Loss of Rap1GAP in Papillary Thyroid Cancer

Nellore, Anoma; Paziana, Karolina; Ma, Changqing; Tsygankova, Oxana M.; Wang, Yan; Puttaswamy, Kanchan; Iqbal, Ammarah U.; Franks, Susanna R.; Lv, Yu; Troxel, Andrea B.; Feldman, Michael D.; Meinkoth, Judy L.; Brose, Marcia S.

doi:10.1210/jc.2008-1042

Cited by 41 publications

(36 citation statements)

References 26 publications

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“…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

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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.

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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

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“…Freshly cut 5-m sections were used for immunohistochemical staining. Sections were processed and stained for Rap1GAP as previously described (37). Slides were scanned on an Aperio Scanscope CS (Aperio Inc., Vista, CA) virtual slide scanner using ϫ40 magnification (0.5-m/pixel resolution).…”

Section: Methodsmentioning

confidence: 99%

“…(A) Tissue sections containing adjacent normal colonic epithelium and tumor tissue were stained for Rap1GAP as previously described (37,47). (B) Rap1GAP staining was quantified by H score (23).…”

Section: Fig 1 Decreased Expression Of Rap1gap In Primary Colorectalmentioning

confidence: 99%

“…on May 11, 2018 by guest http://mcb.asm.org/ adjacent normal tissues and stained with a highly specific Rap1GAP antibody (37,47). Prominent staining for Rap1GAP was detected in areas of normal colonic epithelium (Fig.…”

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confidence: 97%

“…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). Mutations of unknown significance in RAP1GAP have been identified in breast cancer (42).…”

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confidence: 99%

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

Tsygankova

Tang

et al. 2010

Molecular and Cellular Biology

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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...

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Ras-related protein 1 and the insulin-like growth factor type I receptor are associated with risk of progression in patients diagnosed with carcinoma in situ

Furstenau

Mitra

Wan

et al. 2010

Breast Cancer Res Treat

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Currently, there are no applied molecular markers to aid in predicting risk of carcinoma in situ (CIS) progression to invasive cancer, and therefore, all women diagnosed with CIS undergo surgery. Standard assessment of protein expression in fixed tissue by immunohistochemistry (IHC) is not quantitative and hence is not well suited for measuring biomarkers. In this study, we developed an original analytical method for IHC quantification. Using our novel image-based uniplex (IBU) method, quantitative protein profiling was performed on 90 samples of the breast (17 histologically normal tissues, 16 benign lesions, 15 CIS, and 42 invasive carcinomas). Differences between groups were assessed using analysis of variance (ANOVA) and mixed effects models. Measuring protein expression on a continuous scale revealed a significant increase in Ras-related protein 1 (Rap1) and the insulin-like growth factor type I receptor (IGF-IR) in conjunction with the presence of cancer invasion. Women with invasive cancers were four times more likely to have increased levels of Rap1 [odds ratio (OR) = 3.91; P = 0.0002] and IGF-IR (OR=4.33; P<0.0001) than women with non-invasive lesions. Furthermore, expression of both proteins was also increased significantly in CIS adjacent to invasive tumors compared with non-cancerous tissue. These novel findings of a significant up-regulation of Rap1 and IGF-IR in CIS progressing to invasive cancers warrant further investigation of Rap1 and IGF-IR together as a dual biomarker to aid in predicting risk of progression and ultimately providing non-surgical treatment options to those at lower risk.

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Loss of Rap1GAP in Papillary Thyroid Cancer

Abstract: These data indicate that loss of Rap1GAP is a frequent event in PTC. The more frequent and greater down-regulation of Rap1GAP in PTCs compared with adenomas suggests a role for Rap1GAP depletion in the progression of human thyroid tumors, possibly through unrestrained Rap activity.

Cited by 41 publications

References 26 publications

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

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

Ras-related protein 1 and the insulin-like growth factor type I receptor are associated with risk of progression in patients diagnosed with carcinoma in situ

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