Cdc42 promotes transendothelial migration of cancer cells through β1 integrin

Reymond, Nicolas; Im, Jae Hong; Garg, Ritu; Vega, Francisco; d’Água, Bárbara Borda; Riou, Philippe; Cox, Susan; Valderrama, Ferran; Muschel, Ruth J.; Ridley, Anne J.

doi:10.1083/jcb.201205169

Cited by 167 publications

(193 citation statements)

References 44 publications

(69 reference statements)

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“…Migration of cancer cells through the endothelial lining of the blood vessels is a critical step of extravasation (39,40). To obtain more direct evidence for the contribution of E6AP to tumor cell extravasation, we measured their ability to cross an endothelial barrier using the transendothelial migration assay.…”

Section: E6ap Expression Impedes Tumor Cell Colonizationmentioning

confidence: 99%

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

et al. 2016

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Metastatic disease is the major cause of breast cancer-related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonization, and metastasis in mice, and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for basal breast cancer. E6AP regulates actin cytoskeletal remodeling via regulation of Rho GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodeling through the control of ECT2 and Rho GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer.Cancer Res; 76(14); 4236-48. Ó2016 AACR.

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Section: E6ap Expression Impedes Tumor Cell Colonizationmentioning

confidence: 99%

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

et al. 2016

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“…Cdc42 was initially identified as a mediator of cell polarity and division in Saccharomyces cerevisiae [24, 25]. Recent studies show that deregulation of Cdc42 is involved in the activation of many cellular cascades such as cell polarity, cytoskeleton remolding, proliferation, migration, adhesion membrane trafficking, and transportation, and leads to the development of many pathological disorders including cancers in humans [26-28]. Stimulation of the G-protein-coupled receptor kinase interacting protein 1 (GIT1)-Rac/Cdc42 axis is important for cell motility in NSCLC, and thus activating of Rac1/Cdc42 is critical for the GIT1-induced invasiveness of NSCLC [29].…”

Section: Discussionmentioning

confidence: 99%

The Long Intergenic Noncoding RNA 00707 Promotes Lung Adenocarcinoma Cell Proliferation and Migration by Regulating Cdc42

Zou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lung cancer (LC) is a serious disease with high morbidity and mortality. Long noncoding RNAs (lncRNAs) have garnered attention because they participate in diverse human disorders, including cancer. Our study examined the long intergenic noncoding RNA 00707 (LINC00707). The effects of LINC00707 on lung adenocarcinoma (LAD) and molecular mechanisms are unclear. This study is aimed to investigate the role of LINC00707 in the malignant processes of LAD. Methods: Quantitative reverse transcription PCR (qRT-PCR) was used to examine the expression level of LINC00707 in tissues and cell lines. The association of LINC00707 expression and postoperative prognosis was analyzed by the Kaplan-Meier method and log-rank test. Cell proliferation was evaluated in vitro and in vivo. Transwell assays were performed to examine cell migration. Cell cycle and apoptosis was determined by flow -cytometric and western blot analyses. Microarray analysis was conducted to screen for the downstream target gene Cdc42 of LINC00707, which was identified by qRT-PCR, functional analysis, and rescue experiment. Results: The expression level of LINC00707 was clearly upregulated in LAD tissues compared to that in corresponding normal tissues. Its overexpression was related to advanced TNM stage, larger tumor size, lymphatic metastasis, and poor prognosis. Functional assays revealed that LINC00707 knockdown repressed LAD cell proliferation both in vitro and in vivo. This process may involve the inducing of G1 arrest and apoptosis. Moreover, cell migration was impaired after LINC00707 inhibition. Microarray analysis and rescue assays suggested that Cdc42 is an important target gene involved in the carcinogenesis of LINC00707. Conclusions: In summary, LINC00707 is a noncoding oncogene that exerts important regulatory functions in LAD, suggesting its potential as a biomarker in the prognosis and treatment of LAD.

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“…It was initially identified in Saccharomyces cerevisiae as a cell-cycle mutant that contributed to the regulation of budding and mating projection (39). Previous studies have demonstrated that CDC42 is involved in cell proliferation, cell cycle progression, cytoskeletal remodeling, migration and invasion (40)(41)(42)(43). Consistent with its important functions in these distinct physiological and pathological processes, abnormal expression of CDC42 has been identified in numerous diseases, particularly in human cancer.…”

Section: Cdc42 Is Involved In Mir29a-induced Effects In Nsclc Cellsmentioning

confidence: 84%

MicroRNA-29a functions as a potential tumor suppressor through directly targeting CDC42 in non-small cell lung cancer

Wang

et al. 2017

Oncology Letters

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Abstract. The expression and function of microRNA-29a (miR-29a) have been investigated in various types of cancer. In the present study, the expression, function and underlying molecular mechanism of miR-29a were investigated in non-small cell lung cancer (NSCLC). The expression level of miR-29a in NSCLC was determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, migration and invasion ability were determined using Cell Counting Kit-8, cell migration and invasion assays, respectively. Bioinformatics analysis and dual-luciferase reporter assays were performed to determine whether cell division cycle 42 (CDC42) is a direct target gene of miR-29a. To assess CDC42 mRNA and protein expression following transfection with miR-29a, RT-qPCR and western blotting were performed. Following knockdown of CDC42, functional assays were performed to investigate the roles of CDC42 in NSCLC. The results demonstrated that miR-29a was downregulated in NSCLC and the decreased expression level of miR-29a was significantly associated with advanced tumor-node-metastasis classification and metastasis. In addition, upregulation of miR-29a inhibited cell proliferation, migration and invasion in NSCLC, whereas downregulation of miR-29a had the opposite effects. Furthermore, CDC42 was identified as a direct target gene of miR-29a in vitro. miR-29a was demonstrated to function as a tumor suppressor in NSCLC by directly targeting CDC42 and may be investigated further as a target therapy for NSCLC.

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Cdc42 promotes transendothelial migration of cancer cells through β1 integrin

Abstract: Cdc42 induces β1 integrin expression at the transcriptional level via the transcription factor SRF to promote cancer cell interaction with endothelial cells.

Cited by 167 publications

References 44 publications

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

The Long Intergenic Noncoding RNA 00707 Promotes Lung Adenocarcinoma Cell Proliferation and Migration by Regulating Cdc42

MicroRNA-29a functions as a potential tumor suppressor through directly targeting CDC42 in non-small cell lung cancer

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