Loss of HLTF function promotes intestinal carcinogenesis

Molecular Cancer

Research

Zinnatun Nabi¹  Hao Ding¹  Xiaoli Wu¹  Sumit Sandhu¹  Mojgan Rastegar²  Sabine Mai³  Sam Kung⁴ 

[1] Department of Biochemistry and Medical Genetics, University of Manitoba, 745 Bannatyne Avenue, MB R3E 0J9, Winnipeg, Canada;Department of Biochemistry and Medical Genetics, University of Manitoba, 745 Bannatyne Avenue, MB R3E 0J9, Winnipeg, Canada;Department of Immunology, University of Manitoba, 750 McDermot Avenue, MB R3E 0T5, Winnipeg, Canada;Regenerative Medicine Program, University of Manitoba, 745 Bannatyne Avenue, MB R3E 0J9, Winnipeg, Canada;Department of Biochemistry and Medical Genetics, University of Manitoba, 745 Bannatyne Avenue, MB R3E 0J9, Winnipeg, Canada;Manitoba Institute of Cell Biology, 675 McDermot Avenue, MB R3E 0V9, Winnipeg, Canada;Department of Immunology, University of Manitoba, 750 McDermot Avenue, MB R3E 0T5, Winnipeg, Canada;

关键词: HLTF;    Mouse gene-targeting;    Adenomatous polyposis coli (Apc);    Intestinal adenocarcinoma;    Colonic tumor or cancer;    Chromosomal instability;    HCT116 cells;   

DOI  :  10.1186/1476-4598-11-18

 received in 2012-01-16, accepted in 2012-03-27,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundHLTF (Helicase-like Transcription Factor) is a DNA helicase protein homologous to the SWI/SNF family involved in the maintenance of genomic stability and the regulation of gene expression. HLTF has also been found to be frequently inactivated by promoter hypermethylation in human colon cancers. Whether this epigenetic event is required for intestinal carcinogenesis is unknown.ResultsTo address the role of loss of HLTF function in the development of intestinal cancer, we generated Hltf deficient mice. These mutant mice showed normal development, and did not develop intestinal tumors, indicating that loss of Hltf function by itself is insufficient to induce the formation of intestinal cancer. On the Apcmin/+ mutant background, Hltf- deficiency was found to significantly increase the formation of intestinal adenocarcinoma and colon cancers. Cytogenetic analysis of colon tumor cells from Hltf-/-/Apcmin/+ mice revealed a high incidence of gross chromosomal instabilities, including Robertsonian fusions, chromosomal fragments and aneuploidy. None of these genetic alterations were observed in the colon tumor cells derived from Apcmin/+ mice. Increased tumor growth and genomic instability was also demonstrated in HCT116 human colon cancer cells in which HLTF expression was significantly decreased.ConclusionTaken together, our results demonstrate that loss of HLTF function promotes the malignant transformation of intestinal or colonic adenomas to carcinomas by inducing genomic instability. Our findings highly suggest that epigenetic inactivation of HLTF, as found in most human colon cancers, could play an important role in the progression of colon tumors to malignant cancer.

【 授权许可】

Unknown   
© Sandhu et al; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.