Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis
Ghrelin is an appetite‐regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS‐R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tu...
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| Published in | The Journal of pathology Vol. 237; no. 1; pp. 50 - 61 |
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| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
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Chichester, UK
John Wiley & Sons, Ltd
01.09.2015
Wiley Subscription Services, Inc |
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| Abstract | Ghrelin is an appetite‐regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS‐R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up‐regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786–0, ACHN and A‐498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E‐cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter‐binding activity of Snail. Snail silencing blocked the ghrelin‐mediated effects on E‐cadherin repression and cell migration. Snail–E‐cadherin regulation was mediated by GHS‐R‐triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin‐induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS‐R–PI3K–Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset]. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
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| AbstractList | Ghrelin is an appetite‐regulating molecule that promotes growth hormone (
GH
) release and food intake through growth hormone secretagogue receptor (
GHS
‐R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (
RCC
) arises. However, whether ghrelin is up‐regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic
RCC
. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of
RCC
cell lines 786–0,
ACHN
and A‐498. Furthermore, knockdown of ghrelin expression reduced
in vitro
migration and
in vivo
metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for
RCC
metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (
IPA
) and
MetaCore
pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of
E‐cadherin
. We further observed that Ghrelin increased the expression, nuclear translocation and promoter‐binding activity of Snail. Snail silencing blocked the ghrelin‐mediated effects on E‐cadherin repression and cell migration. Snail–E‐cadherin regulation was mediated by
GHS
‐R‐triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with
PI3K
inhibitors,
LY294002
and wortmannin, as well as Akt
siRNA
, decreased ghrelin‐induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the
GHS
‐R–
PI3K
–Akt axis, which may contribute to
RCC
metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (
TCGA
) [
KIRC
gene expression (
IlluminaHiSeq
) dataset]. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up-regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786-0, ACHN and A-498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E-cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter-binding activity of Snail. Snail silencing blocked the ghrelin-mediated effects on E-cadherin repression and cell migration. Snail-E-cadherin regulation was mediated by GHS-R-triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin-induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS-R-PI3K-Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset]. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up-regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786-0, ACHN and A-498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E-cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter-binding activity of Snail. Snail silencing blocked the ghrelin-mediated effects on E-cadherin repression and cell migration. Snail-E-cadherin regulation was mediated by GHS-R-triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin-induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS-R-PI3K-Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset].Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up-regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786-0, ACHN and A-498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E-cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter-binding activity of Snail. Snail silencing blocked the ghrelin-mediated effects on E-cadherin repression and cell migration. Snail-E-cadherin regulation was mediated by GHS-R-triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin-induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS-R-PI3K-Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset]. Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up-regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786-0, ACHN and A-498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E-cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter-binding activity of Snail. Snail silencing blocked the ghrelin-mediated effects on E-cadherin repression and cell migration. Snail-E-cadherin regulation was mediated by GHS-R-triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin-induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS-R-PI3K-Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset]. |
| Author | Hsu, Shih-Lan Lin, Tsung-Chieh Hsiao, Michael Liu, Yu-Peng Chan, Yung-Chieh Su, Chia-Yi Yang, Chung-Shi Lin, Yuan-Feng |
| Author_xml | – sequence: 1 givenname: Tsung-Chieh surname: Lin fullname: Lin, Tsung-Chieh organization: Genomics Research Centre, Academia Sinica, Taipei, Taiwan – sequence: 2 givenname: Yu-Peng surname: Liu fullname: Liu, Yu-Peng organization: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan – sequence: 3 givenname: Yung-Chieh surname: Chan fullname: Chan, Yung-Chieh organization: Genomics Research Centre, Academia Sinica, Taipei, Taiwan – sequence: 4 givenname: Chia-Yi surname: Su fullname: Su, Chia-Yi organization: Genomics Research Centre, Academia Sinica, Taipei, Taiwan – sequence: 5 givenname: Yuan-Feng surname: Lin fullname: Lin, Yuan-Feng organization: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan – sequence: 6 givenname: Shih-Lan surname: Hsu fullname: Hsu, Shih-Lan email: mhsiao@gate.sinica.edu.tw organization: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan – sequence: 7 givenname: Chung-Shi surname: Yang fullname: Yang, Chung-Shi email: mhsiao@gate.sinica.edu.tw organization: Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan – sequence: 8 givenname: Michael surname: Hsiao fullname: Hsiao, Michael email: mhsiao@gate.sinica.edu.tw organization: Genomics Research Centre, Academia Sinica, Taipei, Taiwan |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25925728$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2015 Pathological Society of Great Britain and Ireland |
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| Keywords | migration ghrelin renal cell carcinoma Snail metastasis E-cadherin |
| Language | English |
| License | Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
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| Notes | ark:/67375/WNG-1Z8F7PWX-W istex:0271617852D2D5AB2E414650516D0AB2D1438A18 Appendix S1 Supplementary materials and methodsExpression profile of ghrelin in matched renal clear cell carcinomas and adjacent normal tissue. Ghrelin levels in 48 matched renal clear cell carcinomas and adjacent normal tissue were compared. Raw data were retrieved from microarray dataset KIRC gene expression (IlluminaHiSeq); T, tumour; N, normal. Relative difference in ghrelin expression was obtained by GhrelinT - GhrelinN; differences above ± 0.5 were considered as threshold and are shownRelative expression of ghrelin in RCC cell lines. Expression of the molecules indicated was evaluated by western blot in cell lines 769-P, 786-0, A-498, A-704 and ACHNRCC cell proliferation is not affected by ghrelin: 1 × 104 cells of (A-C) 786-0, ACHN and A-498, with 0, 90, 180 and 360 nm ghrelin, and (D, E) 769-P and 786-0 cells with ghrelin knockdown were seeded in cell culture plates. Cell numbers were counted at time points of 48 and 96 h. NS, non-silence control; sh4 and sh6, ghrelin knockdown clonesGhrelin promotes RCC cell migration in vitro. Cells were treated with 0, 90, 180 and 360 nm ghrelin for 48 h. Level of cell migration was evaluated by wound-healing assay, and representative images of cell migration are shownGhrelin treatment-mediated cell migration is reduced upon ghrelin knockdown. The indicated 786-0 cells were treated with 360 nm ghrelin. Cell migration was evaluated by Transwell assay (A, B) and wound-healing assay (C, D)Bioinformatics analysis of gene expression profile identifies an association between ghrelin, EMT and Snail signalling. Representative network showing the regulation of ghrelin in relation to the knowledge-based interaction molecules of Snail. The network was built based on the Snail interactome in the IPA database overlaid with the microarray data from ghrelin treatment of 786-0 cells. The intensity of the node colour indicates the degree of (red) up- and (green) down-regulation following ghrelin treatment in 786-0 cells; symbols are illustrated in the table (right)Ghrelin induces EMT. Cells were treated with 180 nm ghrelin for 48 h prior to immunofluorescence staining. The expression and distribution of N-cadherin, MMP9 and Twist are shown. Nuclear twist and nuclei (Hoechst-stained) are indicated by arrows ArticleID:PATH4552 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
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| References | Ueberberg B, Unger N, Saeger W, et al. Expression of ghrelin and its receptor in human tissues. Horm Metab Res 2009; 41: 814-821. Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2: 76-83. Hu CT, Wu JR, Chang TY, et al. The transcriptional factor Snail simultaneously triggers cell cycle arrest and migration of human hepatoma HepG2. J Biomed Sci 2008; 15: 343-355. Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 2004; 50: 1511-1525. Wu Y, Zhou BP. TNFα/NF-κB/Snail pathway in cancer cell migration and invasion. Br J Cancer 2010; 102: 639-644. Cardiff RD. Epithelial to mesenchymal transition tumors: fallacious or Snail's pace? Clin Cancer Res 2005; 11: 8534-8537. Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002; 3: 155-166. Aybar MJ, Nieto MA, Mayor R. Snail precedes Slug in the genetic cascade required for the specification and migration of the Xenopus neural crest. Development 2003; 130: 483-494. Friedl P. Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Biol 2004; 16: 14-23. Lehembre F, Yilmaz M, Wicki A, et al. NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin. EMBO J 2008; 27: 2603-2615. Park S, Jiang H, Zhang H, et al. Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release. Proc Natl Acad Sci USA 2012; 109: 19003-19008. Zhou BP, Deng J, Xia W, et al. Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004; 6: 931-940. Mori K, Yoshimoto A, Takaya K, et al. Kidney produces a novel acylated peptide, ghrelin. FEBS Lett 2000; 486: 213-216. Toshinai K, Mondal MS, Nakazato M, et al. Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochem Biophys Res Commun 2001; 281: 1220-1225. Lo HW, Hsu SC, Xia W, et al. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res 2007; 67: 9066-9076. Nagase Y, Takata K, Moriyama N, et al. Immunohistochemical localization of glucose transporters in human renal cell carcinoma. J Urol 1995; 153: 798-801. Olson MF, Sahai E. The actin cytoskeleton in cancer cell motility. Clin Exp Metast 2009; 26: 273-287. Inui A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2001; 2: 551-560. Tsolakis AV, Portela-Gomes GM, Stridsberg M, et al. Malignant gastric ghrelinoma with hyperghrelinemia. J Clin Endocrinol Metab 2004; 89: 3739-3744. Dixit VD, Weeraratna AT, Yang H, et al. Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility. J Biol Chem 2006; 281: 16681-16690. Scheid MP, Woodgett JR. PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2001; 2: 760-768. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet 2009; 373: 1119-1132. Ho MY, Tang SJ, Chuang MJ, et al. TNFα induces epithelial-mesenchymal transition of renal cell carcinoma cells via a GSK3β-dependent mechanism. Mol Cancer Res 2012; 10: 1109-1119. Wang L, Chen Q, Li G, et al. Ghrelin stimulates angiogenesis via GHSR1a-dependent MEK/ERK and PI3K/Akt signal pathways in rat cardiac microvascular endothelial cells. Peptides 2012; 33: 92-100. Kojima M, Kangawa K. Ghrelin, an orexigenic signaling molecule from the gastrointestinal tract. Curr Opin Pharmacol 2002; 2: 665-668. Batlle E, Sancho E, Franci C, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000; 2: 84-89. Dornonville de la Cour C, Bjorkqvist M, Sandvik AK, et al. A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control. Regul Pept 2001; 99: 141-150. Yang Z, Rayala S, Nguyen D, et al. Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res 2005; 65: 3179-3184. Luo WR, Li SY, Cai LM, et al. High expression of nuclear Snail, but not cytoplasmic staining, predicts poor survival in nasopharyngeal carcinoma. Ann Surg Oncol 2012; 19: 2971-2979. Lidgren A, Bergh A, Grankvist K, et al. Glucose transporter-1 expression in renal cell carcinoma and its correlation with hypoxia inducible factor-1α. BJU Int 2008; 101: 480-484. Grille SJ, Bellacosa A, Upson J, et al. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 2003; 63: 2172-2178. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996; 335: 865-875. Usami Y, Satake S, Nakayama F, et al. Snail-associated epithelial-mesenchymal transition promotes oesophageal squamous cell carcinoma motility and progression. J Pathol 2008; 215: 330-339. Onder TT, Gupta PB, Mani SA, et al. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 2008; 68: 3645-3654. Kageyama H, Funahashi H, Hirayama M, et al. Morphological analysis of ghrelin and its receptor distribution in the rat pancreas. Regul Pept 2005; 126: 67-71. Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 2004; 4: 118-132. Acevedo VD, Gangula RD, Freeman KW, et al. Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell 2007; 12: 559-571. Du C, Zhang C, Hassan S, et al. Protein kinase D1 suppresses epithelial-to-mesenchymal transition through phosphorylation of snail. Cancer Res 2010; 70: 7810-7819. Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 2004; 5: 816-826. Baldanzi G, Filigheddu N, Cutrupi S, et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002; 159: 1029-1037. Duxbury MS, Waseem T, Ito H, et al. Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness. Biochem Biophys Res Commun 2003; 309: 464-468. Perl AK, Wilgenbus P, Dahl U, et al. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 1998; 392: 190-193. Hemavathy K, Ashraf SI, Ip YT. Snail/slug family of repressors: slowly going into the fast lane of development and cancer. Gene 2000; 257: 1-12. Barnett BP, Hwang Y, Taylor MS, et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science 2010; 330: 1689-1692. De Craene B, van Roy F, Berx G. Unraveling signalling cascades for the Snail family of transcription factors. Cell Signal 2005; 17: 535-547. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2: 442-454. Campbell SC, Flanigan RC, Clark JI. Nephrectomy in metastatic renal cell carcinoma. Curr Treat Options Oncol 2003; 4: 363-372. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407: 908-913. Walter T, Chardon L, Hervieu V, et al. Major hyperghrelinemia in advanced well-differentiated neuroendocrine carcinomas: report of three cases. Eur J Endocrinol 2009; 161: 639-645. Graham TR, Zhau HE, Odero-Marah VA, et al. Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res 2008; 68: 2479-2488. Olmeda D, Moreno-Bueno G, Flores JM, et al. SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma MDA-MB-231 cells. Cancer Res 2007; 67: 11721-11731. Lin TC, Lee TC, Hsu SL, et al. The molecular mechanism of leptin secretion and expression induced by aristolochic acid in kidney fibroblast. PLoS One 2011; 6: e16654.*Cited in Supplementary materials and methods Chen JH, Huang SM, Chen CC, et al. Ghrelin induces cell migration through GHS-R, CaMKII, AMPK, and NF-κB signaling pathway in glioma cells. J Cell Biochem 2011; 112: 2931-2941. Yamamoto T, Seino Y, Fukumoto H, et al. Over-expression of facilitative glucose transporter genes in human cancer. Biochem Biophys Res Commun 1990; 170: 223-230. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol 2001; 166: 1611-1623. 2009; 41 2000; 257 2010; 102 2004; 4 2004; 6 2002; 159 2004; 5 2012; 19 2005; 65 2000; 2 2008; 101 2011; 112 2012; 10 1998; 392 2000; 407 2008; 27 1990; 170 2003; 4 2008; 68 2009; 161 2000; 486 2006; 281 1996; 335 2001; 99 2010; 70 2007; 67 2001; 166 2001; 281 2004; 89 2002; 2 2008; 15 2002; 3 2009; 373 1995; 153 2011; 6 2007; 12 2012; 33 2009; 26 2012; 109 2003; 130 2003; 309 2004; 50 2004; 16 2005; 126 2010; 330 2008; 215 2001; 2 2005; 17 2003; 63 2005; 11 e_1_2_7_5_1 e_1_2_7_3_1 e_1_2_7_9_1 e_1_2_7_7_1 e_1_2_7_19_1 e_1_2_7_17_1 e_1_2_7_15_1 e_1_2_7_41_1 e_1_2_7_13_1 e_1_2_7_43_1 e_1_2_7_11_1 e_1_2_7_45_1 e_1_2_7_47_1 e_1_2_7_26_1 e_1_2_7_28_1 e_1_2_7_50_1 e_1_2_7_25_1 e_1_2_7_31_1 e_1_2_7_52_1 e_1_2_7_23_1 e_1_2_7_33_1 e_1_2_7_54_1 e_1_2_7_21_1 e_1_2_7_35_1 e_1_2_7_56_1 e_1_2_7_37_1 e_1_2_7_39_1 e_1_2_7_6_1 e_1_2_7_4_1 e_1_2_7_8_1 e_1_2_7_18_1 e_1_2_7_16_1 e_1_2_7_40_1 e_1_2_7_2_1 e_1_2_7_14_1 e_1_2_7_42_1 e_1_2_7_12_1 e_1_2_7_44_1 e_1_2_7_10_1 e_1_2_7_46_1 e_1_2_7_48_1 e_1_2_7_27_1 e_1_2_7_29_1 e_1_2_7_51_1 e_1_2_7_30_1 Grille SJ (e_1_2_7_49_1) 2003; 63 e_1_2_7_53_1 e_1_2_7_24_1 e_1_2_7_32_1 e_1_2_7_55_1 e_1_2_7_22_1 e_1_2_7_34_1 e_1_2_7_20_1 e_1_2_7_36_1 e_1_2_7_38_1 |
| References_xml | – reference: Dornonville de la Cour C, Bjorkqvist M, Sandvik AK, et al. A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control. Regul Pept 2001; 99: 141-150. – reference: Wang L, Chen Q, Li G, et al. Ghrelin stimulates angiogenesis via GHSR1a-dependent MEK/ERK and PI3K/Akt signal pathways in rat cardiac microvascular endothelial cells. Peptides 2012; 33: 92-100. – reference: Friedl P. Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Biol 2004; 16: 14-23. – reference: Chen JH, Huang SM, Chen CC, et al. Ghrelin induces cell migration through GHS-R, CaMKII, AMPK, and NF-κB signaling pathway in glioma cells. J Cell Biochem 2011; 112: 2931-2941. – reference: Yamamoto T, Seino Y, Fukumoto H, et al. Over-expression of facilitative glucose transporter genes in human cancer. Biochem Biophys Res Commun 1990; 170: 223-230. – reference: Mori K, Yoshimoto A, Takaya K, et al. Kidney produces a novel acylated peptide, ghrelin. FEBS Lett 2000; 486: 213-216. – reference: Perl AK, Wilgenbus P, Dahl U, et al. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 1998; 392: 190-193. – reference: Yang Z, Rayala S, Nguyen D, et al. Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res 2005; 65: 3179-3184. – reference: Hemavathy K, Ashraf SI, Ip YT. Snail/slug family of repressors: slowly going into the fast lane of development and cancer. Gene 2000; 257: 1-12. – reference: Olson MF, Sahai E. The actin cytoskeleton in cancer cell motility. Clin Exp Metast 2009; 26: 273-287. – reference: Luo WR, Li SY, Cai LM, et al. High expression of nuclear Snail, but not cytoplasmic staining, predicts poor survival in nasopharyngeal carcinoma. Ann Surg Oncol 2012; 19: 2971-2979. – reference: Batlle E, Sancho E, Franci C, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000; 2: 84-89. – reference: Aybar MJ, Nieto MA, Mayor R. Snail precedes Slug in the genetic cascade required for the specification and migration of the Xenopus neural crest. Development 2003; 130: 483-494. – reference: Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet 2009; 373: 1119-1132. – reference: Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2: 76-83. – reference: Tsolakis AV, Portela-Gomes GM, Stridsberg M, et al. Malignant gastric ghrelinoma with hyperghrelinemia. J Clin Endocrinol Metab 2004; 89: 3739-3744. – reference: Nagase Y, Takata K, Moriyama N, et al. Immunohistochemical localization of glucose transporters in human renal cell carcinoma. J Urol 1995; 153: 798-801. – reference: Lehembre F, Yilmaz M, Wicki A, et al. NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin. EMBO J 2008; 27: 2603-2615. – reference: Scheid MP, Woodgett JR. PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2001; 2: 760-768. – reference: Toshinai K, Mondal MS, Nakazato M, et al. Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochem Biophys Res Commun 2001; 281: 1220-1225. – reference: Acevedo VD, Gangula RD, Freeman KW, et al. Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell 2007; 12: 559-571. – reference: Cardiff RD. Epithelial to mesenchymal transition tumors: fallacious or Snail's pace? Clin Cancer Res 2005; 11: 8534-8537. – reference: Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 2004; 5: 816-826. – reference: Inui A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2001; 2: 551-560. – reference: Kageyama H, Funahashi H, Hirayama M, et al. Morphological analysis of ghrelin and its receptor distribution in the rat pancreas. Regul Pept 2005; 126: 67-71. – reference: Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002; 3: 155-166. – reference: Baldanzi G, Filigheddu N, Cutrupi S, et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002; 159: 1029-1037. – reference: Lo HW, Hsu SC, Xia W, et al. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res 2007; 67: 9066-9076. – reference: De Craene B, van Roy F, Berx G. Unraveling signalling cascades for the Snail family of transcription factors. Cell Signal 2005; 17: 535-547. – reference: Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 2004; 4: 118-132. – reference: Wu Y, Zhou BP. TNFα/NF-κB/Snail pathway in cancer cell migration and invasion. Br J Cancer 2010; 102: 639-644. – reference: Usami Y, Satake S, Nakayama F, et al. Snail-associated epithelial-mesenchymal transition promotes oesophageal squamous cell carcinoma motility and progression. J Pathol 2008; 215: 330-339. – reference: Zhou BP, Deng J, Xia W, et al. Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004; 6: 931-940. – reference: Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996; 335: 865-875. – reference: Barnett BP, Hwang Y, Taylor MS, et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science 2010; 330: 1689-1692. – reference: *Lin TC, Lee TC, Hsu SL, et al. The molecular mechanism of leptin secretion and expression induced by aristolochic acid in kidney fibroblast. PLoS One 2011; 6: e16654.*Cited in Supplementary materials and methods – reference: Campbell SC, Flanigan RC, Clark JI. Nephrectomy in metastatic renal cell carcinoma. Curr Treat Options Oncol 2003; 4: 363-372. – reference: Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2: 442-454. – reference: Du C, Zhang C, Hassan S, et al. Protein kinase D1 suppresses epithelial-to-mesenchymal transition through phosphorylation of snail. Cancer Res 2010; 70: 7810-7819. – reference: Graham TR, Zhau HE, Odero-Marah VA, et al. Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res 2008; 68: 2479-2488. – reference: Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407: 908-913. – reference: Onder TT, Gupta PB, Mani SA, et al. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 2008; 68: 3645-3654. – reference: Grille SJ, Bellacosa A, Upson J, et al. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 2003; 63: 2172-2178. – reference: Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 2004; 50: 1511-1525. – reference: Duxbury MS, Waseem T, Ito H, et al. Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness. Biochem Biophys Res Commun 2003; 309: 464-468. – reference: Hu CT, Wu JR, Chang TY, et al. The transcriptional factor Snail simultaneously triggers cell cycle arrest and migration of human hepatoma HepG2. J Biomed Sci 2008; 15: 343-355. – reference: Ueberberg B, Unger N, Saeger W, et al. Expression of ghrelin and its receptor in human tissues. Horm Metab Res 2009; 41: 814-821. – reference: Park S, Jiang H, Zhang H, et al. Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release. Proc Natl Acad Sci USA 2012; 109: 19003-19008. – reference: Ho MY, Tang SJ, Chuang MJ, et al. TNFα induces epithelial-mesenchymal transition of renal cell carcinoma cells via a GSK3β-dependent mechanism. Mol Cancer Res 2012; 10: 1109-1119. – reference: Lidgren A, Bergh A, Grankvist K, et al. Glucose transporter-1 expression in renal cell carcinoma and its correlation with hypoxia inducible factor-1α. BJU Int 2008; 101: 480-484. – reference: Kojima M, Kangawa K. Ghrelin, an orexigenic signaling molecule from the gastrointestinal tract. Curr Opin Pharmacol 2002; 2: 665-668. – reference: Dixit VD, Weeraratna AT, Yang H, et al. 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2005 end-page: 547 article-title: Unraveling signalling cascades for the Snail family of transcription factors publication-title: Cell Signal – volume: 67 start-page: 9066 year: 2007 end-page: 9076 article-title: Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial–mesenchymal transition in cancer cells via up‐regulation of TWIST gene expression publication-title: Cancer Res – volume: 6 start-page: e16654 year: 2011 article-title: The molecular mechanism of leptin secretion and expression induced by aristolochic acid in kidney fibroblast publication-title: PLoS One – volume: 26 start-page: 273 year: 2009 end-page: 287 article-title: The actin cytoskeleton in cancer cell motility publication-title: Clin Exp Metast – volume: 330 start-page: 1689 year: 2010 end-page: 1692 article-title: Glucose and weight control in mice with a designed ghrelin ‐acyltransferase inhibitor publication-title: Science – volume: 2 start-page: 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publication-title: Nat Rev Mol Cell Biol – volume: 153 start-page: 798 year: 1995 end-page: 801 article-title: Immunohistochemical localization of glucose transporters in human renal cell carcinoma publication-title: J Urol – volume: 2 start-page: 84 year: 2000 end-page: 89 article-title: The transcription factor snail is a repressor of E‐cadherin gene expression in epithelial tumour cells publication-title: Nat Cell Biol – volume: 10 start-page: 1109 year: 2012 end-page: 1119 article-title: TNFα induces epithelial–mesenchymal transition of renal cell carcinoma cells via a GSK3β‐dependent mechanism publication-title: Mol Cancer Res – volume: 2 start-page: 551 year: 2001 end-page: 560 article-title: Ghrelin: an orexigenic and somatotrophic signal from the stomach publication-title: Nat Rev Neurosci – volume: 5 start-page: 816 year: 2004 end-page: 826 article-title: Integrin signalling during tumour progression publication-title: Nat Rev Mol Cell Biol – volume: 392 start-page: 190 year: 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| Snippet | Ghrelin is an appetite‐regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS‐R).... Ghrelin is an appetite‐regulating molecule that promotes growth hormone ( GH ) release and food intake through growth hormone secretagogue receptor ( GHS ‐R).... Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R).... |
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| SubjectTerms | Animals Binding Sites Cadherins - genetics Cadherins - metabolism Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - metabolism Carcinoma, Renal Cell - mortality Carcinoma, Renal Cell - secondary Cell Line, Tumor Cell Movement - drug effects E-cadherin Gene Expression Profiling - methods Gene Expression Regulation, Neoplastic ghrelin Ghrelin - genetics Ghrelin - metabolism Humans Kidney Neoplasms - genetics Kidney Neoplasms - metabolism Kidney Neoplasms - mortality Kidney Neoplasms - pathology Male metastasis Mice, Inbred NOD Mice, SCID migration Neoplasm Invasiveness Oligonucleotide Array Sequence Analysis Phosphatidylinositol 3-Kinase - antagonists & inhibitors Phosphatidylinositol 3-Kinase - metabolism Phosphorylation Promoter Regions, Genetic - drug effects Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Receptors, Ghrelin - genetics Receptors, Ghrelin - metabolism renal cell carcinoma RNA Interference Signal Transduction Snail Snail Family Transcription Factors Time Factors Transcription Factors - genetics Transcription Factors - metabolism Transfection |
| Title | Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis |
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