ARHGDIB

Gene Summary

Gene:ARHGDIB; Rho GDP dissociation inhibitor (GDI) beta
Aliases: D4, GDIA2, GDID4, LYGDI, Ly-GDI, RAP1GN1, RhoGDI2
Location:12p12.3
Summary:Members of the Rho (or ARH) protein family (see MIM 165390) and other Ras-related small GTP-binding proteins (see MIM 179520) are involved in diverse cellular events, including cell signaling, proliferation, cytoskeletal organization, and secretion. The GTP-binding proteins are active only in the GTP-bound state. At least 3 classes of proteins tightly regulate cycling between the GTP-bound and GDP-bound states: GTPase-activating proteins (GAPs), guanine nucleotide-releasing factors (GRFs), and GDP-dissociation inhibitors (GDIs). The GDIs, including ARHGDIB, decrease the rate of GDP dissociation from Ras-like GTPases (summary by Scherle et al., 1993 [PubMed 8356058]).[supplied by OMIM, Dec 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:rho GDP-dissociation inhibitor 2
HPRD
Source:NCBIAccessed: 27 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 August 2015 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.

  • Western Blotting
  • Neoplasm Metastasis
  • Drug Resistance
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors
  • Disease Progression
  • Up-Regulation
  • Breast Cancer
  • Cell Movement
  • siRNA
  • Bladder Cancer
  • Proteins
  • Antineoplastic Agents
  • Transfection
  • RNA Interference
  • Plasma Membrane Calcium-Transporting ATPases
  • Down-Regulation
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
  • rho GTP-Binding Proteins
  • Tumor Suppressor Gene
  • Adenocarcinoma
  • Cell Proliferation
  • Tumor Markers
  • Neoplasm Invasiveness
  • Neoplasm Proteins
  • src-Family Kinases
  • Guanine Nucleotide Dissociation Inhibitors
  • Cisplatin
  • Sulfonamides
  • RTPCR
  • Ovarian Cancer
  • Tumor Suppressor Proteins
  • Lung Cancer
  • Gene Knockdown Techniques
  • RHOA
  • rho Guanine Nucleotide Dissociation Inhibitor beta
  • Chromosome 12
  • Apoptosis
  • rho Guanine Nucleotide Dissociation Inhibitor alpha
  • Oligonucleotide Array Sequence Analysis
Tag cloud generated 27 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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

Latest Publications: ARHGDIB (cancer-related)

Niu H, Wu B, Peng Y, et al.
RNA interference-mediated knockdown of RhoGDI2 induces the migration and invasion of human lung cancer A549 cells via activating the PI3K/Akt pathway.
Tumour Biol. 2015; 36(1):409-19 [PubMed] Related Publications
Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a tumor suppressor gene for cellular migration and invasion. However, the underlying mechanism and effector targets of RhoGDI2 in lung cancer are still not fully understood. In this study, a vector-expressed small hairpin RNA (shRNA) of RhoGDI2 was transfected into the human lung cancer cell line A549. After the successful transfection, the down-regulation of RhoGDI2 promoted the proliferation, migration, and invasion of lung cancer cells in vitro through the increasing expression and activities of the matrix metallopeptidase 9 (MMP-9) and PI3K/Akt pathways. Transiently transfecting the small interfering RNA (siRNA) of MMP-9 into the RhoGDI2 shRNA cells reduced the MMP-9 expression. Both transfecting the siRNA and adding the MMP-9 antibody into the RhoGDI2 shRNA cells led to a decrease in the invasion and migration of the lung cancer cells. The blockade of the PI3K/Akt pathway by LY294002 resulted in abolishment of the effects of RhoGDI2 shRNA in Akt phosphorylation and MMP-9 expression. This result suggests that the down-regulated RhoGDI2 contributed to the migration and invasion of the lung cancer cell line via activating the PI3K/Akt pathway and the ensuing increase in the expression and activity of MMP-9. In conclusion, we report that the shRNA-mediated knockdown of RhoGDI2 induces the invasion and migration of lung cancer due to cross-talk with the PI3K/Akt pathway and MMP-9. Verifying the role and molecular mechanism of the participation of RhoGDI2 in the migration and invasion of lung cancer may provide a target for better treatment.

Marino N, Collins JW, Shen C, et al.
Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines.
Clin Exp Metastasis. 2014; 31(7):771-86 [PubMed] Related Publications
Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.

He SJ, Gu YY, Yu L, et al.
High expression and frequently humoral immune response of melanoma-associated antigen D4 in glioma.
Int J Clin Exp Pathol. 2014; 7(5):2350-60 [PubMed] Free Access to Full Article Related Publications
MAGE-D4 is a novel member of MAGE super-family. It has preliminarily been demonstrated that MAGE-D4 mRNA is not expressed in majority of normal tissues except for brain and ovary in which only trace amount of MAGE-D4 mRNA can be detected, but predominantly expressed in glioma. MAGE-D4 protein expression and its immunogenicity in glioma have not been elucidated well. This study was designed to analyze MAGE-D4 expression both at mRNA and protein level, characteristic of humoral immune response, and their relationships with glioma patients' clinicopathological parameters. Recombinant MAGE-D4 protein and antiserum were generated. Quantitative RT-PCR analysis revealed that MAGE-D4 mRNA expression was overall up-regulated in 41 glioma specimens compared with that in 14 normal brain tissues. Immunohistochemistry analysis showed that 78% (21/27) glioma tissues expressed MAGE-D4 protein, which was predominantly located in the cytoplasm of tumor cells, but absent in any neuroglia cell of normal brain tissues. ELISA analysis demonstrated that humoral response against MAGE-D4 was detected in 17% (7/41) of glioma patients' sera but not in 77 healthy donors. No apparent correlation was observed between the expression and immunogenicity of MAGE-D4 with clinicopathological parameters of glioma. In summary, these results indicate that MAGE-D4 is highly expressed in glioma and can develop specifically humoral response in glioma patients, which supports that it may be a promising biomarker for glioma diagnosis and immunotherapy.

Hooshmand S, Ghaderi A, Yusoff K, et al.
Differentially expressed proteins in ER+ MCF7 and ER- MDA- MB-231 human breast cancer cells by RhoGDI-α silencing and overexpression.
Asian Pac J Cancer Prev. 2014; 15(7):3311-7 [PubMed] Related Publications
BACKGROUND: The consequence of Rho GDP dissociation inhibitor alpha (RhoGDIα) activity on migration and invasion of estrogen receptor positive (ER+) and negative (ER-) breast cancer cells has not been studied using the proteomic approach. Changes in expression of RhoGDIα and other proteins interacting directly or indirectly with RhoGDIα in MCF7 and MDA-MB-231, with different metastatic potentials is of particular interest.
MATERIALS AND METHODS: ER+ MCF7 and ER- MDA-MB-231 cell lines were subjected to two-dimensional electrophoresis (2-DE) and spots of interest were identified by matrix-assisted laser desorption/ionization time of- flight/time- of-flight (MALDI-TOF/TOF) mass spectrometry (MS) analysis after downregulation of RhoGDIα using short interfering RNA (siRNA) and upregulated using GFP-tagged ORF clone of RhoGDIα.
RESULTS: The results showed a total of 35 proteins that were either up- or down-regulated in these cells. Here we identifed 9 and 15 proteins differentially expressed with silencing of RhoGDIα in MCF-7 and the MDA-MB-231 cells, respectively. In addition, 10 proteins were differentially expressed in the upregulation of RhoGDIα in MCF7, while only one protein was identified in the upregulation of RhoGDIα in MDA-MB-231. Based on the biological functions of these proteins, the results revealed that proteins involved in cell migration are more strongly altered with RhoGDI-α activity. Although several of these proteins have been previously indicated in tumorigenesis and invasiveness of breast cancer cells, some ohave not been previously reported to be involved in breast cancer migration. Hence, these proteins may serve as useful candidate biomarkers for tumorigenesis and invasiveness of breast cancer cells.
CONCLUSIONS: Future studies are needed to determine the mechanisms by which these proteins regulate cell migration. The combination of RhoGDIα with other potential biomarkers may be a more promising approach in the inhibition of breast cancer cell migration.

Yi B, Hu Y, Qin G, et al.
Depletion of RhoGDI2 expression inhibits the ability of invasion and migration in pancreatic carcinoma.
Int J Mol Med. 2014; 34(1):205-12 [PubMed] Related Publications
Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a regulator of tumor metastasis, although its role in tumor progression remains controversial. In this study, we examined the expression of RhoGDI2 in PC tissues and cell lines. To investigate the function of RhoGDI2 in PC cells, RhoGDI2 expression was depleted in PANC-1 and Patu8988 cells by small interfering RNA (siRNA). RhoGDI2 was found to be overexpressed in pancreatic carcinoma (PC) tissues and PC cell lines. Additionally, the results showed that depletion of RhoGDI2 significantly inhibited cell motility and invasion in vitro, but did not affect cell proliferation. The clinical study together with the experimental data confirmed that RhoGDI2 modulated the expression of matrix metalloproteinase 2 (MMP2). Taken together, findings of the present study indicated that RhoGDI2 is involved in pancreatic tumor malignancy and metastasis. Thus, RhoGDI2 is a potential target for the gene therapy of PC.

Gallo MB, Falso MJ, Balem F, et al.
The anti-promyelocytic leukemia mode of action of two endophytic secondary metabolites unveiled by a proteomic approach.
Planta Med. 2014; 80(6):473-81 [PubMed] Related Publications
As a result of a program to find antitumor compounds of endophytes from medicinal Asteraceae, the steroid (22E,24R)-8,14-epoxyergosta-4,22-diene-3,6-dione (a) and the diterpene aphidicolin (b) were isolated from the filamentous fungi Papulaspora immersa and Nigrospora sphaerica, respectively, and exhibited strong cytotoxicity against HL-60 cells. A proteomic approach was used in an attempt to identify the drugs' molecular targets and their respective antiproliferative mode of action. Results suggested that the (a) growth inhibition effect occurs by G2/M cell cycle arrest via reduction of tubulin alpha and beta isomers and 14-3-3 protein gamma expression, followed by a decrease of apoptotic and inflammatory proteins, culminating in mitochondrial oxidative damage that triggered autophagy-associated cell death. Moreover, the decrease observed in the expression levels of several types of histones indicated that (a) might be disarming oncogenic pathways via direct modulation of the epigenetic machinery. Effects on cell cycle progression and induction of apoptosis caused by (b) were confirmed. In addition, protein expression profiles also revealed that aphidicolin is able to influence microtubule dynamics, modulate proteasome activator complex expression, and control the inflammatory cascade through overexpression of thymosin beta 4, RhoGDI2, and 14-3-3 proteins. Transmission electron micrographs of (b)-treated cells unveiled dose-dependent morphological characteristics of autophagy- or oncosis-like cell death.

Song Q, Xu Y, Yang C, et al.
miR-483-5p promotes invasion and metastasis of lung adenocarcinoma by targeting RhoGDI1 and ALCAM.
Cancer Res. 2014; 74(11):3031-42 [PubMed] Related Publications
The nodal regulatory properties of microRNAs (miRNA) in metastatic cancer may offer new targets for therapeutic control. Here, we report that upregulation of miR-483-5p is correlated with the progression of human lung adenocarcinoma. miR-483-5p promotes the epithelial-mesenchymal transition (EMT) accompanied by invasive and metastatic properties of lung adenocarcinoma. Mechanistically, miR-483-5p is activated by the WNT/β-catenin signaling pathway and exerts its prometastatic function by directly targeting the Rho GDP dissociation inhibitor alpha (RhoGDI1) and activated leukocyte cell adhesion molecule (ALCAM), two putative metastasis suppressors. Furthermore, we found that downregulation of RhoGDI1 enhances expression of Snail, thereby promoting EMT. Importantly, miR-483-5p levels are positively correlated with β-catenin expression, but are negatively correlated with the levels of RhoGDI1 and ALCAM in human lung adenocarcinoma. Our findings reveal that miR-483-5p is a critical β-catenin-activated prometastatic miRNA and a negative regulator of the metastasis suppressors RhoGDI1 and ALCAM.

Unland R, Kerl K, Schlosser S, et al.
Epigenetic repression of the dopamine receptor D4 in pediatric tumors of the central nervous system.
J Neurooncol. 2014; 116(2):237-49 [PubMed] Related Publications
Epigenetic alterations are common events in cancer. Using a genome wide methylation screen (Restriction Landmark Genomic Scanning-RLGS) we identified the gene for the dopamine receptor D4 (DRD4) as tumor-specific methylated. As DRD4 is involved in early brain development and may thus be involved in developmentally dependent tumors of the CNS in children epigenetic deregulation of DRD4 and its functional consequences were analyzed in vitro. CpG methylation of DRD4 was detected in 18/24 medulloblastomas, 23/29 ependymomas, 6/6 high-grade gliomas, 7/10 CNS PNET and 8/8 cell lines by qCOBRA and bisulfite sequencing. Real-time RT-PCR demonstrated a significantly inferior expression of DRD4 in primary tumors compared to cell lines and non-malignant control tissues. Epigenetic deregulation of DRD4 was analyzed in reexpression experiments and restoration of DRD4 was observed in medulloblastoma (MB) cells treated with 5-Aza-CdR. Reexpression was not accompanied by demethylation of the DRD4 promoter but by a significant decrease of H3K27me3 and of bound enhancer of zeste homologue 2 (EZH2). Knockdown of EZH2 demonstrated DRD4 as a direct target for inhibition by EZH2. Stimulation of reexpressed DRD4 resulted in an activation of ERK1/2. Our analyses thus disclose that DRD4 is epigenetically repressed in CNS tumors of childhood. DRD4 is a direct target of EZH2 in MB cell lines. EZH2 appears to dominate over aberrant DNA methylation in the epigenetic inhibition of DRD4, which eventually leads to inhibition of a DRD4-mediated stimulation of the ERK1/2 kinase pathway.

Salim T, Sand-Dejmek J, Sjölander A
The inflammatory mediator leukotriene D₄ induces subcellular β-catenin translocation and migration of colon cancer cells.
Exp Cell Res. 2014; 321(2):255-66 [PubMed] Related Publications
The abnormal activation of the Wnt/β-catenin pathway frequently occurs in colorectal cancer. The nuclear translocation of β-catenin activates the transcription of target genes that promote cell proliferation, survival, and invasion. The pro-inflammatory mediator leukotriene D4 (LTD4) exerts its effects through the CysLT1 receptor. We previously reported an upregulation of CysLT1R in patients with colon cancer, suggesting the importance of leukotrienes in colon cancer. The aim of this study was to investigate the impact of LTD4 on Wnt/β-catenin signaling and its effects on proliferation and migration of colon cancer cells. LTD4 stimulation led to an increase in β-catenin expression, β-catenin nuclear translocation and the subsequent transcription of MYC and CCND1. Furthermore, LTD4 significantly reduced the expression of E-cadherin and β-catenin at the plasma membrane and increased the migration and proliferation of HCT116 colon cancer cells. The effects of LTD4 can be blocked by the inhibition of CysLT1R. Furthermore, LTD4 induced the inhibition of glycogen synthase kinase 3 (GSK)-3β activity, indicating a crosstalk between the G-protein-coupled receptor CysLT1 and the Wnt/β-catenin pathway. In conclusion, LTD4, which can be secreted from macrophages and leukocytes in the tumor microenvironment, induces β-catenin translocation and the activation of β-catenin target genes, resulting in the increased proliferation and migration of colon cancer cells.

Kim IK, Park SM, Cho HJ, et al.
14-3-3σ attenuates RhoGDI2-induced cisplatin resistance through activation of Erk and p38 in gastric cancer cells.
Oncotarget. 2013; 4(11):2045-56 [PubMed] Free Access to Full Article Related Publications
Rho GDP dissociation inhibitor 2 (RhoGDI2) promotes tumor growth and malignant progression and enhances chemoresistance of gastric cancer. Recently, we noted an inverse correlation between RhoGDI2 and 14-3-3σ expression, which suggests that 14-3-3σ is a target of gastric cancer metastasis and the chemoresistance-promoting effect of RhoGDI2. Herein, we evaluated whether 14-3-3σ is regulated by RhoGDI2 and is functionally important for the RhoGDI2-induced cisplatin resistance of gastric cancer cells. We used highly metastatic and cisplatin-resistant RhoGDI2-overexpressing SNU-484 cells and observed decreased 14-3-3σ mRNA and protein expression. Depletion of 14-3-3σ in SNU-484 control cells enhanced cisplatin resistance, whereas restoration of 14-3-3σ in RhoGDI2-overexpressing SNU-484 cells impaired cisplatin resistance in vitro and in vivo. We also found that the phosphorylation levels of Erk and p38 kinases significantly decreased in RhoGDI2-overexpressing SNU-484 cells and recovered after 14-3-3σ expression, and that decreased activities of these kinases were critical for RhoGDI2-induced cisplatin resistance. In conclusion, 14-3-3σ is a RhoGDI2-regulated gene that appears to be important for suppressing the chemoresistance of gastric cancer cells.

Takami H, Kanda M, Oya H, et al.
Evaluation of MAGE-D4 expression in hepatocellular carcinoma in Japanese patients.
J Surg Oncol. 2013; 108(8):557-62 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Though Melanoma-associated antigen (MAGE) family genes have received lots of attention as cancer-related genes and targets for immunotherapy, MAGE-D4 expression in hepatocellular carcinoma (HCC) has not yet been evaluated.
METHODS: MAGE-D4 mRNA expression was assayed in nine HCC cell lines and 94 HCC surgical specimens obtained from Japanese patients by quantitative real-time reverse transcription polymerase chain reaction, and the correlations between MAGE-D4 mRNA expression and clinicopathological factors were evaluated. The expression and distribution of MAGE-D4b protein were evaluated immunohistochemically.
RESULTS: MAGE-D4 mRNA was overexpressed in five of nine HCC cell lines and 34 of 94 primary HCCs (36.2%). Median overall survival (14.8 vs. 118 months, P < 0.001) and relapse-free survival (2.7 vs. 18.3 months, P < 0.001) were significantly shorter in patients with high than with low-moderate MAGE-D4 expression. Multivariate analysis for overall survival showed that MAGE-D4 overexpression was independently prognostic for survival (hazard ratio 2.88, P = 0.009) and significantly associated with high alpha-fetoprotein concentration (P < 0.001), poor tumor differentiation (P = 0.003) and vascular invasion (P = 0.021). MAGE-D4b protein expression patterns were consistent with those of MAGE-D4 mRNA.
CONCLUSIONS: Overexpression of MAGE-D4 may be a predictive marker of early recurrence and mortality in patients with HCC.

Maehama T, Fukasawa M, Date T, et al.
A class II phosphoinositide 3-kinase plays an indispensable role in hepatitis C virus replication.
Biochem Biophys Res Commun. 2013; 440(1):150-6 [PubMed] Related Publications
Phosphoinositides function as fundamental signaling molecules and play roles in diverse cellular processes. Certain types of viruses may employ host cell phosphoinositide signaling systems to facilitate their replication cycles. Here we demonstrate that the β isoform of class II PI3K (PI3K-C2β) plays an indispensable role in hepatitis C virus (HCV) propagation in human hepatocellular carcinoma cells. Knockdown of PI3K-C2β abrogated HCV propagation in the cell. Using an HCV replicon system, we found that knockdown of PI3K-C2β substantially repressed the full-genome replication, while showing relatively small reductions in sub-genome replication, in which structural proteins including core protein were deleted. We also found that HCV core protein showed the binding activity towards D4-phosphorylated phosphoinositides and overlapped localization with phosphatidylinositol 3,4-bisphosphate in the cell. These results suggest that the phosphoinositide generated by PI3K-C2β plays an indispensable role in the HCV replication cycle through the binding to HCV core protein.

Bengtsson AM, Jönsson G, Magnusson C, et al.
The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-induced differentiation of colon cancer cells.
BMC Cancer. 2013; 13:336 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT(1)R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT(2)R) is lost. Further, our previous data indicate that patients with high CysLT(1)R and low CysLT(2)R expression have a poor prognosis. In this study, we examined whether the balance between CysLT(1)R and CysLT(2)R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA).
METHODS: To determine the effect of ATRA on CysLT(2)R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions.
RESULTS: ATRA treatment induces CysLT(2)R mRNA and protein expression without affecting CysLT(1)R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor (RAR) dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C4 synthase, the enzyme responsible for the production of the ligand for CysLT(2)R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT(2)R-specific inhibitor.
CONCLUSIONS: This study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway.

Duan W, Xu Y, Dong Y, et al.
Ectopic expression of miR-34a enhances radiosensitivity of non-small cell lung cancer cells, partly by suppressing the LyGDI signaling pathway.
J Radiat Res. 2013; 54(4):611-9 [PubMed] Free Access to Full Article Related Publications
miR-34a is transcriptionally induced by the tumor suppressor gene p53, which is often downregulated in non-small cell lung cancer (NSCLC). To address whether the downstream signal of miR-34a is sufficient to induce apoptosis and to alter cellular radiosensitivity, a chemical synthetic miR-34a mimic was delivered into A549 and H1299 cells, with or without co-treatment of γ-irradiation. Results showed that ectopic expression of miR-34a induced dose-dependent cell growth inhibition and apoptosis in a p53-independent manner in both NSCLC cell lines. Interestingly, LyGDI was discovered as a new target gene of miR-34a, and downregulation of LyGDI promoted Rac1 activation and membrane translocation, resulting in cell apoptosis. Furthermore, restoration of miR-34a indirectly reduced cyclooxygenase-2 (COX-2) expression. Taken together, these results demonstrate that restoration of miR-34a expression enhances radiation-induced apoptosis, partly by suppressing the LyGDI signaling pathway, and miR-34a could possibly be used as a radiosensitizer for non-small cell lung cancer therapy.

Jones A, Friedrich K, Rohm M, et al.
TSC22D4 is a molecular output of hepatic wasting metabolism.
EMBO Mol Med. 2013; 5(2):294-308 [PubMed] Free Access to Full Article Related Publications
In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. Here, we show that tumour growth triggers hepatic metabolic dysfunction as part of the cancer cachectic phenotype, particularly by reduced hepatic very-low-density-lipoprotein (VLDL) secretion and hypobetalipoproteinemia. As a molecular cachexia output pathway, hepatic levels of the transcription factor transforming growth factor beta 1-stimulated clone (TSC) 22 D4 were increased in cancer cachexia. Mimicking high cachectic levels of TSC22D4 in healthy livers led to the inhibition of hepatic VLDL release and lipogenic genes, and diminished systemic VLDL levels under both normal and high fat dietary conditions. Liver-specific ablation of TSC22D4 triggered hypertriglyceridemia through the induction of hepatic VLDL secretion. Furthermore, hepatic TSC22D4 expression levels were correlated with the degree of body weight loss and VLDL hypo-secretion in cancer cachexia, and TSC22D4 deficiency rescued tumour cell-induced metabolic dysfunction in hepatocytes. Therefore, hepatic TSC22D4 activity may represent a molecular rationale for peripheral energy deprivation in subjects with metabolic wasting diseases, including cancer cachexia.

Herzfeld T, Nolte D, Grznarova M, et al.
X-linked dystonia parkinsonism syndrome (XDP, lubag): disease-specific sequence change DSC3 in TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism.
Hum Mol Genet. 2013; 22(5):941-51 [PubMed] Related Publications
X-chromosomal dystonia parkinsonism syndrome (XDP, 'lubag') is associated with sequence changes within the TAF1/DYT3 multiple transcript system. Although most sequence changes are intronic, one, disease-specific single-nucleotide change 3 (DSC3), is located within an exon (d4). Transcribed exon d4 occurs as part of multiple splice variants. These variants include exons d3 and d4 spliced to exons of TAF1, and an independent transcript composed of exons d2-d4. Location of DSC3 in exon d4 and utilization of this exon in multiple splice variants suggest an important role of DSC3 in the XDP pathogenesis. To test this hypothesis, we transfected neuroblastoma cells with four expression constructs, including exons d2-d4 [d2-d4/wild-type (wt) and d2-d4/DSC3] and d3-d4 (d3-d4/wt and d3-d4/DSC3). Expression profiling revealed a dramatic effect of DSC3 on overall gene expression. Three hundred and sixty-two genes differed between cells containing d2-d4/wt and d2-d4/DSC3. Annotation clustering revealed enrichment of genes related to vesicular transport, dopamine metabolism, synapse function, Ca(2+) metabolism and oxidative stress. Two hundred and eleven genes were differentially expressed in d3-d4/wt versus d3-d4/DSC3. Annotation clustering highlighted genes in signal transduction and cell-cell interaction. The data show an important role of physiologically occurring transcript d2-d4 in normal brain function. Interference with this role by DSC3 is a likely pathological mechanism in XDP. Disturbance of dopamine function and of Ca(2+) metabolism can explain abnormal movement; loss of protection against reactive oxygen species may account for the neurodegenerative changes in XDP. Although d3-d4 also affect genes potentially related to neurodegenerative processes, their physiologic role as splice variants of TAF1 awaits further exploration.

Wakefield A, Soukupova J, Montagne A, et al.
Bcl3 selectively promotes metastasis of ERBB2-driven mammary tumors.
Cancer Res. 2013; 73(2):745-55 [PubMed] Related Publications
Bcl3 is a putative proto-oncogene deregulated in hematopoietic and solid tumors. Studies in cell lines suggest that its oncogenic effects are mediated through the induction of proliferation and inhibition of cell death, yet its role in endogenous solid tumors has not been established. Here, we address the oncogenic effect of Bcl3 in vivo and describe how this Stat3-responsive oncogene promotes metastasis of ErbB2-positive mammary tumors without affecting primary tumor growth or normal mammary function. Deletion of the Bcl3 gene in ErbB2-positive (MMTV-Neu) mice resulted in a 75% reduction in metastatic tumor burden in the lungs with a 3.6-fold decrease in cell turnover index in these secondary lesions with no significant effect on primary mammary tumor growth, cyclin D1 levels, or caspase-3 activity. Direct inhibition of Bcl3 by siRNA in a transplantation model of an Erbb2-positive mammary tumor cell line confirmed the effect of Bcl3 in malignancy, suggesting that the effect of Bcl3 was intrinsic to the tumor cells. Bcl3 knockdown resulted in a 61% decrease in tumor cell motility and a concomitant increase in the cell migration inhibitors Nme1, Nme2, and Nme3, the GDP dissociation inhibitor Arhgdib, and the metalloprotease inhibitors Timp1 and Timp2. Independent knockdown of Nme1, Nme2, and Arhgdib partially rescued the Bcl3 motility phenotype. These results indicate for the first time a cell-autonomous disease-modifying role for Bcl3 in vivo, affecting metastatic disease progression rather than primary tumor growth.

Gordiev M, Engstrom PF, Khasanov R, et al.
Genetic analysis of polymorphisms in dopamine receptor and transporter genes for association with smoking among cancer patients.
Eur Addict Res. 2013; 19(2):105-11 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Smoking among Russian cancer patients may be related to variations in the DRD2/ANKK1 (Taq1), DRD4 (exon III VNTR), and SLC6A3 genes.
METHODS: Seven hundred fifty patients provided smoking history and DNA.
RESULTS: Current smokers were more likely to be DRD2 A2 allele carriers versus nonsmokers (former/never smokers; 69 vs. 56%; OR = 1.69; 95% CI 1.13-2.53, p = 0.01) and former smokers (69 vs. 59%; OR = 1.54; 95% CI 0.97-2.46, p = 0.07). Ever smokers (current/former smokers) were more likely to be DRD2 A2 allele carriers versus never smokers (65 vs. 55%; OR = 1.50; 95% CI 1.00-2.27, p = 0.05). The risk of current smoking among DRD2 A2 allele carriers was present if the DRD4 short allele was also present (OR = 1.76; 95% CI 1.12-2.78, p = 0.02), and the risk of ever smoking among DRD2 A2 allele carriers was present if the DRD4 short allele was also present (OR = 1.62; 95% CI 1.02-2.55, p = 0.04). DRD2 A2 allele carriers had a shorter period of previous abstinence versus DRD2 A1 carriers (p = 0.02). Effects were not statistically significant when controlling for multiple comparisons.
CONCLUSIONS: The DRD2 A2 allele may increase the risk of smoking among cancer patients, convergent with studies using non-Western samples. However, additional replication is needed.

Tobi M, Kim M, Weinstein DH, et al.
Prospective markers for early diagnosis and prognosis of sporadic pancreatic ductal adenocarcinoma.
Dig Dis Sci. 2013; 58(3):744-50 [PubMed] Related Publications
BACKGROUND AND AIM: Sporadic pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer. No proven screening strategies are available and frequent cross-sectional imaging studies (CT/MRI) are impractical even in patients thought to be at higher risk than the general population. Few PDA biomarkers have been studied prospectively for screening. Here, we prospectively evaluated the Adnab-9 monoclonal antibody in stool, pancreaticobiliary secretions, and tissue for screening and prognostic value in sporadic PDA. We also evaluated the prognostic value of characterized early biomarkers in pancreaticobiliary secretions.
METHODS: Adnab-9 diagnostic ability was tested in stool in 249 and 1,132 patients from China and the US, respectively. Immunohistochemistry was performed in 22 tissue samples with Adnab-9 antibody and anti-Defensin 5, a constituent of Paneth cells. Pancreatobiliary secretions were collected from 12 PDA patients and 9 controls. The enriched PCR method was performed to detect K-ras mutations. ELISA was performed with Adnab-9, anti-Her-2/neu, and monoclonal antibody D4 (anti-Reg I).
RESULTS: Adnab-9 alone was diagnostic and prognostic when measured in pancreatic secretions, feces, and tissues of PDA patients compared to controls (p < 0.05). Significantly, Adnab-9 fecal binding can precede the clinical diagnosis by 2.3 years, potentially allowing earlier clinical intervention. In pancreatic secretions, a combination of K-ras and Her-2/neu when appropriately standardized can be diagnostic in 75 % of PDA.
CONCLUSIONS: Our study suggests that Adnab-9 may be an effective marker for diagnosis and prognosis of PDA. Adnab-9 may be reflective of the presence of Paneth cells confirmed by Defensin-5 staining. These cells may modulate the biological activity of the cancer and confer a better prognosis.

Said N, Sanchez-Carbayo M, Smith SC, Theodorescu D
RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration.
J Clin Invest. 2012; 122(4):1503-18 [PubMed] Free Access to Full Article Related Publications
Half of patients with muscle-invasive bladder cancer develop metastatic disease, and this is responsible for most of the deaths from this cancer. Low expression of RhoGTP dissociation inhibitor 2 (RhoGDI2; also known as ARHGDIB and Ly-GDI) is associated with metastatic disease in patients with muscle-invasive bladder cancer. Moreover, a reduction in metastasis is observed upon reexpression of RhoGDI2 in xenograft models of metastatic cancer. Here, we show that RhoGDI2 suppresses lung metastasis in mouse models by reducing the expression of isoforms V1 and V3 of the proteoglycan versican (VCAN; also known as chondroitin sulfate proteoglycan 2 [CSPG2]). In addition, we found that high versican levels portended poor prognosis in patients with bladder cancer. The functional importance of tumor expression of versican in promoting metastasis was established in in vitro and in vivo studies in mice that implicated a role for the chemokine CCL2 (also known as MCP1) and macrophages. Further analysis indicated that RhoGDI2 suppressed metastasis by altering inflammation in the tumor microenvironment. In summary, we demonstrate what we believe to be a new mechanism of metastasis suppression that works by reducing host responses that promote metastatic colonization of the lung. Therapeutic targeting of these interactions may provide a novel adjuvant strategy for delaying the appearance of clinical metastasis in patients.

Cho HJ, Baek KE, Kim IK, et al.
Proteomics-based strategy to delineate the molecular mechanisms of RhoGDI2-induced metastasis and drug resistance in gastric cancer.
J Proteome Res. 2012; 11(4):2355-64 [PubMed] Related Publications
Rho GDP dissociation inhibitor 2 (RhoGDI2) was initially identified as a regulator of the Rho family of GTPases. Our recent works suggest that RhoGDI2 promotes tumor growth and malignant progression, as well as enhances chemoresistance in gastric cancer. Here, we delineate the mechanism by which RhoGDI2 promotes gastric cancer cell invasion and chemoresistance using two-dimensional gel electrophoresis (2-DE) on proteins derived from a RhoGDI2-overexpressing SNU-484 human gastric cancer cell line and control cells. Differentially expressed proteins were identified using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS). In total, 47 differential protein spots were identified; 33 were upregulated, and 14 were downregulated by RhoGDI2 overexpression. Upregulation of SAE1, Cathepsin D, Cofilin1, CIAPIN1, and PAK2 proteins was validated by Western blot analysis. Loss-of-function analysis using small interference RNA (siRNA) directed against candidate genes reveals the need for CIAPIN1 and PAK2 in RhoGDI2-induced cancer cell invasion and Cathepsin D and PAK2 in RhoGDI2-mediated chemoresistance in gastric cancer cells. These data extend our understanding of the genes that act downstream of RhoGDI2 during the progression of gastric cancer and the acquisition of chemoresistance.

Zeller C, Dai W, Steele NL, et al.
Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling.
Oncogene. 2012; 31(42):4567-76 [PubMed] Related Publications
Multiple DNA methylation changes in the cancer methylome are associated with the acquisition of drug resistance; however it remains uncertain how many represent critical DNA methylation drivers of chemoresistance. Using isogenic, cisplatin-sensitive/resistant ovarian cancer cell lines and inducing resensitizaton with demethylating agents, we aimed to identify consistent methylation and expression changes associated with chemoresistance. Using genome-wide DNA methylation profiling across 27 578 CpG sites, we identified loci at 4092 genes becoming hypermethylated in chemoresistant A2780/cp70 compared with the parental-sensitive A2780 cell line. Hypermethylation at gene promoter regions is often associated with transcriptional silencing; however, expression of only 245 of these hypermethylated genes becomes downregulated in A2780/cp70 as measured by microarray expression profiling. Treatment of A2780/cp70 with the demethylating agent 2-deoxy-5'-azacytidine induces resensitization to cisplatin and re-expression of 41 of the downregulated genes. A total of 13/41 genes were consistently hypermethylated in further independent cisplatin-resistant A2780 cell derivatives. CpG sites at 9 of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS and PSMB9) acquired methylation in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 genes (ARMCX2, COL1A1, MDK, MEST and MLH1) acquired methylation in drug-resistant ovarian cancer-sustaining (side population) cells. MLH1 has a direct role in conferring cisplatin sensitivity when reintroduced into cells in vitro. This combined genomics approach has identified further potential key drivers of chemoresistance whose expression is silenced by DNA methylation that should be further evaluated as clinical biomarkers of drug resistance.

Drost AC, Seitz G, Boehmler A, et al.
The G protein-coupled receptor CysLT1 mediates chemokine-like effects and prolongs survival in chronic lymphocytic leukemia.
Leuk Lymphoma. 2012; 53(4):665-73 [PubMed] Related Publications
The G protein-coupled receptor (GPCR) CXCR4 is involved in bone marrow tropism and survival of chronic lymphocytic leukemia (CLL) cells. The function of the GPCRs cysteinyl leukotriene receptor 1 (CysLT1) and CysLT2 remains elusive. Here we demonstrate that in CLL and normal B lymphocytes, CysLT1 mRNA is consistently expressed, in contrast to low CysLT2 levels. Similar to the CXCR4 ligand CXCL12, the cysteinyl leukotriene (cysLT) LTD(4) induces calcium fluxes, actin polymerization, and chemotaxis. These effects are blocked by specific CysLT1 antagonists. Their inhibition by pertussis toxin suggests Giα/o protein involvement. Furthermore, CysLT1 mediates MAP-kinase phosphorylation, which implicates contribution of cysLT to survival. Indeed, CysLT1 antagonists induce apoptosis and reduce viability independent of Gαi/o protein signaling. Considering the production of cysLTs in the bone marrow, our data suggest that CysLT1 induces chemokine-like effects, supports accumulation and survival of CLL cells in the bone marrow and thus represents a potential treatment target.

Ma L, Ohyagi Y, Nakamura N, et al.
Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine.
J Alzheimers Dis. 2011; 27(1):225-37 [PubMed] Related Publications
Apomorphine hydrochloride (APO) is known to be a dopamine receptor agonist, and has recently been found to be a novel drug for Alzheimer's disease (AD). We found that APO treatment ameliorated oxidative stress in an AD mouse model and specifically attenuated the hydrogen peroxide-induced p53-related apoptosis in the SH-SY5Y neuroblastoma cell line. To further understand the mechanism behind this action, we investigated the actions of APO on intracellular redox systems, such as the glutathione cycle and catalase. We studied the effects of specific inhibitors for glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (BCNU, MCS, and ATZ, respectively) on the effects of APO. Treatments with MCS or BCNU, but not ATZ, significantly attenuated the protective effects of APO. Interestingly, APO treatment elevated GPx activity, but did not increase the expression of the GPx1 protein. Although BCNU treatment attenuated APO effects, GR activity was not elevated by APO treatment. The same effects were observed in primary neuronal cultures. In addition, treatment with dopamine D1, D2, D3 and D4 receptor antagonists did not counteract the protective action of APO. Thus, APO may enhance GPx activity through dopamine receptor-independent pathways.

Bence M, Koller J, Sasvari-Szekely M, Keszler G
Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells.
J Neural Transm. 2012; 119(1):17-24 [PubMed] Related Publications
Histone deacetylase inhibitors are promising anti-tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies. However, little is known about any effects of these drugs on the central nervous system. The aim of the present study was to analyze the effects of trichostatin A (TSA)--a broad-spectrum histone deacetylase inhibitor--on the transcriptional regulation of several genes involved in dopamine- and serotonergic neurotransmission. To this end, short-term parallel cultures of SK-NF-I neuroblastoma cells were treated with TSA either alone or in combination with hypoxia, and mRNA levels of dopamine receptor D3 (DRD3) and D4 (DRD4), dopamine transporter (DAT), dopamine hydroxylase (DBH), dopamine receptor regulating factor (DRRF), catechol-O-methyltransferase (COMT), serotonin receptor 1A (HTR1A), monoamino oxidase A (MAO-A), serotonin transporter (SLC6A4) and tryptophan hydroxylase 2 (TPH2) were determined by quantitative PCR. We found that TSA did not antagonize the hypoxia-induced activation of D3 and D4 dopamine receptor genes, implying that induction of these genes is not mediated directly by hypoxia inducible factor-1alpha. On the other hand, TSA dramatically upregulated the expression of DAT and SLC6A4 (45-fold and 15-fold, respectively), while transcript levels of MAO-A and COMT were significantly reduced (by 70% and by more than 90%, respectively). Induction of DAT protein expression was detected by western blotting. These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons.

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.

Solár P, Sytkowski AJ
Differentially expressed genes associated with cisplatin resistance in human ovarian adenocarcinoma cell line A2780.
Cancer Lett. 2011; 309(1):11-8 [PubMed] Related Publications
Ovarian cancer cells are usually initially sensitive to platinum-based chemotherapy, such as cisplatin (CDDP), but typically become resistant over time. Such drug resistance is a serious impediment to successful disease treatment, and the molecular mechanisms responsible for resistance are not fully understood. In search of novel mechanisms that may lead to the development of CDDP chemoresistance, we used subtractive hybridization to identify differentially expressed genes in CDDP resistant CP70 and C200 cells vs. CDDP sensitive A2780 human ovarian adenocarcinoma cells. We analyzed 256 randomly selected clones. Subtraction efficiency was determined by dot blot and DNA sequencing. Confirmation of differentially expressed cDNAs was done by virtual northern blot analysis, and 17 genes that were differentially expressed in CDDP resistant cell lines vs. CDDP sensitive A2780 cells were identified. The expression of 10 of these genes was low or undetectable in sensitive A2780 cells in comparison to resistant cells and an additional seven genes were more highly expressed in resistant CP70 and C200 vs. A2780 cells. Our identified genes are involved in numerous and diverse cellular processes, such as inhibition of apoptosis (ARHGDIB), stress response (HSPCA, TRA1), chromatin condensation (CNAP1, RanBP2), invasiveness of cells (MMP10), alteration of Ca(2+) homeostasis (ASPH, ATP2B1) and others. Further characterization of these genes and gene products should yield important insights into the biology of CDDP resistance in ovarian carcinoma.

Gambineri A, Tomassoni F, Munarini A, et al.
A combination of polymorphisms in HSD11B1 associates with in vivo 11{beta}-HSD1 activity and metabolic syndrome in women with and without polycystic ovary syndrome.
Eur J Endocrinol. 2011; 165(2):283-92 [PubMed] Related Publications
OBJECTIVE: Regeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) within liver and adipose tissue may be of pathophysiological importance in obesity and the metabolic syndrome. single nucleotide polymorphisms (SNPs) in HSD11B1, the gene encoding 11β-HSD1, have been associated with type 2 diabetes and hypertension in population-based cohort studies, and with hyperandrogenism in patients with the polycystic ovary syndrome (PCOS). However, the functional consequences of these SNPs for in vivo 11β-HSD1 expression and activity are unknown.
METHODS: We explored associations of well-characterised hormonal and metabolic phenotypes with two common SNPs (rs846910 and rs12086634) in HSD11B1 in 600 women (300 with PCOS) and investigated 11β-HSD1 expression and activity in a nested study of 40 women from this cohort.
RESULTS: HSD11B1 genotypes (as single SNPs and as the combination of the two minor allele SNPs) were not associated with PCOS. Women who were heterozygous for rs846910 A and homozygous for rs12086634 T (GA, TT genotype) had a higher risk of metabolic syndrome, regardless of the diagnosis of PCOS (odds ratio in the whole cohort=2.77 (95% confidence interval (CI) 1.16-6.67), P=0.023). In the nested cohort, women with the GA, TT genotype had higher HSD11B1 mRNA levels in adipose tissue, and higher rates of appearance of cortisol and d3-cortisol (16.1±0.7 nmol/min versus 12.1±1.1, P=0.044) during 9,11,12,12-2H4-cortisol (d4-cortisol) steady-state infusion.
CONCLUSIONS: We conclude that, in a population of Southern European Caucasian women with and without PCOS, alleles of HSD11B1 containing the two SNPs rs846910 A and rs12086634 T confer increased 11β-HSD1 expression and activity, which associates with the metabolic syndrome.

Liu J, Zhang D, Luo W, et al.
X-linked inhibitor of apoptosis protein (XIAP) mediates cancer cell motility via Rho GDP dissociation inhibitor (RhoGDI)-dependent regulation of the cytoskeleton.
J Biol Chem. 2011; 286(18):15630-40 [PubMed] Free Access to Full Article Related Publications
X-linked inhibitor of apoptosis protein (XIAP) overexpression has been found to be associated with malignant cancer progression and aggression in individuals with many types of cancers. However, the molecular basis of XIAP in the regulation of cancer cell biological behavior remains largely unknown. In this study, we found that a deficiency of XIAP expression in human cancer cells by either knock-out or knockdown leads to a marked reduction in β-actin polymerization and cytoskeleton formation. Consistently, cell migration and invasion were also decreased in XIAP-deficient cells compared with parental wild-type cells. Subsequent studies demonstrated that the regulation of cell motility by XIAP depends on its interaction with the Rho GDP dissociation inhibitor (RhoGDI) via the XIAP RING domain. Furthermore, XIAP was found to negatively regulate RhoGDI SUMOylation, which might affect its activity in controlling cell motility. Collectively, our studies provide novel insights into the molecular mechanisms by which XIAP regulates cancer invasion and offer a further theoretical basis for setting XIAP as a potential prognostic marker and specific target for treatment of cancers with metastatic properties.

Jiang L, Lai YK, Zhang J, et al.
Targeting S100P inhibits colon cancer growth and metastasis by Lentivirus-mediated RNA interference and proteomic analysis.
Mol Med. 2011; 17(7-8):709-16 [PubMed] Free Access to Full Article Related Publications
S100P was recently found to be overexpressed in a variety of cancers and is considered a potential target for cancer therapy, but the functional role or mechanism of action of S100P in colon cancer is not fully understood. In the present study, we knocked down the gene expression of S100P in colon cancer cells using lentivirus-mediated RNA interference. This step resulted in significant inhibition of cancer cell growth, migration and invasion in vitro and tumor growth and liver metastasis in vivo. Moreover, S100P downstream target proteins were identified by proteomic analysis in colon cancer DLD-1 cells with deletion of S100P. Knockdown of S100P led to downregulation of thioredoxin 1 and β-tubulin and upregulation of Rho guanosine diphosphate (GDP) dissociation inhibitor α (RhoGDIA), all potential therapeutic targets in cancer. Taken together, these findings suggest that S100P plays an important role in colon tumorigenesis and metastasis, and the comprehensive and comparative analyses of proteins associated with S100P could contribute to understanding the downstream signal cascade of S100P, leading to tumorigenesis and metastasis.

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