A Critical Role for Rac1 in Tumor Progression of Human Colorectal Adenocarcinoma Cells

Espina, Carolina; Céspedes, María Virtudes; García‐Cabezas, Miguel Ángel; Pulgar, María Teresa Gómez del; Boluda, Alicia; Oroz, Lourdes García; Cejas, Paloma; Nistal, Manuel; Mangues, Ramón; Lacal, Juan Carlos

doi:10.2353/ajpath.2008.070561

Cited by 57 publications

(46 citation statements)

References 60 publications

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“…Expression of DN Rac1T17N led to a decrease in several markers of malignancy, including colony formation, migration and in vivo tumor growth (Kwei et al, 2006). Chan et al (2005) describe the role of Rac1 in human tumor cell invasion and recently a critical function for Rac1 in tumor progression of human colorectal adenocarcinoma cells was reported (Espina et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

et al. 2010

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Oncolytic Newcastle disease virus (NDV) replicates selectively in most human tumor cells but not in normal cells. The relationship between tumorigenesis and the selective susceptibility of most tumor cells to oncolytic NDV replication is poorly understood. A multistage skin carcinogenesis model derived from non-tumorigenic HaCaT cells was used to systematically investigate the molecular mechanisms involved in the oncolytic NDVsensitivity associated with tumorigenic transformation. No significant differences in interferon signaling were observed between the virus-sensitive tumor cells and the virus-resistant non-tumorigenic parental cells. Oncogenic H-Ras, which had been used for tumorigenic transformation, was shown to be necessary for virus replication but was not sufficient to render cells susceptible to NDV replication. By using an siRNA screening approach to search for virus-sensitizing genes in the tumorigenic cells, we could identify the small GTPase Rac1 as an oncogenic protein that is essential for NDV replication and anchorage-independent growth in tumorigenic cells. Furthermore, Rac1 expression was sufficient to render non-tumorigenic cells susceptible to NDV replication and to oncolytic cytotoxicity. This study establishes Rac1 as a link between tumorigenesis and oncolytic virus sensitivity in the HaCaT multistage skin carcinogenesis model.

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Section: Discussionmentioning

confidence: 99%

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

et al. 2010

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“…Indeed, altering Rac1 activation in a colon cancer cell line regulated tumor formation in mice (Espina et al, 2008) and deletion of the Rac1 gene in lung epithelium inhibited K-Ras-induced lung tumors (Kissil et al, 2007). The manner how Rac1 affects proliferation and apoptosis during tumorigenesis in vivo, however, was not studied.…”

Section: Rac1 In Skin Tumorsmentioning

confidence: 99%

“…In a colorectal carcinoma model involving orthotopic injection of adenocarcinoma cells into mice, Rac1 overexpression promoted, and Rac1 knockdown decreased tumor progression (Espina et al, 2008). More recently, activation of Rac proteins was described to be crucial for the development of chronic myelogenous leukemia (Thomas et al, 2007) and K-Ras-induced lung cancer (Kissil et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

et al. 2010

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Rac1 has a role in proliferation and survival of tumor cells in vitro. The exact effects of Rac1 on growth, apoptosis and corresponding signaling pathways during tumorigenesis in vivo, however, have not been explored yet. Using mice with a keratinocyte-restricted deletion of the Rac1 gene, we found that Rac1 is essential for DMBA/TPAinduced skin tumor formation. This corresponded to a decreased keratinocyte hyperproliferation, although apoptosis was not detectably altered. Activated Rac1 promoted Erk-dependent hyperproliferation by Pak1-mediated Mek activation independent of Mek1 phosporylation at serine 298. Rac1 was furthermore required for Pak2-dependent hyperactivation of Akt, which under in vivo condition was restricted to the suprabasal cell layers corresponding to a suprabasal-specific expression of Pak2. It is surprising that none of these signaling pathways was altered in untreated Rac1-deficient skin, indicating a hyperproliferation-specific function of Rac1 in vivo. These data suggest that blocking of Rac1 function might allow tumor-specific growth repression, as Rac1 is not required for normal growth and growth signaling controlling pathways in skin in vivo.

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“…Animals were kept until death. Next, a complete necropsy examination of each animal was performed as already described (Espina et al, 2008). Every visceral organ was formalin fixed and paraffin embedded in toto.…”

Section: Cell Lines Vector Constructions and Luciferase Assaymentioning

confidence: 99%

DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer

Moncho-Amor

Cáceres²,

Bandrés

et al. 2010

Oncogene

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DUSP1/MKP1 is a dual-specific phosphatase that regulates MAPKs activity, with an increasingly recognized role in tumor biology. To understand more about the involvement of DUSP1 in lung cancer, we performed gene expression analyses of parental and DUSP1-interfered H460 non-small-cell lung cancer (NSCLC) cells. Downregulation of DUSP1 induced changes in the expression levels of genes involved in specific biological pathways, including angiogenesis, MAP kinase phosphatase activity, cell-cell signaling, growth factor and tyrosine-kinase receptor activity. Changes in the expression of some of these genes were due to modulation of c-Jun-N-terminal kinase and/or p38 activity by DUSP1. Complementary functional assays were performed to focus on the implication of DUSP1 in angiogenesis and metastasis. In H460 cells, interference of DUSP1 resulted in a diminished capacity to invade through Matrigel, to grow tumors in nude mice and also to induce metastasis through tail-vein injection. Furthermore, the angiogenic potential of H460 cells was also impaired, correlating with a decrease in VEGFC production and indicating that DUSP1 could be required to induce angiogenesis. Finally, we studied whether a similar relationship occurred in patients. In human NSCLC specimens, DUSP1 was mainly expressed in those tumor cells close to CD31 vascular structures and a statistically significant correlation was found between VEGFC and DUSP1 expression. Overall, these results provide evidence for a role of DUSP1 in angiogenesis, invasion and metastasis in NSCLC.

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A Critical Role for Rac1 in Tumor Progression of Human Colorectal Adenocarcinoma Cells

Cited by 57 publications

References 60 publications

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer

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