Dr. Ma's overall goal is to acquire the skills and knowledge to pursue research in the field of human cancer biology and become an independent physician-scientist in this field, which is a considerable departure from his prior experience. Pursuing the outlined practical and didactic training and other mentored activities will be key toward achieving this end. The overall research goal is to elucidate the role of the homeobox gene Hsal 2 in ovarian cancer initiation and development. Determining the underlying mechanisms of this very aggressive cancer is critical for developing new therapies and improving survival. The PI's prior research demonstrated a new tumor suppressor gene, Hsal 2, homologous to the Sal homeobox gene in Drosophila, that is altered or missing in most ovarian epithelial cancer cells. Re-expression of this gene inhibits growth and DNA synthesis of an ovarian cancer cell line and inhibits tumor formation in nude mice. The PI has also demonstrated that the transcriptional regulation of Hsal 2 is controlled by two independent promoters and that Hsal 2 promoter usage is altered in some human cancers. In mice, Hsal 2 is able to bind to the large T antigen of polyoma virus, a virus that induces a broad variety of neoplasms. His studies provide strong evidence that Hsal 2 may be a potential tumor suppressor gene for ovarian cancer. These and other observations led to the hypothesis that Hsal 2 isoforms may play a role in the initiation and development of ovarian cancer. To test this, two specific aims will examine the functional roles and underlying mechanisms of expression of Hsal 2 isoforms.
Aim 1 will determine the role of altered Hsal 2 isoform expression in ovarian cancer initiation and progression by studying the effect of Hsal 2 isoform overexpression on tumorigenicity, identifying target genes that are subordinate to Hsal 2 isoform expression, and characterizing upstream regulators of Hsal 2 isoforms.
Aim 2 will determine the underlying mechanism of altered Hsal 2 isoform expression in ovarian cancer by delineating the usage of Hsal 2 P1 and P2 promoters and measuring the methylation status of CpG islands in Hsal 2 isoform promoters and correlating this with their expression in ovarian cancer. These studies will provide insight into the mechanism(s) of Hsal 2 in controlling growth and differentiation of ovarian normal epithelial cells. If down-regulation of Hsal 2 is shown to activate certain oncogenic pathways or repress tumor suppressor gene pathway(s) in ovarian cancer cells, therapeutic drugs that specifically target these pathways could be designed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA097185-01A1
Application #
6680966
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$133,650
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Lu, Jiayun; Jeong, Ha-Won; Jeong, Hawon et al. (2009) Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. PLoS One 4:e5577
Yang, Jianchang; Chai, Li; Gao, Chong et al. (2008) SALL4 is a key regulator of survival and apoptosis in human leukemic cells. Blood 112:805-13
Yang, Jianchang; Chai, Li; Liu, Fang et al. (2007) Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Natl Acad Sci U S A 104:10494-9
Chai, Li; Yang, Jianchang; Di, Chunhui et al. (2006) Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development. J Biol Chem 281:18918-26
Ma, Yupo; Cui, Wei; Yang, Jianchang et al. (2006) SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood 108:2726-35
Zhang, Jinqiu; Tam, Wai-Leong; Tong, Guo Qing et al. (2006) Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 8:1114-23