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Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo

BACKGROUND: Evidence suggests that dysregulation of energy-sensing pathways closely associates with renal cell carcinoma (RCC) development. The metabolic regulation is largely controlled by 5′-AMP activated protein kinase (AMPK) which is activated through phosphorylation by LKB1. METHODS: The expres...

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Autores principales: Duivenvoorden, W C, Beatty, L K, Lhotak, S, Hill, B, Mak, I, Paulin, G, Gallino, D, Popovic, S, Austin, R C, Pinthus, J H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566816/
https://www.ncbi.nlm.nih.gov/pubmed/23322200
http://dx.doi.org/10.1038/bjc.2012.574
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author Duivenvoorden, W C
Beatty, L K
Lhotak, S
Hill, B
Mak, I
Paulin, G
Gallino, D
Popovic, S
Austin, R C
Pinthus, J H
author_facet Duivenvoorden, W C
Beatty, L K
Lhotak, S
Hill, B
Mak, I
Paulin, G
Gallino, D
Popovic, S
Austin, R C
Pinthus, J H
author_sort Duivenvoorden, W C
collection PubMed
description BACKGROUND: Evidence suggests that dysregulation of energy-sensing pathways closely associates with renal cell carcinoma (RCC) development. The metabolic regulation is largely controlled by 5′-AMP activated protein kinase (AMPK) which is activated through phosphorylation by LKB1. METHODS: The expression of LKB1 was determined by reverse transcription–PCR using 10 clinical clear cell RCC (ccRCC) samples and their adjacent normal renal parenchyma, and by immunohistochemical staining of two tissue microarrays containing 201 ccRCC and 26 normal kidney samples. Expression of LKB1 was knocked down in human ccRCC 786-O cells (shLKB1) and compared with cells expressing scrambled control shRNA (shControl). AMPK signalling, proliferation, invasion, and VEGF secretion was measured. The cells were subcutaneously injected into mice to determine tumour growth in vivo. RESULTS: At the protein and transcript levels, a significant reduction in LKB1 expression in tumour compared with normal tissue was found. In vitro, knockdown of LKB1 resulted in reduced AMPK signalling and increased cellular proliferation, invasion, and VEGF secretion compared with shControl cells. In vivo, growth of shLKB1 ccRCC xenografts in nude mice was significantly increased compared with shControl xenografts. CONCLUSION: Collectively, our results suggest that LKB1 acts as a tumour suppressor in most sporadic cases of ccRCC and that underexpression of LKB1 is a common event in the disease.
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spelling pubmed-35668162014-02-05 Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo Duivenvoorden, W C Beatty, L K Lhotak, S Hill, B Mak, I Paulin, G Gallino, D Popovic, S Austin, R C Pinthus, J H Br J Cancer Translational Therapeutics BACKGROUND: Evidence suggests that dysregulation of energy-sensing pathways closely associates with renal cell carcinoma (RCC) development. The metabolic regulation is largely controlled by 5′-AMP activated protein kinase (AMPK) which is activated through phosphorylation by LKB1. METHODS: The expression of LKB1 was determined by reverse transcription–PCR using 10 clinical clear cell RCC (ccRCC) samples and their adjacent normal renal parenchyma, and by immunohistochemical staining of two tissue microarrays containing 201 ccRCC and 26 normal kidney samples. Expression of LKB1 was knocked down in human ccRCC 786-O cells (shLKB1) and compared with cells expressing scrambled control shRNA (shControl). AMPK signalling, proliferation, invasion, and VEGF secretion was measured. The cells were subcutaneously injected into mice to determine tumour growth in vivo. RESULTS: At the protein and transcript levels, a significant reduction in LKB1 expression in tumour compared with normal tissue was found. In vitro, knockdown of LKB1 resulted in reduced AMPK signalling and increased cellular proliferation, invasion, and VEGF secretion compared with shControl cells. In vivo, growth of shLKB1 ccRCC xenografts in nude mice was significantly increased compared with shControl xenografts. CONCLUSION: Collectively, our results suggest that LKB1 acts as a tumour suppressor in most sporadic cases of ccRCC and that underexpression of LKB1 is a common event in the disease. Nature Publishing Group 2013-02-05 2013-01-15 /pmc/articles/PMC3566816/ /pubmed/23322200 http://dx.doi.org/10.1038/bjc.2012.574 Text en Copyright © 2013 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Translational Therapeutics
Duivenvoorden, W C
Beatty, L K
Lhotak, S
Hill, B
Mak, I
Paulin, G
Gallino, D
Popovic, S
Austin, R C
Pinthus, J H
Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo
title Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo
title_full Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo
title_fullStr Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo
title_full_unstemmed Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo
title_short Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo
title_sort underexpression of tumour suppressor lkb1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566816/
https://www.ncbi.nlm.nih.gov/pubmed/23322200
http://dx.doi.org/10.1038/bjc.2012.574
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