Loss of expression of LyGDI (ARHGDIB), a rho GDP‐dissociation inhibitor, in Hodgkin lymphoma<sup>*</sup>

Ma, Liya; Xu, Gaixiang; Sotnikova, Anna; Szczepanowski, Monika; Giefing, Maciej; Krause, Kristina; Krams, Matthias; Siebert, Reiner; Jin, Jie; Klapper, Wolfram

doi:10.1111/j.1365-2141.2007.06782.x

Cited by 45 publications

(33 citation statements)

References 19 publications

(28 reference statements)

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“…By contrast, D4-GDI is reduced in bladder cancer compared with benign tissue (27). In addition, D4-GDI (LyGDI) is highly expressed in non-Hodgkin lymphoma, but not in Hodgkin lymphoma (26). The difference in D4-GDI expression patterns may reflect the diversity of genetic backgrounds and/or tumor stages as well as activation versus inhibition of Rac or other Rho GTPases in the course of cancer progression (21).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Silencing of D4-GDI Inhibits Growth and Invasive Behavior in MDA-MB-231 Cells by Activation of Rac-dependent p38 and JNK Signaling

Zhang

Rosado

Moon

et al. 2009

Journal of Biological Chemistry

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The Rho GDP dissociation inhibitor D4-GDI is overexpressed in some human breast cancer cell lines (Zhang, Y., and Zhang, B. (2006) Cancer Res. 66, 5592-5598). Here, we show that silencing of D4-GDI by RNA interference abrogates tumor growth and lung metastasis of otherwise highly invasive MDA-MB-231 breast cancer cells. Under anchorage-independent culture conditions, D4-GDI-depleted cells undergo rapid apoptosis (anoikis), which is known to hinder metastasis. We also found that D4-GDI associates with Rac1 and Rac3 in breast cancer cells, but not with other Rho GTPases tested (Cdc42, RhoA, RhoC, and TC10). Silencing of D4-GDI results in constitutive Rac1 activation and translocation from the cytosol to cellular membrane compartments and in sustained activation of p38 and JNK kinases. Rac1 blockade inhibits p38/JNK kinase activities and the spontaneous anoikis of D4-GDI knockdown cells. These results suggest that D4-GDI regulates cell function by interacting primarily with Rac GTPases and may play an integral role in breast cancer tumorigenesis. D4-GDI could prove to be a potential new target for therapeutic intervention.Human breast cancer is a heterogeneous disease with diverse metastatic behavior and treatment responses (1). Attempts to classify this disease into clinically relevant subtypes have yielded multiple sets of gene expression signatures of noninvasive and invasive breast cancers (2-6). However, only a few genes overlap among the results from different laboratories, and most of the genes are not yet characterized as functional mediators of breast cancer progression. The molecular basis of breast tumorigenesis remains to be fully understood.Rho GTPases, including Rac1, Rac3, Cdc42, and RhoA, are pivotal regulators of cell morphology, gene expression, cell proliferation, and apoptosis (7). The aberrant signaling through these molecules has been implicated in many aspects of tumorigenesis, including uncontrolled cell growth and metastatic phenotypes (8 -12). In particular, Rac1 and its isoforms are key regulators of malignant transformation and invasive behavior of cancer cells (13)(14)(15)(16)(17). This is achieved at least partially by their ability to control cell growth under anchorage-independent conditions and resistance to anoikis, apoptosis induced by loss of adhesion (18 -20).As molecular switches, Rac/Rho GTPases cycle between inactive GDP-bound and active GTP-bound states (21). Their biological activity is tightly controlled by the Rho-GDP dissociation inhibitors (RhoGDIs), 2 including RhoGDI (RhoGDI-1 or RhoGDI-␣), D4-GDI (RhoGDI-2 or RhoGDI-␤), and RhoGDI-3 (RhoGDI-␥). These proteins are thought to form stable complexes with individual Rho GTPases, thus keeping them in the cytosol. Upon growth factor stimulation, the GTPases are directed to effector sites, such as the plasma membrane, for activation (21-23). Thus, the expression levels of RhoGDIs relative to Rho GTPases must be precisely controlled to achieve normal cell function. RhoGDI binds most Rho GTPases in most types of cells (22). Ho...

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Section: Discussionmentioning

confidence: 99%

“…For instance, D4-GDI is widely expressed in hematopoietic tissues (24,25) and is selectively down-regulated in Hodgkin lymphoma cells compared with non-Hodgkin lymphoma (26). Moreover, D4-GDI is reduced as a function of disease progression in bladder cancer (27)(28)(29).…”

mentioning

confidence: 99%

Silencing of D4-GDI Inhibits Growth and Invasive Behavior in MDA-MB-231 Cells by Activation of Rac-dependent p38 and JNK Signaling

Zhang

Rosado

Moon

et al. 2009

Journal of Biological Chemistry

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“…For example, RhoGDI2 suppresses invasion and metastasis in bladder cancer and mouse lung cancer [[19,27,28,29] and is a positive prognostic factor [42]. Moreover, RhoGDI2 is selectively down-regulated in Hodgkin lymphoma cells compared with non-Hodgkin lymphoma [43]. But for gastric, ovarian and breast cancers, RhoGDI2 promoted their growth and invasion behavior [23,24,25,26].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of RhoGDI2 Mediated Lung Cancer Epithelial-Mesenchymal Transition Suppression

Huang¹,

Wu²,

Jiang³

et al. 2014

Cell Physiol Biochem

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Background: The aim of this study was to evaluate the function of RhoGDI2 in lung cancer epithelial-mesenchymal transition (EMT) process and to illustrate the underlying mechanisms that will lead to improvement of lung cancer treatment. Methods: The RhoGDI2 knock-down and overexpressing A549 cell lines were first constructed. The influence of RhoGDI2 on cytoskeleton in A549 cells was studied using two approaches: G-LISA-based Rac1 activity measurement and immunostaining-based F-actin distribution. The expression levels of key EMT genes were analyzed using real time quantitative polymerase chain reaction (RT-qPCR), western blot and immunostaining in untreated and RhoGDI2 knock-down or overexpressing A549 cells in both in vivo and in vitro experimental settings. Results: Our study showed that the activity of Rac1, a key gene that is crucial for the initiation and metastasis of human lung adenocarcinoma, causing the redistribution of F-actin with partial loss of cell-cell adhesions and stress fibers, was significantly suppressed by RhoGDI2. RhoGDI2 promoted the expression of EMT marker gene E-cadherin and repressed EMT promoting genes Slug, Snail, α-SMA in both A549 cells and lung and liver organs derived from the mouse models. Knocking-down RhoGDI2 induced abnormal morphology for lung organs. Conclusion: These findings indicate that RhoGDI2 repressed the activity of Rac1 and may be involved in the rearrangement of cytoskeleton in lung cancer cells. RhoGDI2 suppresses the metastasis of lung cancer mediated through EMT by regulating the expression of key genes such as E-cadherin, Slug, Snail and α-SMA in both in vivo and in vitro models.

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“…For example, RhoGDI2 suppresses invasion and metastasis in bladder cancer (3,5) and is a positive prognostic factor (6). Moreover, RhoGDI2 is selectively down-regulated in Hodgkin lymphoma cells compared with non-Hodgkin lymphoma (7). In contrast, RhoGDI2 is thought to be involved in the growth and invasive behavior in ovarian, breast and gastric cancers (8)(9)(10).…”

Section: Introductionmentioning

confidence: 96%

Expression profile of RhoGDI2 in lung cancers and role of RhoGDI2 in lung cancer metastasis

Huang

Li²,

Cheng³

et al. 2010

Oncol Rep

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Abstract. Rho GDP dissociation inhibitors (RhoGDIs) are important regulators of the GTP hydrolase activity and biological functions of Rho GTPases. RhoGDI2 has been shown to be a metastasis suppressor in bladder cancer and several other cancers. However, the underlying mechanism, effector targets, and the cognate biological functions of RhoGDI2 are not fully understood. To investigate the possible role of RhoGDI2 in lung cancer tumorigenesis and metastasis, the expression pattern of RhoGDI2 in various lung cancer tissue samples and lung cancer-derived cell lines were profiled at both mRNA and protein levels. Furthermore, possible interplay between PI3K/Akt/mTOR pathway activation/inhibition and RhoGDI2 signalling is examined in lung cancer-related cell lines. Our results suggest that RhoGDI2 is likely to be involved in lung tumor malignancy and metastasis.

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Loss of expression of LyGDI (ARHGDIB), a rho GDP‐dissociation inhibitor, in Hodgkin lymphoma^*

Cited by 45 publications

References 19 publications

Silencing of D4-GDI Inhibits Growth and Invasive Behavior in MDA-MB-231 Cells by Activation of Rac-dependent p38 and JNK Signaling

Silencing of D4-GDI Inhibits Growth and Invasive Behavior in MDA-MB-231 Cells by Activation of Rac-dependent p38 and JNK Signaling

Mechanisms of RhoGDI2 Mediated Lung Cancer Epithelial-Mesenchymal Transition Suppression

Expression profile of RhoGDI2 in lung cancers and role of RhoGDI2 in lung cancer metastasis

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Loss of expression of LyGDI (ARHGDIB), a rho GDP‐dissociation inhibitor, in Hodgkin lymphoma*

Cited by 45 publications

References 19 publications

Silencing of D4-GDI Inhibits Growth and Invasive Behavior in MDA-MB-231 Cells by Activation of Rac-dependent p38 and JNK Signaling

Silencing of D4-GDI Inhibits Growth and Invasive Behavior in MDA-MB-231 Cells by Activation of Rac-dependent p38 and JNK Signaling

Mechanisms of RhoGDI2 Mediated Lung Cancer Epithelial-Mesenchymal Transition Suppression

Expression profile of RhoGDI2 in lung cancers and role of RhoGDI2 in lung cancer metastasis

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Loss of expression of LyGDI (ARHGDIB), a rho GDP‐dissociation inhibitor, in Hodgkin lymphoma^*