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Am J Pathol. 2009 Mar;174(3):854-68. doi: 10.2353/ajpath.2009.080523. Epub 2009 Jan 29.

HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells.

Author information

1
Department of Regeneration Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.

Abstract

Pancreatic cancer is a highly aggressive malignancy due to elevated mitotic activities and epithelial-mesenchymal transition (EMT). Oncogenic RAS and transforming growth factor-beta signaling are implicated in these malignant features. The mechanisms that underlie EMT need to be addressed since it promotes tissue invasion and metastasis. The high-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor that is primarily expressed in undifferentiated tissues and tumors of mesenchymal origin. However, its role in EMT in pancreatic cancer is largely unknown. Here we report that HMGA2 is involved in EMT maintenance in human pancreatic cancer cells. Specific knockdown of HMGA2 inhibited cell proliferation, leading to an epithelial-state transition that restores cell-cell contact due to E-cadherin up-regulation. Consistently, an inverse correlation between HMGA2-positive cells and E-cadherin-positive cells was found in cancer tissues. Inhibition of the RAS/MEK pathway also induced an epithelial transition, together with HMGA2 down-regulation. Transcriptional repressors of the E-cadherin gene, such as SNAIL, decreased after HMGA2 knockdown since HMGA2 directly activated the SNAlL gene promoter. The decrease of SNAIL after RAS/MEK inhibition was suppressed by HMGA2 overexpression. Further, let-7 microRNA-mediated HMGA2 down-regulation had no effect on the prevention of the transformed phenotype in these cells. These data shed light on the importance of HMGA2 in reversibly maintaining EMT, suggesting that HMGA2 is a potential therapeutic target for the treatment of pancreatic cancer.

PMID:
19179606
PMCID:
PMC2665746
DOI:
10.2353/ajpath.2009.080523
[Indexed for MEDLINE]
Free PMC Article

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