HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.

<h4>Background</h4>Although metastatic colon cancer is a leading cause of cancer death worldwide, the molecular mechanisms that enable colon cancer cells to metastasize remain unclear. Emerging evidence suggests that metastatic cells develop by usurping transcriptional networks from embr...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Amy Belton, Alexander Gabrovsky, Young Kyung Bae, Ray Reeves, Christine Iacobuzio-Donahue, David L Huso, Linda M S Resar
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cf7f5c65cba94c97b365e6fa24a397bf
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:cf7f5c65cba94c97b365e6fa24a397bf
record_format	dspace
spelling	oai:doaj.org-article:cf7f5c65cba94c97b365e6fa24a397bf2021-11-18T07:29:45ZHMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.1932-620310.1371/journal.pone.0030034https://doaj.org/article/cf7f5c65cba94c97b365e6fa24a397bf2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22276142/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Although metastatic colon cancer is a leading cause of cancer death worldwide, the molecular mechanisms that enable colon cancer cells to metastasize remain unclear. Emerging evidence suggests that metastatic cells develop by usurping transcriptional networks from embryonic stem (ES) cells to facilitate an epithelial-mesenchymal transition (EMT), invasion, and metastatic progression. Previous studies identified HMGA1 as a key transcription factor enriched in ES cells, colon cancer, and other aggressive tumors, although its role in these settings is poorly understood.<h4>Methods/principal findings</h4>To determine how HMGA1 functions in metastatic colon cancer, we manipulated HMGA1 expression in transgenic mice and colon cancer cells. We discovered that HMGA1 drives proliferative changes, aberrant crypt formation, and intestinal polyposis in transgenic mice. In colon cancer cell lines from poorly differentiated, metastatic tumors, knock-down of HMGA1 blocks anchorage-independent cell growth, migration, invasion, xenograft tumorigenesis and three-dimensional colonosphere formation. Inhibiting HMGA1 expression blocks tumorigenesis at limiting dilutions, consistent with depletion of tumor-initiator cells in the knock-down cells. Knock-down of HMGA1 also inhibits metastatic progression to the liver in vivo. In metastatic colon cancer cells, HMGA1 induces expression of Twist1, a gene involved in embryogenesis, EMT, and tumor progression, while HMGA1 represses E-cadherin, a gene that is down-regulated during EMT and metastatic progression. In addition, HMGA1 is among the most enriched genes in colon cancer compared to normal mucosa.<h4>Conclusions</h4>Our findings demonstrate for the first time that HMGA1 drives proliferative changes and polyp formation in the intestines of transgenic mice and induces metastatic progression and stem-like properties in colon cancer cells. These findings indicate that HMGA1 is a key regulator, both in metastatic progression and in the maintenance of a stem-like state. Our results also suggest that HMGA1 or downstream pathways could be rational therapeutic targets in metastatic, poorly differentiated colon cancer.Amy BeltonAlexander GabrovskyYoung Kyung BaeRay ReevesChristine Iacobuzio-DonahueDavid L HusoLinda M S ResarPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 1, p e30034 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amy Belton Alexander Gabrovsky Young Kyung Bae Ray Reeves Christine Iacobuzio-Donahue David L Huso Linda M S Resar HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.
description	<h4>Background</h4>Although metastatic colon cancer is a leading cause of cancer death worldwide, the molecular mechanisms that enable colon cancer cells to metastasize remain unclear. Emerging evidence suggests that metastatic cells develop by usurping transcriptional networks from embryonic stem (ES) cells to facilitate an epithelial-mesenchymal transition (EMT), invasion, and metastatic progression. Previous studies identified HMGA1 as a key transcription factor enriched in ES cells, colon cancer, and other aggressive tumors, although its role in these settings is poorly understood.<h4>Methods/principal findings</h4>To determine how HMGA1 functions in metastatic colon cancer, we manipulated HMGA1 expression in transgenic mice and colon cancer cells. We discovered that HMGA1 drives proliferative changes, aberrant crypt formation, and intestinal polyposis in transgenic mice. In colon cancer cell lines from poorly differentiated, metastatic tumors, knock-down of HMGA1 blocks anchorage-independent cell growth, migration, invasion, xenograft tumorigenesis and three-dimensional colonosphere formation. Inhibiting HMGA1 expression blocks tumorigenesis at limiting dilutions, consistent with depletion of tumor-initiator cells in the knock-down cells. Knock-down of HMGA1 also inhibits metastatic progression to the liver in vivo. In metastatic colon cancer cells, HMGA1 induces expression of Twist1, a gene involved in embryogenesis, EMT, and tumor progression, while HMGA1 represses E-cadherin, a gene that is down-regulated during EMT and metastatic progression. In addition, HMGA1 is among the most enriched genes in colon cancer compared to normal mucosa.<h4>Conclusions</h4>Our findings demonstrate for the first time that HMGA1 drives proliferative changes and polyp formation in the intestines of transgenic mice and induces metastatic progression and stem-like properties in colon cancer cells. These findings indicate that HMGA1 is a key regulator, both in metastatic progression and in the maintenance of a stem-like state. Our results also suggest that HMGA1 or downstream pathways could be rational therapeutic targets in metastatic, poorly differentiated colon cancer.
format	article
author	Amy Belton Alexander Gabrovsky Young Kyung Bae Ray Reeves Christine Iacobuzio-Donahue David L Huso Linda M S Resar
author_facet	Amy Belton Alexander Gabrovsky Young Kyung Bae Ray Reeves Christine Iacobuzio-Donahue David L Huso Linda M S Resar
author_sort	Amy Belton
title	HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.
title_short	HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.
title_full	HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.
title_fullStr	HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.
title_full_unstemmed	HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.
title_sort	hmga1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/cf7f5c65cba94c97b365e6fa24a397bf
work_keys_str_mv	AT amybelton hmga1inducesintestinalpolyposisintransgenicmiceanddrivestumorprogressionandstemcellpropertiesincoloncancercells AT alexandergabrovsky hmga1inducesintestinalpolyposisintransgenicmiceanddrivestumorprogressionandstemcellpropertiesincoloncancercells AT youngkyungbae hmga1inducesintestinalpolyposisintransgenicmiceanddrivestumorprogressionandstemcellpropertiesincoloncancercells AT rayreeves hmga1inducesintestinalpolyposisintransgenicmiceanddrivestumorprogressionandstemcellpropertiesincoloncancercells AT christineiacobuziodonahue hmga1inducesintestinalpolyposisintransgenicmiceanddrivestumorprogressionandstemcellpropertiesincoloncancercells AT davidlhuso hmga1inducesintestinalpolyposisintransgenicmiceanddrivestumorprogressionandstemcellpropertiesincoloncancercells AT lindamsresar hmga1inducesintestinalpolyposisintransgenicmiceanddrivestumorprogressionandstemcellpropertiesincoloncancercells
_version_	1718423377418387456

HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.

Ejemplares similares