Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis

Tsung Chieh Lin, Yu Peng Liu, Yung Chieh Chan, Chia Yi Su, Yuan Feng Lin, Shih Lan Hsu, Chung Shi Yang, Michael Hsiao

Research output: Contribution to journalArticle

19 Citations (Scopus)

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].

Original languageEnglish
Pages (from-to)50-61
Number of pages12
JournalJournal of Pathology
Volume237
Issue number1
DOIs
Publication statusPublished - Sep 1 2015

Fingerprint

Ghrelin
Snails
Renal Cell Carcinoma
Neoplasm Metastasis
Ghrelin Receptor
Cadherins
Phosphatidylinositol 3-Kinases
Distal Kidney Tubule
Phosphorylation
Kidney
Neoplasms
Proximal Kidney Tubule
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Aptitude
Atlases
Appetite
Microarray Analysis
Small Interfering RNA
Growth Hormone
Cell Movement

Keywords

  • E-cadherin
  • ghrelin
  • metastasis
  • migration
  • renal cell carcinoma
  • Snail

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis. / Lin, Tsung Chieh; Liu, Yu Peng; Chan, Yung Chieh; Su, Chia Yi; Lin, Yuan Feng; Hsu, Shih Lan; Yang, Chung Shi; Hsiao, Michael.

In: Journal of Pathology, Vol. 237, No. 1, 01.09.2015, p. 50-61.

Research output: Contribution to journalArticle

Lin, Tsung Chieh ; Liu, Yu Peng ; Chan, Yung Chieh ; Su, Chia Yi ; Lin, Yuan Feng ; Hsu, Shih Lan ; Yang, Chung Shi ; Hsiao, Michael. / Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis. In: Journal of Pathology. 2015 ; Vol. 237, No. 1. pp. 50-61.
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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].",
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AU - Lin, Tsung Chieh

AU - Liu, Yu Peng

AU - Chan, Yung Chieh

AU - Su, Chia Yi

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AU - Hsu, Shih Lan

AU - Yang, Chung Shi

AU - Hsiao, Michael

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