Rho GTPase expression in tumourigenesis: Evidence for a significant link

Pulgar, Teresa Gómez del; Benitah, Salvador Aznar; Valerón, Pilar F.; Espina, Carolina; Lacal, Juan Carlos

doi:10.1002/bies.20238

Cited by 207 publications

(179 citation statements)

References 90 publications

(89 reference statements)

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“…Indeed, it has been clearly established that the family of Rho proteins (RhoA, RhoB, and RhoC) play a central role in a wide array of cellular responses involving changes in the actin cytoskeleton. Strikingly, in light of our data, previous studies have shown that Rho-regulated cellular events include alterations in both epithelial shape and motility (71,72), two processes clearly evident upon MT1-MMP overexpression in our keratinocyte model system. In our studies we also demonstrate that the phenotypic changes induced by MT1-MMP in keratinocytes involve ROCK1/ROCK2 and non-muscle myosin downstream of Rho activation.…”

Section: Discussionsupporting

confidence: 78%

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Dangi-Garimella

Redig

Shields

et al. 2010

Journal of Biological Chemistry

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Matrix metalloproteinases (MMPs) 2 are a large family of highly conserved metalloendopeptidases with proteolytic activity directed against a variety of extracellular matrix (ECM) substrates (1-3). MMPs have been implicated in basement membrane proteolysis, activation of growth factors, and cleavage of cell-adhesion molecules. Extending mechanistic investigation to cancer biology, numerous studies have shown that MMP overexpression enhances the invasive activity of tumor cell lines (4 -6). Analysis of human disease further supports the pro-tumorigenic role of MMPs, as increased expression of these proteases in tumor samples is clinically associated with invasion, metastasis, poor prognosis, and shorter survival times (7,8). In the specific case of squamous cell carcinoma (SCC), increased expression of membrane type 1-MMP (MT1-MMP, MMP14) is associated with ECM breakdown, tissue invasion, and lymph node metastasis (8).However, several animal studies have now clearly demonstrated that multiple members of the MMP family provide a paradoxically protective effect during the relentless molecular destruction that characterizes malignant progression. MMPs may have been initially identified as potent pro-tumorigenic proteases, but their simultaneous ability to function in an opposing, anti-tumorigenic role is now equally well established (9, 10). Such data underscore both the complexity of MMP activity in cellular signaling events as well as the importance of stringently evaluating the context in which these proteases take on either an anti-tumorigenic or pro-tumorigenic role. Intriguingly, several recent studies using SCC models have begun to suggest a putative mechanism through which MMPs may be induced to function primarily as anti-tumorigenic proteases. When exposed to carcinogens, MMP3-null mice developed squamous cell skin cancers that not only grew faster but were also strikingly less differentiated than those of control animals (11). Significantly, orthotopic injection of MMP3-expressing tumor cells resulted in pronounced tumor cell differentiation (12). However, although such findings indicate that MMPs may inhibit SCC progression by promoting tumor cell differentiation, the precise mechanism through which these proteinases regulate this process has not yet been elucidated.In normal tissue keratinocyte differentiation is a complex process mediated by cell-ECM and cell-cell interactions that subsequently activate downstream signaling pathways (13-15). Specifically, among structural proteins, integrins mediate primarily cell-ECM interactions, whereas cadherins are responsible for cell-cell interactions (13). In vitro activation of integrins or inhibition of cadherins after ligation or dominant negative expression, respectively, results in negative regulation of human keratinocyte differentiation (16 -18). Furthermore, beyond structural proteins, Rho GTPases are also known to be an important component of keratinocyte differentiation pathways. Rho signaling has been shown to mediate cell-cell and cell-matrix adhesion...

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Section: Discussionsupporting

confidence: 78%

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Dangi-Garimella

Redig

Shields

et al. 2010

Journal of Biological Chemistry

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“…RhoBTB3 is a member of the RHOBTB subfamily of Rho GTPases that play a role in mediating cell size, proliferation, apoptosis, survival, polarity, call adhesion and membrane trafficking [36]. Recent studies have suggested that RhoB is involved in tumor suppression.…”

Section: Discussionmentioning

confidence: 99%

Microarray Analysis Reveals Distinct Gene Expression Profiles Among Different Tumor Histology, Stage and Disease Outcomes in Endometrial Adenocarcinoma

et al. 2010

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BackgroundEndometrial cancer is the most common gynecologic malignancy in developed countries and little is known about the underlying mechanism of stage and disease outcomes. The goal of this study was to identify differentially expressed genes (DEG) between late vs. early stage endometrioid adenocarcinoma (EAC) and uterine serous carcinoma (USC), as well as between disease outcomes in each of the two histological subtypes.Methodology/Principal FindingGene expression profiles of 20 cancer samples were analyzed (EAC = 10, USC = 10) using the human genome wide illumina bead microarrays. There was little overlap in the DEG sets between late vs. early stages in EAC and USC, and there was an insignificant overlap in DEG sets between good and poor prognosis in EAC and USC. Remarkably, there was no overlap between the stage-derived DEGs and the prognosis-derived DEGs for each of the two histological subtypes. Further functional annotation of differentially expressed genes showed that the composition of enriched function terms were different among different DEG sets. Gene expression differences for selected genes of various stages and outcomes were confirmed by qRT-PCR with a high validation rate.ConclusionThis data, although preliminary, suggests that there might be involvement of distinct groups of genes in tumor progression (late vs. early stage) in each of the EAC and USC. It also suggests that these genes are different from those involved in tumor outcome (good vs. poor prognosis). These involved genes, once clinically verified, may be important for predicting tumor progression and tumor outcome.

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“…Many lines of evidence now show that Rho GTPases are involved in cancer initiation and progression (Vega and Ridley, 2008). However, unlike mutational activation of Ras that is observed in many human cancers, it appears that it is the expression of Rho proteins and their regulators that is altered in many cancer types (Go´mez del Pulgar et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Northey

Primeau

et al. 2010

Oncogene

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RhoA, Rac1 and Cdc42, the best-characterized members of the Rho family of small GTPases, are critical regulators of many cellular activities. Cdc42 GTPaseactivating protein (CdGAP) is a serine-and proline-rich RhoGAP protein showing GAP activity against both Cdc42 and Rac1 but not RhoA. CdGAP is phosphorylated downstream of the MEK-ERK (extracellular signalregulated kinase) pathway in response to serum and is required for normal cell spreading and polarized lamellipodia formation. In this study, we found that CdGAP protein and mRNA levels are highly increased in mammary tumor explants expressing an activated Neu/ ErbB-2 (Neu-NT) receptor. In response to transforming growth factor-b (TGFb) stimulation, Neu-NT-expressing mammary tumor explants demonstrate a clear induction in cell motility and invasion. We show that downregulation of CdGAP expression by small interfering RNA abrogates the ability of TGFb to induce cell motility and invasion of Neu-NT-expressing mammary tumor explants. However, it has no effect on TGFb-mediated cell adhesion on type 1 collagen and fibronectin. Interestingly, protein expression of E-Cadherin is highly increased in Neu-NT-expressing mammary tumor explants depleted of CdGAP. In addition, complete loss of E-Cadherin expression is not observed in CdGAP-depleted cells during TGFb-mediated epithelial to mesenchymal transition. Downregulation of the CdGAP expression also decreases cell proliferation of Neu-NT-expressing mammary tumor explants independently of TGFb. Rescue analysis using re-expression of various CdGAP deletion-mutant proteins revealed that the proline-rich domain (PRD) but not the GAP domain of CdGAP is essential to mediate TGFbinduced cell motility and invasion. Finally, we found that TGFb induces the expression and phosphorylation of CdGAP in mammary epithelial NMuMG cells. Taken together, these studies identify CdGAP as a novel molecular target in TGFb signaling and implicate CdGAP as an essential component in the synergistic interaction between TGFb and Neu/ErbB-2 signaling pathways in breast cancer cells.

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Rho GTPase expression in tumourigenesis: Evidence for a significant link

Cited by 207 publications

References 90 publications

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Microarray Analysis Reveals Distinct Gene Expression Profiles Among Different Tumor Histology, Stage and Disease Outcomes in Endometrial Adenocarcinoma

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

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