Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases

Berenjeno, Inmaculada M.; Núñez, Fernando Rueda; Bustelo, Xosé R.

doi:10.1038/sj.onc.1210194

Cited by 42 publications

(72 citation statements)

References 27 publications

(27 reference statements)

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“…2B) and SUM1315 (data not shown) cells. Consistent with previous reports (22,25), we observed disassembly of actin fibers and reduction of stress fiber formation, with the density of actin meshwork reduced in these cells on Y27632 treatment ( Fig. 2C; Supplementary Fig.…”

Section: Resultssupporting

confidence: 81%

“…As observed by others (25), p-MLC is greatly decreased on Y27632 treatment in breast cancer cells (Fig. 2D), indicating that the reduction of ROCK activity by Y27632 leads to attenuation of its downstream targets.…”

Section: Resultssupporting

confidence: 60%

“…S3A). Previous studies also suggest that ROCK is implicated in the regulation of c-Myc (25,27,28). c-Myc plays a pivotal role in modulating cell division and transformation (29,30), and clinical studies have shown a strong association between overexpression of c-Myc and tumor metastasis (31)(32)(33).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of Rho-Associated Kinase Signaling Prevents Breast Cancer Metastasis to Human Bone

et al. 2009

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Rho-associated kinase (ROCK) signaling plays a fundamental role in regulating cell morphology, adhesion, and motility. Aberrant expression of ROCK is related to tumor metastases and poor clinical outcome. Here, we show that ROCK expression is increased in metastatic human mammary tumors and breast cancer cell lines compared with nonmetastatic tumors and cell lines. Overexpression of ROCK confers a metastatic phenotype on the nonmetastatic MCF-7 cell line. Inhibition of ROCK activity, by either a specific ROCK inhibitor (Y27632) or ROCK-targeted small interfering RNAs, reduces cell migration and proliferation in vitro and metastasis to bone in vivo using a novel "human breast cancer metastasis to human bone" mouse model. Expression of the c-Mycregulated miR-17-92 cluster is shown to be elevated in metastatic breast cancer cells compared with nonmetastatic cells and diminished by Y27632 treatment. Furthermore, blockade of miR-17 is shown to decrease breast cancer cell invasion/ migration in vitro and metastasis in vivo. Together, these findings suggest that augmented ROCK signaling contributes to breast cancer metastasis. The effects of ROCK on tumor cell invasion/motility and growth may derive from regulating cytoskeletal actin-myosin contraction and modulating the c-Myc pathway, including c-Myc-dependent microRNAs. Inhibition of ROCK or the pathway it stimulates, therefore, may represent a novel approach for treatment of breast cancer metastases. [Cancer Res 2009;69(22):8742-51]

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Section: Resultssupporting

confidence: 81%

Section: Resultssupporting

confidence: 60%

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Inhibition of Rho-Associated Kinase Signaling Prevents Breast Cancer Metastasis to Human Bone

et al. 2009

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“…Gene sets used in this analysis were described previously [GSE3151, GSE3158 ] or were generated from existing datasets. Additional datasets for pathway signatures were: STAT3 (Dauer et al, 2005), TNF [GSE2638 and GSE2639 (Viemann et al, 2006)], RHOA [GSE5913 (Berenjeno et al, 2007)], TGFβ [GSE1724 (Renzoni et al, 2004)], endotoxin [GSE3284 (Calvano et al, 2005)] and immune (Galon et al, 2006). The signatures were applied to several datasets including the developmental dataset [http://breast-cancer-research.com/content/ supplementary/bcr753-s1.txt ] and the pubertal dataset [GSE6453 (McBryan et al, 2007)].…”

Section: Pathway Signaturesmentioning

confidence: 99%

Patterns of cell signaling pathway activation that characterize mammary development

et al. 2008

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Previous work has detailed the histological and biochemical changes associated with mammary development and remodeling. We have now made use of gene expression profiling, and in particular of the previously described signatures of cell signaling pathway activation, to explore the events associated with mammary gland development. We find that there is elevated E2F-specific pathway activity prior to lactation and relatively low levels of other important signaling pathways, such as RAS, MYC and SRC. Upon lactation and continuing into the involution phase, these patterns reverse with a dramatic increase in RAS, SRC and MYC pathway activity and a decline in E2F activity. At the end of involution, these patterns return to that of the adult non-lactating mammary gland. The importance of the changes in E2F pathway activity, particularly during the proliferative phase of mammary development, was confirmed through the analysis of mice deficient for various E2F proteins. Taken together, these results reveal a complex pattern of pathway activity in relation to the various phases of mammary gland development.

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“…Evidence has indicated that cross-talk between c-Myc and RhoA influences their expression. Myc RNA and protein levels were increased in 3T3 cells transformed with constitutively active RhoA (35). Myc is part of a complex that binds to the RhoA promoter, and Myc-induced RhoA transcription promotes cell migration and invasion (22).…”

Section: Discussionmentioning

confidence: 99%

Cooperative antiproliferative effect of coordinated ectopic expression of DLC1 tumor suppressor protein and silencing of MYC oncogene expression in liver cancer cells: Therapeutic implications

Yang¹,

Zhou²,

Tone

et al. 2016

Oncology Letters

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Abstract. Human hepatocellular carcinoma (HCC) is one of the most common types of cancer and has a very poor prognosis; thus, the development of effective therapies for the treatment of advanced HCC is of high clinical priority. In the present study, the anti-oncogenic effect of combined knockdown of c-Myc expression and ectopic restoration of deleted in liver cancer 1 (DLC1) expression was investigated in human liver cancer cells. Expression of c-Myc in human HCC cells was knocked down by stable transfection with a Myc-specific short hairpin (sh) RNA vector. DLC1 expression in Huh7 cells was restored by adenovirus transduction, and the effects of DLC1 expression and c-Myc knockdown on Ras homolog gene family, member A (RhoA) levels, cell proliferation, soft agar colony formation and cell invasion were measured. Downregulation of c-Myc or re-expression of DLC1 led to a marked reduction in RhoA levels, which was associated with decreases in cell proliferation, soft agar colony formation and invasiveness; this inhibitory effect was augmented with a combination of DLC1 transduction and c-Myc suppression. To determine whether liver cell-specific delivery of DLC1 was able to enhance the inhibitory effect of c-Myc knockdown on tumor growth in vivo, DLC1 vector DNA complexed with galactosylated polyethylene glycol-linear polyethyleneimine was administered by tail vein injection to mice bearing subcutaneous xenografts of Huh7 cells transfected with shMyc or control shRNA. A cooperative inhibitory effect of DLC1 expression and c-Myc knockdown on the growth of Huh7-derived tumors was observed, suggesting that targeted liver cell delivery of DLC1 and c-Myc shRNA may serve as a possible gene therapy modality for the treatment of human HCC. IntroductionHuman hepatocellular carcinoma (HCC) is one of the most common and lethal types of cancer, and its incidence is increasing worldwide (1,2). As numerous cases of HCC are diagnosed at later stages when the prognosis is poor, the development of effective therapy for advanced and metastatic HCC is a high clinical priority (1,2). HCC is a heterogeneous disorder with a complex pattern of genetic alterations, and increasing our knowledge of the specific genes and signaling pathways involved in the pathogenesis of HCC is critical for identifying novel clinical tools for diagnosis, classification and targeted therapy of the disease (3,4).Despite the heterogeneity of genomic alterations in HCC, certain chromosomes or chromosomal sites are more frequently deleted or amplified, resulting in deregulation of crucial genes that may ultimately trigger malignant transformation of healthy hepatocytes (5). Chromosome 8 exhibits a highly recurrent pattern of DNA copy number loss on the short arm (8p21-p22) and gain on the long arm (8q22-q24) (5,6), and these genetic alterations are associated with HCC subclasses with a less favorable outcome (7). The 8p and 8q sites correspond with the loci of the tumor suppressor gene deleted in liver cancer 1 (DLC1) and the c-Myc proto-oncogene, respectively (8...

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Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases

Cited by 42 publications

References 27 publications

Inhibition of Rho-Associated Kinase Signaling Prevents Breast Cancer Metastasis to Human Bone

Inhibition of Rho-Associated Kinase Signaling Prevents Breast Cancer Metastasis to Human Bone

Patterns of cell signaling pathway activation that characterize mammary development

Cooperative antiproliferative effect of coordinated ectopic expression of DLC1 tumor suppressor protein and silencing of MYC oncogene expression in liver cancer cells: Therapeutic implications

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