<i>KiSS-1</i>/G Protein-Coupled Receptor 54 Metastasis Suppressor Pathway Increases Myocyte-Enriched Calcineurin Interacting Protein 1 Expression and Chronically Inhibits Calcineurin Activity

Stathatos, Nikolaos; Bourdeau, Isabelle; Espinosa, Allan V.; Saji, Motoyasu; Vasko, Vasily; Burman, Kenneth D.; Stratakis, Constantine A.; Ringel, Matthew D.

doi:10.1210/jc.2005-0963

Cited by 71 publications

(72 citation statements)

References 31 publications

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“…However, DSCR1 is an NFATc inhibitor, and NFATc has been implicated in invasion and proliferation (91)(92)(93)106) of tumor cells. It has also been reported that silencing of DSCR1 is associated with metastatic behavior of tumor cells (94).…”

Section: Discussionmentioning

confidence: 93%

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Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Bush

Havens

Necela

et al. 2007

Journal of Biological Chemistry

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Activation of PPAR␥ in MOSER cells inhibits anchoragedependent and anchorage-independent growth and invasion through Matrigel-coated transwell membranes. We carried out a longitudinal two-class microarray analysis in which mRNA abundance was measured as a function of time in cells treated with a thiazolidinedione PPAR␥ agonist or vehicle. A statistical machine learning algorithm that employs an empirical Bayesian implementation of the multivariate HotellingT2 score was used to identify differentially regulated genes. HotellingT2 scores, MB statistics, and maximum median differences were used as figures of merit to interrogate genomic ontology of these targets. Three major cohorts of genes were regulated: those involved in metabolism, DNA replication, and migration/motility, reflecting the cellular phenotype that attends activation of PPAR␥. The bioinformatic analysis also inferred that PPAR␥ regulates calcium signaling. This response was unanticipated, because calcium signaling has not previously been associated with PPAR␥ activation. Ingenuity pathway analysis inferred that the nodal point in this cross-talk was Down syndrome critical region 1 (DSCR1). DSCR1 is an endogenous calcineurin inhibitor that blocks dephosphorylation and activation of members of the cytoplasmic component of nuclear factor of activated T cells transcription factors. Lentiviral short hairpin RNA-mediated knockdown of DSCR1 blocks PPAR␥ inhibition of proliferation and invasion, indicating that DSCR1 is required for suppression of transformed properties of early stage colorectal cancer cells by PPAR␥. These data reveal a novel, heretofore unappreciated link between PPAR␥ and calcium signaling and indicate that DSCR1, which has previously been thought to function by suppression of the angiogenic response in endothelial cells, may also play a direct role in transformation of epithelial cells.

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Section: Discussionmentioning

confidence: 93%

“…It is known that DSCR1 is silenced in some tumor cells (94). Loss of DSCR1 in such cells is associated with metastasis.…”

Section: Discussionmentioning

confidence: 99%

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Bush

Havens

Necela

et al. 2007

Journal of Biological Chemistry

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“…Cell migration was examined by using a Boyden chamber (8-m pore size), and cells were stained by using a Diff-Quick staining kit (Dade Behring, Newark, DE). Percent migration of total cells was calculated as described (46). All migration experiments were performed on at least three occasions in duplicate.…”

Section: Discussionmentioning

confidence: 99%

Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion

Vasko

Espinosa

Scouten

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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280

231

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Papillary thyroid carcinomas (PTCs) that invade into local structures are associated with a poor prognosis, but the mechanisms for PTC invasion are incompletely defined, limiting the development of new therapies. To characterize biological processes involved in PTC invasion, we analyzed the gene expression profiles of microscopically dissected intratumoral samples from central and invasive regions of seven widely invasive PTCs and normal thyroid tissue by oligonucleotide microarray and performed confirmatory expression and functional studies. In comparison with the central regions of primary PTCs, the invasive fronts overexpressed TGF ␤, NFB and integrin pathway members, and regulators of small G proteins and CDC42. Moreover, reduced levels of mRNAs encoding proteins involved in cell-cell adhesion and communication were identified, consistent with epithelial-to-mesenchymal transition (EMT). To confirm that aggressive PTCs were characterized by EMT, 34 additional PTCs were examined for expression of vimentin, a hallmark of EMT. Overexpression of vimentin was associated with PTC invasion and nodal metastasis. Functional, in vitro studies demonstrated that vimentin was required both for the development and maintenance of a mesenchymal morphology and invasiveness in thyroid cancer cells. We conclude that EMT is common in PTC invasion and that vimentin regulates thyroid cancer EMT in vitro.cdc42 ͉ runx2 ͉ thyroid cancer ͉ vimentin T hyroid carcinoma is the most common classical endocrine malignancy, and its incidence is rising rapidly, due almost entirely to an increase in papillary thyroid carcinoma (PTC) diagnoses (1). Patients diagnosed with PTC at an early stage have an excellent prognosis; however, individuals with large, invasive tumors and/or distant metastases have a 5-year survival rate of Ϸ40% (2, 3). Thus, there is a need to better understand the molecular causes of thyroid cancer progression to develop new treatment options.The genetic defects believed to be responsible for PTC initiation have been identified in the majority of cases; these include genetic rearrangements involving the tyrosine kinase domain of RET and activating mutations of BRAF and RAS (3-5). Although some correlation studies support an association between specific genetic alterations and aggressive cancer behavior (6-9), there are a number of events that are found nearly exclusively in aggressive PTCs, including mutations of P53 (10, 11), dysregulated ␤-catenin signaling (12), up-regulation of cyclin D1 (13), and overexpression of metastasis-promoting, angiogenic, and/or cell adhesion-related genes (14-20). We have determined that invasive regions of primary PTCs are frequently characterized by enhanced Akt activity and cytosolic p27 localization (21, 22). We, and others, have also demonstrated functional roles for PI3 kinase, Akt, and p27 in PTC cell invasion in vitro (16,23,24). However, the correlation between increased Akt activity and invasion was not found for PTCs with activating BRAF mutations. Most importantly, these focused s...

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“…Even though, Kisspeptins are not always associated positively with some cancers, currently a large body of evidence suggests that, it does appear to inhibit the cancer cell invasion. Different mechanisms of function include increase in ERK1/2 phosphorylation, decrease in MMP-2 as in the placenta as well as to inhibit the metastatic properties of its chemokine receptor CXCR4 have been hypothesised for this inhibition of metastasis process (Stathatos et al, 2005;Yoshioka et al, 2008). These findings may open the possibility of future clinical application of these proteins, KiSS-1 for prevention of cancer invasion and metastasis, and thus may improve patient prognosis.…”

Section: Kiss-1 As a Molecular Target For Cancermentioning

confidence: 99%

Kisspeptins (KiSS-1): Essential Players in Suppressing Tumor Metastasis

Prabhu

Sakthivel²,

Guruvayoorappan³

2013

Asian Pacific Journal of Cancer Prevention

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KiSS-1/G Protein-Coupled Receptor 54 Metastasis Suppressor Pathway Increases Myocyte-Enriched Calcineurin Interacting Protein 1 Expression and Chronically Inhibits Calcineurin Activity

Abstract: These data suggest a role for MCIP-1 and calcineurin inhibition in GPR54-mediated metastasis suppression in human cancers.

Cited by 71 publications

References 31 publications

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion

Kisspeptins (KiSS-1): Essential Players in Suppressing Tumor Metastasis

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