Downregulation of Rap1GAP through Epigenetic Silencing and Loss of Heterozygosity Promotes Invasion and Progression of Thyroid Tumors

Zuo, Hui; Gandhi, Manoj; Edreira, Martín M.; Hochbaum, Daniel; Nimgaonkar, Vishwajit L.; Zhang, Ping; DiPaola, James; Evdokimova, Viktoria; Altschuler, Daniel L.; Nikiforov, Yuri E.

doi:10.1158/0008-5472.can-09-2812

Cited by 83 publications

(79 citation statements)

References 21 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although a role for tumor-suppressor genes in thyroid carcinogenesis has not been assessed yet, functional studies have allowed some genes downregulated in PTCs to be classified as tumor suppressors, based on their ability to modulate transformed properties of thyroid tumor cell lines (Ferrario et al, 2008;Latini et al, 2008;Pallante et al, 2008;Vizioli et al, 2010;Zuo et al, 2010). With this study, we have demonstrated that TIMP3 exerts a negative regulatory role in thyroid tumor cells, thus corroborating its oncosuppressor role suggested by hypermetylation and gene expression studies.…”

Section: Discussionsupporting

confidence: 75%

“…Putative oncosuppressor genes relevant for thyroid carcinomas have been suggested by methylation studies (Xing 2007(Xing , 2008. In the past few years, some genes identified as downregulated in the context of gene expression studies were classified as tumor suppressors by functional studies, as their re-expression modulated transformed properties of thyroid carcinoma cell lines (Ferrario et al, 2008;Latini et al, 2008;Pallante et al, 2008;Vizioli et al, 2010;Zuo et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

et al. 2011

View full text Add to dashboard Cite

Papillary thyroid carcinoma (PTC) arises from the thyroid follicular epithelium and represents the most frequent thyroid malignancy. PTC is associated with gene rearrangements generating RET/PTC and TRK oncogenes, and to the BRAFV600E activating point mutation. A role of tumor-suppressor genes in the pathogenesis of PTC has not been assessed yet. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene, encoding a metalloproteinases inhibitor and capable of inhibiting growth, angiogenesis, invasion and metastasis of several cancers, was found to be silenced by promoter methylation in a consistent fraction of PTCs, in association with tumor aggressiveness and BRAFV600E mutation, thus suggesting an oncosuppressor role. To explore this possibility, in this study we performed gene expression and functional studies. Analysis of gene expression data produced in our laboratory as well as meta-analysis of publicly available data sets confirmed the downregulation of TIMP3 gene expression in PTC with respect to normal thyroid. The functional consequences of TIMP3 downregulation were investigated in the PTC-derived NIM1 cell line, in which the expression of TIMP3 is silenced. Restoration of TIMP3 expression by exposure to soluble TIMP3 protein or by complementary DNA transfection had no effect on the growth rate of NIM1 cells. Instead, it affected the adhesive, migratory and invasive capabilities of NIM1 cells by modulating several proteins involved in these processes. A striking effect was observed in vivo, as TIMP3 reduced the tumorigenicity of NIM1 cells by repressing angiogenesis and macrophage infiltration. Our data indicate that the loss of TIMP3 expression exerts a functional role in the pathogenesis of PTC.

show abstract

Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

et al. 2011

View full text Add to dashboard Cite

show abstract

“…7A) and previous studies suggest Rap1GAP and its family members Rap1GAPII, Spa1/SIPA1, and E6TP1 possess tumor metastasis suppressor activities. Rap1GAP protein levels are decreased in several types of cancer, including pancreatic adenocarcinoma (55), papillary thyroid carcinoma (56,57), colorectal carcinoma (58), and melanoma (59). The implication of Rap1GAP as a tumor suppressor was largely deduced based upon experimental results using forced overexpression of full-length Rap1GAP (60,61).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Regulates Renal Cell Carcinoma Invasion through the EP4 Receptor-Rap GTPase Signal Transduction Pathway

Zhang

Frilot

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Prognosis for patients with early stage kidney cancer has improved, but the treatment options for patients with locally advanced disease and metastasis remain few. Understanding the molecular mechanisms that regulate invasion and metastasis is critical for developing successful therapies to treat these patients. Proinflammatory prostaglandin E 2 plays an important role in cancer initiation and progression via activation of cognate EP receptors that belong to the superfamily of G proteincoupled receptors. Here we report that prostaglandin E 2 promotes renal cancer cell invasion through a signal transduction pathway that encompasses EP4 and small GTPase Rap. Inactivation of Rap signaling with Rap1GAP, like inhibition of EP4 signaling with ligand antagonist or knockdown with shRNA, reduces the kidney cancer cell invasion. Human kidney cells evidence increased EP4 and decreased Rap1GAP expression levels in the malignant compared with benign samples. These results support the idea that targeted inhibition of EP4 signaling and restoration of Rap1GAP expression constitute a new strategy to control kidney cancer progression.

show abstract

“…Rap1GAP protein levels are decreased in pancreatic adenocarcinomas (53), papillary thyroid carcinomas (37,47,57), and melanomas (56). Rap1GAP downregulation has been shown to arise as a consequence of proteasomal degradation (46), loss of heterozygosity (37,53), and promoter methylation (56,57).…”

mentioning

confidence: 99%

Downregulation of Rap1GAP in Human Tumor Cells Alters Cell/Matrix and Cell/Cell Adhesion

Tsygankova

Tang

et al. 2010

Molecular and Cellular Biology

View full text Add to dashboard Cite

Rap1GAP expression is decreased in human tumors. The significance of its downregulation is unknown. We show that Rap1GAP expression is decreased in primary colorectal carcinomas. To elucidate the advantages conferred on tumor cells by loss of Rap1GAP, Rap1GAP expression was silenced in human colon carcinoma cells. Suppressing Rap1GAP induced profound alterations in cell adhesion. Rap1GAP-depleted cells exhibited defects in cell/cell adhesion that included an aberrant distribution of adherens junction proteins. Depletion of Rap1GAP enhanced adhesion and spreading on collagen. Silencing of Rap expression normalized spreading and restored E-cadherin, ␤-catenin, and p120-catenin to cell/cell contacts, indicating that unrestrained Rap activity underlies the alterations in cell adhesion. The defects in adherens junction protein distribution required integrin signaling as E-cadherin and p120-catenin were restored at cell/cell contacts when cells were plated on poly-L-lysine. Unexpectedly, Src activity was increased in Rap1GAP-depleted cells. Inhibition of Src impaired spreading and restored E-cadherin at cell/cell contacts. These findings provide the first evidence that Rap1GAP contributes to cell/cell adhesion and highlight a role for Rap1GAP in regulating cell/matrix and cell/cell adhesion. The frequent downregulation of Rap1GAP in epithelial tumors where alterations in cell/cell and cell/matrix adhesion are early steps in tumor dissemination supports a role for Rap1GAP depletion in tumor progression.Mammalian Rap proteins Rap1a/b and Rap2a/b/c are members of the Ras superfamily of small GTPases. Rap proteins are active when bound to GTP and inactive when bound to GDP. Cellular Rap activity is regulated by the concerted action of guanine nucleotide exchange factors that activate Rap (RapGEFs) and Rap-specific GTPaseactivating proteins (RapGAPs) that inactivate Rap (reviewed in reference 10). The Rap1GAP family is composed of several members, including Rap1GAP, Rap1GAPII, Spa-1/SIPA1, and E6TP1/SIPA1L1. Several lines of evidence suggest that RapGAPs function as tumor and/or invasion suppressors. Downregulation of E6TP1 by human papillomavirus protein E6 contributes to cervical cancer (20, 21), and Spa-1 deficiency in mice induces a spectrum of myelodysplastic disorders similar to chronic myelogenous leukemia (26). The SPA1 gene was identified as a candidate for the metastasis efficiency modifier locus in mice (38). Although the relevance of this observation to humans is not yet clear, single-nucleotide polymorphisms in the SPA1 gene in human breast tumors have been associated with lymph node involvement and poor survival (15). Intriguingly, Spa-1 interacts with Brd4 (18) and Rrp-1b (13), the protein products of genes associated with patterns of extracellular matrix protein gene expression characteristic of metastatic tumors (14).The RAP1GAP gene maps to 1p35-36, a chromosomal region subject to copy number alterations in human tumors (36, 49). Rap1GAP protein levels are decreased in pancreatic adenocarcinomas (53), pap...

show abstract

Downregulation of Rap1GAP through Epigenetic Silencing and Loss of Heterozygosity Promotes Invasion and Progression of Thyroid Tumors

Cited by 83 publications

References 21 publications

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

Prostaglandin E2 Regulates Renal Cell Carcinoma Invasion through the EP4 Receptor-Rap GTPase Signal Transduction Pathway

Downregulation of Rap1GAP in Human Tumor Cells Alters Cell/Matrix and Cell/Cell Adhesion

Contact Info

Product

Resources

About