun N-terminal kinase (JNK) signaling was activated, and the JNK inhibitor SP600125 reduced RhoB expression and suppressed the apoptosis of NUGC-3 cells. Knockdowns of mitogen-activated protein kinase kinase (MKK) 4/7, JNK1/2 and c-Jun downregulated RhoB expression and rescued cells from apoptotic death in the presence of NSC126188. The JNK inhibitor SP600125 suppressed transcriptional activation of RhoB in the presence of NSC126188, as indicated by a reporter assay that used luciferase under the RhoB promoter. The ability of NSC126188 to increase luciferase activity through both the p300-binding site and the inverted CCAAT sequence (iCCAAT box) suggests that JNK signaling to upregulate RhoB expression is mediated through both the p300-binding site and the iCCAAT box. However, the JNK inhibitor SP600125 did not inhibit the upregulation of RhoB by farnesyltransferase inhibitor (FTI)-277. The p300-binding site did not affect activation of the RhoB promoter by FTI-277 in NUGC-3 cells, suggesting that the transcriptional activation of RhoB by NSC126188 occurs by a different mechanism than that reported for FTIs. Our data indicate that NSC126188 increases RhoB expression via JNK-mediated signaling through a p300-binding site and iCCAAT box resulting in apoptosis of NUGC-3 cells.

Related: Apoptosis EP300 gene Signal Transduction Stomach Cancer Gastric Cancer


Marlow LA, D'Innocenzi J, Zhang Y, et al.
Detailed molecular fingerprinting of four new anaplastic thyroid carcinoma cell lines and their use for verification of RhoB as a molecular therapeutic target.
J Clin Endocrinol Metab. 2010; 95(12):5338-47 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Anaplastic thyroid carcinoma (ATC) is a highly aggressive carcinoma in need of therapeutic options. One critical component of drug discovery is the availability of well-characterized cell lines for identification of molecular mechanisms related to tumor biology and drug responsiveness. Up to 42% of human thyroid cancer cell lines are redundant or not of correct tissue origin, and a comprehensive analysis is currently nonexistent. Mechanistically, RhoB has been identified as a novel molecular target for ATC therapy.
OBJECTIVE: The aim was to develop four ATC cell lines detailing genetic, molecular, and phenotypic characteristics and to test five classes of drugs on the cell lines to determine whether they inhibited cell proliferation in a RhoB-dependent fashion.
DESIGN: Four cell lines were derived from ATC tumors. Short tandem DNA repeat and mutational status of the originating tumors and cell lines were performed along with molecular and phenotypic characterizations. Compounds were tested for growth inhibition and ability to up-regulate RhoB.
RESULTS: Cell line authenticity was confirmed by DNA short tandem repeat analysis. Each proved unique regarding expression of thyroid markers, oncogene status, amplified and deleted genes, and proliferative growth rates. FTI-277, GGTI-286, lovastatin, romidepsin, and UCN-01 up-regulated RhoB and inhibited cell proliferation in a dose-responsive fashion with only romidepsin and FTI-277 being RhoB dependent.
CONCLUSIONS: Molecular descriptions of thyroid lines were matched to the originating tumors, setting a new standard for cell line characterization. Furthermore, suppressed RhoB is implicated as a molecular target for therapy against ATC because five classes of drugs up-regulate RhoB and inhibit growth dose-responsively.

Related: Apoptosis Thyroid Cancer


Connolly EC, Van Doorslaer K, Rogler LE, Rogler CE
Overexpression of miR-21 promotes an in vitro metastatic phenotype by targeting the tumor suppressor RHOB.
Mol Cancer Res. 2010; 8(5):691-700 [PubMed] Related Publications
Metastasis is a multistep process that involves the deregulation of oncogenes and tumor suppressors beyond changes required for primary tumor formation. RHOB is known to have tumor suppressor activity, and its knockdown is associated with more aggressive tumors as well as changes in cell shape, migration, and adhesion. This study shows that oncogenic microRNA, miR-21, represses RHOB expression by directly targeting the 3' untranslated region. Loss of miR-21 is associated with an elevation of RHOB in hepatocellular carcinoma cell lines Huh-7 and HepG2 and in the metastatic breast cancer cell line MDA-MB-231. Using in vitro models of distinct stages of metastasis, we showed that loss of miR-21 also causes a reduction in migration, invasion, and cell elongation. The reduction in migration and cell elongation can be mimicked by overexpression of RHOB. Furthermore, changes in miR-21 expression lead to alterations in matrix metalloproteinase-9 activity. Therefore, we conclude that miR-21 promotes multiple components of the metastatic phenotype in vitro by regulating several important tumor suppressors, including RHOB.

Related: Liver Cancer miR-21


Kim BK, Kim DM, Chung KS, et al.
NSC126188, a piperazine alkyl derivative, induces apoptosis via upregulation of RhoB in HeLa cells.
Invest New Drugs. 2011; 29(5):853-60 [PubMed] Related Publications
We describe here a piperazine alkyl derivative, NSC126188, which induced apoptosis of HeLa cells by upregulating RhoB expression. NSC126188 caused multi-septation of fission yeast and hypersensitized a ∆rho3 mutant, which implicates the involvement of functional human homolog RhoB. The treatment of cells with NSC126188 induced apoptosis and a dramatic increase in RhoB expression. In addition, RhoB knockdown using siRNA rescued cells from apoptosis, indicating a crucial role of RhoB in NSC126188-induced apoptosis. In a reporter assay using luciferase and EGFP under control of the RhoB promoter, NSC126188 increased both luciferase activity and the expression of EGFP, implicating transcriptional activation of RhoB by NSC126188. Furthermore, NSC126188 demonstrated in vivo anti-tumor activity, inhibiting tumor growth by 66.8% in a nude mouse xenograft using PC-3 human prostate cancer cells. These results suggest that NSC126188 is a potential lead compound and that upregulation of RhoB is associated with NSC126188-induced apoptosis.

Related: Apoptosis Prostate Cancer


Cimbora-Zovko T, Fritz G, Mikac N, Osmak M
Downregulation of RhoB GTPase confers resistance to cisplatin in human laryngeal carcinoma cells.
Cancer Lett. 2010; 295(2):182-90 [PubMed] Related Publications
Acquired resistance to cisplatin represents a major obstacle to an efficient chemotherapy. We found downregulation of RhoB expression in cisplatin-resistant tumor cell lines from different origin. In cisplatin-resistant laryngeal carcinoma subline overexpression of farnesylated or geranylgeranylated RhoB increased cisplatin-induced cell death, while silencing of RhoB expression diminished sensitivity of parental HEp-2 cells via decreased cellular accumulation of cisplatin. However, since RhoB silencing in additional tumor cell lines did not alter their sensitivity to cisplatin, we can assume that RhoB downregulation does not provide general protective role in cell response to cisplatin. Nevertheless, gene therapy involving restoration of RhoB expression might improve the efficiency of cisplatin treatment, especially in patients with laryngeal carcinoma that acquired resistance to this chemotherapeutic drug.

Related: Cisplatin Cancer of the Larynx Laryngeal Cancer - Molecular Biology


Yoneda M, Hirokawa YS, Ohashi A, et al.
RhoB enhances migration and MMP1 expression of prostate cancer DU145.
Exp Mol Pathol. 2010; 88(1):90-5 [PubMed] Related Publications
Rho family protein regulates variety of cellular functions as cytoskeletal organization, cell proliferation and apoptosis. In the present study, we demonstrate that RhoB-overexpressed prostate cancer cells showed an enhanced cell motility and the administration of the GSK-3 inhibitors inhibited this increase in migration. Among the extracellular matrix and adhesion-related molecules, MMP1 RNA expression was increased in RhoB-overexpressed cells, administration of MMP inhibitor suppressed the collagen gel invasion in these cells. This is the first report evaluating RhoB function and the downstream signaling events in prostate cancer cell. Our results indicate that RhoB promotes cell motility and invasion in a metastatic prostate cancer cell.

Related: MMP1 Prostate Cancer Signal Transduction


Smith MJ, Culhane AC, Donovan M, et al.
Analysis of differential gene expression in colorectal cancer and stroma using fluorescence-activated cell sorting purification.
Br J Cancer. 2009; 100(9):1452-64 [PubMed] Free Access to Full Article Related Publications
Tumour stroma gene expression in biopsy specimens may obscure the expression of tumour parenchyma, hampering the predictive power of microarrays. We aimed to assess the utility of fluorescence-activated cell sorting (FACS) for generating cell populations for gene expression analysis and to compare the gene expression of FACS-purified tumour parenchyma to that of whole tumour biopsies. Single cell suspensions were generated from colorectal tumour biopsies and tumour parenchyma was separated using FACS. Fluorescence-activated cell sorting allowed reliable estimation and purification of cell populations, generating parenchymal purity above 90%. RNA from FACS-purified and corresponding whole tumour biopsies was hybridised to Affymetrix oligonucleotide microarrays. Whole tumour and parenchymal samples demonstrated differential gene expression, with 289 genes significantly overexpressed in the whole tumour, many of which were consistent with stromal gene expression (e.g., COL6A3, COL1A2, POSTN, TIMP2). Genes characteristic of colorectal carcinoma were overexpressed in the FACS-purified cells (e.g., HOX2D and RHOB). We found FACS to be a robust method for generating samples for gene expression analysis, allowing simultaneous assessment of parenchymal and stromal compartments. Gross stromal contamination may affect the interpretation of cancer gene expression microarray experiments, with implications for hypotheses generation and the stability of expression signatures used for predicting clinical outcomes.

Related: Colorectal (Bowel) Cancer TIMP2


Marlow LA, Reynolds LA, Cleland AS, et al.
Reactivation of suppressed RhoB is a critical step for the inhibition of anaplastic thyroid cancer growth.
Cancer Res. 2009; 69(4):1536-44 [PubMed] Free Access to Full Article Related Publications
Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of the disease for which new therapeutic options are desperately needed. Previously, we showed that the high-affinity peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, RS5444, inhibits cell proliferation of ATC cells via induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21). We show here that up-regulation of RhoB is a critical step in PPARgamma-mediated activation of p21-induced cell stasis. Using multiple independently derived ATC cell lines, we found that treatment with RS5444 leads to the up-regulation of RhoB and subsequent activation of p21, and that silencing of RhoB by RNAi blocks the ability of RS5444 to induce p21 and to inhibit cell proliferation. Our results show that transcriptional regulation of RhoB by the nuclear transcription factor PPARgamma is responsible for the induction of p21 mRNA and protein. We further implicate RhoB as a key signaling effector for the growth inhibition of ATC, as treatment with a histone deacetylase inhibitor shown to increase RhoB expression in lung cancer cells caused the up-regulation of RhoB in ATC cells accompanied by increased expression of p21 and inhibition of cell proliferation; this effect occurred even in ATC cells that were unresponsive to RS5444 due to a lack of expression of PPARgamma. Our results implicate RhoB as a novel intermediate in critical signaling pathways and as an additional target for therapeutic intervention in ATC.

Related: PPARG gene Thyroid Cancer


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