Evidence for protein 4.1B acting as a metastasis suppressor

Cavanna, Tamara; Pokorná, Eva; Veselý, Pavel; Gray, Colin; Zicha, Daniel

doi:10.1242/jcs.000273

Cited by 32 publications

(35 citation statements)

References 31 publications

(31 reference statements)

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“…To study the changes related to acquisition of invasive potential, we used a sarcoma model of metastasis consisting of parental nonmetastatic K2 cells and highly metastatic A3 cells derived from K2 cells (7). Because sarcoma cells are of mesenchymal origin and are thought to use the mesenchymal mode of invasion that is dependent on extracellular protease activity (8), we analyzed the gelatinase activity of K2 and A3 cells.…”

Section: Resultsmentioning

confidence: 99%

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Up-Regulation of Rho/ROCK Signaling in Sarcoma Cells Drives Invasion and Increased Generation of Protrusive Forces

Rösel

Brábek

Tolde

et al. 2008

Molecular Cancer Research

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Tumor cell invasion is the most critical step of metastasis. Determination of the mode of invasion within the particular tumor is critical for effective cancer treatment. Protease-independent amoeboid mode of invasion has been described in carcinoma cells and more recently in sarcoma cells on treatment with protease inhibitors. To analyze invasive behavior, we compared highly metastatic sarcoma cells with parental nonmetastatic cells. The metastatic cells exhibited a functional up-regulation of Rho/ROCK signaling and, similarly to carcinoma cells, an amoeboid mode of invasion. Using confocal and traction force microscopy, we showed that an up-regulation of Rho/ROCK signaling leads to increased cytoskeletal dynamics, myosin light chain localization, and increased tractions at the leading edge of the cells and that all of these contributed to increased cell invasiveness in a three-dimensional collagen matrix. We conclude that cells of mesenchymal origin can use the amoeboid nonmesenchymal mode of invasion as their primary invading mechanism and show the dependence of ROCK-mediated amoeboid mode of invasion on the increased capacity of cells to generate force.

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Section: Resultsmentioning

confidence: 99%

“…This rat sarcoma model in which two closely related cell populations have greatly different capacities to induce metastases in animals offers specific advantages for studying in vitro metastatic transformation (7). In particular, the close genetic relationship of the cell lines provides a ''uniform'' genetic background.…”

Section: Introductionmentioning

confidence: 99%

Up-Regulation of Rho/ROCK Signaling in Sarcoma Cells Drives Invasion and Increased Generation of Protrusive Forces

Rösel

Brábek

Tolde

et al. 2008

Molecular Cancer Research

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“…Decreased motility and increased adhesion due to EPB41L3 re/overexpression has been shown in several different cancer cell lines (29,30). Furthermore, siRNA knockdown of EPB41L3 in nonmetastatic cell lines stimulated migration and the loss of actin stress fibers (31). As detachment of tumor cells from the primary tumor and migration into the surrounding tissue is the first step of the metastatic cascade (32), these functions of EPB41L3 indicate a possible metastasis suppressor activity (33).…”

Section: Discussionmentioning

confidence: 99%

miRNA-223 Promotes Gastric Cancer Invasion and Metastasis by Targeting Tumor Suppressor EPB41L3

Zhang²,

Zhang³

et al. 2011

Molecular Cancer Research

322

234

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Traditional research modes aim to find cancer-specific single therapeutic target. Recently, emerging evidence suggested that some micro-RNAs (miRNA) can function as oncogenes or tumor suppressors. miRNAs are singlestranded, small noncoding RNA genes that can regulate hundreds of downstream target genes. In this study, we evaluated the miRNA expression patterns in gastric carcinoma and the specific role of miR-223 in gastric cancer metastasis. miRNA expression signature was first analyzed by real-time PCR on 10 paired gastric carcinomas and confirmed in another 20 paired gastric carcinoma tissues. With the 2-fold expression difference as a cutoff level, we identified 22 differential expressed mature miRNAs. Sixteen miRNAs were upregulated in gastric carcinoma, including miR-223, miR-21, miR-23b, miR-222, miR-25, miR-23a, miR-221, miR-107, miR-103, miR-99a, miR-100, miR-125b, miR-92, miR-146a, miR-214 and miR-191, and six miRNAs were downregulated in gastric carcinoma, including let-7a, miR-126, miR-210, miR-181b, miR-197, and miR-30aa-5p. After examining these miRNAs in several human gastric originated cell lines, we found that miR-223 is overexpressed only in metastatic gastric cancer cells and stimulated nonmetastatic gastric cancer cells migration and invasion. Mechanistically, miR-223, induced by the transcription factor Twist, posttranscriptionally downregulates EPB41L3 expression by directly targeting its 3 0 -untranslated regions. Significantly, overexpression of miR-223 in primary gastric carcinomas is associated with poor metastasis-free survival. These findings indicate a new regulatory mode, namely, specific miRNA, which is activated by its upstream transcription factor, could suppress its direct targets and lead to tumor invasion and metastasis. Mol Cancer Res; 9(7); 824-33. Ó2011 AACR.

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“…Thirty-eight of these cross-validated in the two screens ( Supplementary Figure 4). Figure 2a shows side views of representative stacks in which knockdown of 4.1B was used as a positive control (Cavanna et al, 2007). We decided to focus on the RSK family as a paradigm to validate the importance of our screen and because of our previous interest in S6 kinases (Pardo et al, 2001.…”

Section: Identification Of Novel Regulators Of Cell Motility In Lung mentioning

confidence: 99%

“…Stacks were analysed with Mathematica (Wolfram Research). siRNAs targeting 4.1B were used as positive control (Cavanna et al, 2007).…”

Section: Invasion Assaymentioning

confidence: 99%

An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis

et al. 2011

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We performed a kinome-wide siRNA screen and identified 70 kinases altering cell migration in A549 lung cancer cells. In particular, ribosomal S6 kinase 1 (RSK1) silencing increased, whereas RSK2 and RSK4 downregulation inhibited cell motility. In a secondary collagenbased three-dimensional invasion screen, 38 of our hits cross-validated, including RSK1 and RSK4. In two further lung cancer cell lines, RSK1 but not RSK4 silencing showed identical modulation of cell motility. We therefore selected RSK1 for further investigation. Bioinformatic analysis followed by co-immunoprecipitation-based validation revealed that the actin regulators VASP and Mena interact with RSK1. Moreover, RSK1 phosphorylated VASP on T278, a site regulating its binding to actin. In addition, silencing of RSK1 enhanced the metastatic potential of these cells in vivo using a zebrafish model. Finally, we investigated the relevance of this finding in human lung cancer samples. In isogenically matched tissue, RSK1 was reduced in metastatic versus primary lung cancer lesions. Moreover, patients with RSK1-negative lung tumours showed increased number of metastases. Our results suggest that the findings of our high-throughput in vitro screen can reliably identify relevant clinical targets and as a proof of principle, RSK1 may provide a biomarker for metastasis in lung cancer patients.

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Evidence for protein 4.1B acting as a metastasis suppressor

Abstract: SummaryEvidence for protein 4.1B acting as a metastasis suppressor

Cited by 32 publications

References 31 publications

Up-Regulation of Rho/ROCK Signaling in Sarcoma Cells Drives Invasion and Increased Generation of Protrusive Forces

Up-Regulation of Rho/ROCK Signaling in Sarcoma Cells Drives Invasion and Increased Generation of Protrusive Forces

miRNA-223 Promotes Gastric Cancer Invasion and Metastasis by Targeting Tumor Suppressor EPB41L3

An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis

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