Frequent overexpression of HMGA2 in human atypical teratoid/rhabdoid tumor and its correlation with let-7a3/let-7b miRNA.

Abstract

PURPOSE:

Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive pediatric malignancies characterized by biallelic inactivation of the SMARCB1 tumor suppressor gene. We searched for novel genomic aberrations by investigating the copy number and expression alterations of let-7a3/let-7b microRNA (miRNA) and correlated these with expression of high-mobility group AT-hook 2 (HMGA2) oncoprotein, a target of let-7 miRNA family, in 18 AT/RT samples to elucidate potential roles of HMGA2 in the pathogenesis of AT/RT.

EXPERIMENTAL DESIGN:

Genomic aberrations, let-7a3/let-7b miRNA and HMGA2 expression in AT/RT tissues were identified using quantitative PCR, reverse transcription PCR (RT-PCR), and immunohistochemistry. The impact of let-7b miRNA on HMGA2 expression and the malignant potential of human rhabdoid tumor cell G401 (SMARCB1(-/-)) were investigated by antisense inhibition and ectopic overexpression studies.

RESULTS:

The copy number of let-7a3/let-7b miRNA was substantially decreased in 4 of 11 AT/RT samples. A significantly inverse correlation between let-7a3/let-7b miRNA expression and HMGA2 mRNA expression was observed in AT/RT tissues (R = -0.34; P < 0.05). Immunohistochemistry analysis demonstrated that HMGA2 was highly overexpressed in 83.3% (15 of 18) of AT/RT tissues. Restoration of let-7 miRNA or knockdown of HMGA2 expression significantly suppressed proliferation and colony formation, and almost abolished the invasive potential of G401 cells.

CONCLUSION:

Reduction of let-7a3/let-7b miRNA may be one of mechanisms leading to overexpression of HMGA2 in AT/RT tissues. HMGA2 oncoprotein plays critical roles in the pathogenesis of AT/RT development; and reconstitution of let-7 miRNA or knockdown of HMGA2 oncoprotein may provide a novel therapeutic strategy for the treatment of patients with AT/RT.

• Authors: Keqiang Zhang, Hanlin Gao, Xiwei Wu, Jinhui Wang, Wendi Zhou, Guihua Sun, Jinghan Wang, Yafan Wang, Bing Mu, Charles Kim, Peiguo Chu, Donald M Ho, David K Ann, Tai-Tong Wong, Yun Yen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 5 Pg. 1179-89 (Mar 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24423609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 AACR

Chemical References

• Chromosomal Proteins, Non-Histone
• DNA-Binding Proteins
• HMGA2 Protein
• MicroRNAs
• SMARCB1 Protein
• SMARCB1 protein, human
• Transcription Factors
• Tumor Suppressor Proteins
• mirnlet7 microRNA, human

Topics

• Cell Line, Tumor
• Cell Proliferation
• Chromosomal Proteins, Non-Histone (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Exome
• Female
• Gene Deletion
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Gene Silencing
• HMGA2 Protein (genetics, metabolism)
• High-Throughput Nucleotide Sequencing
• Humans
• Immunohistochemistry
• MicroRNAs (genetics, metabolism)
• Rhabdoid Tumor (genetics, metabolism, pathology)
• SMARCB1 Protein
• Transcription Factors (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• Young Adult