Cancer mortality and morbidity are mainly related to recurrent chemoresistant diseases in which the molecular mechanisms are poorly understood. The objective of this study is to i) determine the biological roles of a new cancer recurrence-associated gene called NAC-1 (a member of the BTB/POZ gene family), in the development of drug recurrence and to ii) assess the molecular pathways of NAC-1 in contributing to cell survival and chemoresistance. The current project is based on our previous proposal (CA103937) which aimed to identify the potential diagnostic and therapeutic molecules in cancer. Among several novel cancer-associated markers we identified in the previous study, we focus on NAC-1 because the gene is preferentially expressed in recurrent chemoresistant ovarian cancer and its high level of expression in primary tumors is associated with early tumor recurrence. Previous studies have highlighted the emerging roles of BTB/POZ genes such as BCL- 6 in human cancer. In our preliminary study, we demonstrate that NAC-1 molecules homo-dimerize through the BTB/POZ domain. Induced expression of the NAC-1 mutant containing only the BTB/POZ domain disrupts NAC-1 dimerization, prevents tumor formation and promotes tumor cell apoptosis in a mouse xenograft model. Over-expression of NAC-1, on the other hand, enhances tumor growth of ovarian surface epithelial cells and NIH3T3 cells in mice. Based on these findings, we hypothesize that NAC-1 molecules contribute to tumor recurrence by enhancing tumor growth and chemoresistance through NAC-1 homodimerization. The oncogenic phenotypes of NAC-1 are mediated by its downstream genes including Gadd45GIP1 that participates in the Gadd45 pathway. To test this hypothesis, we proposed the following aims.
Aim 1 : Determine whether NAC-1 upregulation contributes to the development of drug resistance.
Aim 2 : Characterize the NAC-1 controlled downstream target genes that are essential for drug resistance and/or survival in tumor cells.
Aim 3 : Assess if Gadd45GIP1 mediates the functions of NAC-1 through the Gadd45 pathway. It is expected that the results from this study will elucidate the roles of NAC-1 in tumor progression and will provide the molecular foundation for future development of NAC-1 targeted therapy in recurrent cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103937-08
Application #
8196865
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2007-12-05
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
8
Fiscal Year
2012
Total Cost
$328,003
Indirect Cost
$128,001
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Yu, Yu; Gaillard, Stephanie; Phillip, Jude M et al. (2015) Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules. Cancer Cell 28:82-96
Jung, Jin-Gyoung; Stoeck, Alexander; Guan, Bin et al. (2014) Notch3 interactome analysis identified WWP2 as a negative regulator of Notch3 signaling in ovarian cancer. PLoS Genet 10:e1004751
Wu, Ren-Chin; Ayhan, Ayse; Maeda, Daichi et al. (2014) Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy. J Pathol 232:473-81
Gao, Min; Wu, Ren-Chin; Herlinger, Alice L et al. (2014) Identification of the NAC1-regulated genes in ovarian cancer. Am J Pathol 184:133-40
Guan, Bin; Magomi, Tae; Wang, Tian-Li et al. (2013) Establishing isogenic inducible cell lines using founder reporter lines and recombinase-mediated cassette exchange. Biotechniques 55:233-42
Yap, Kai Lee; Sysa-Shah, Polina; Bolon, Brad et al. (2013) Loss of NAC1 expression is associated with defective bony patterning in the murine vertebral axis. PLoS One 8:e69099
Sheu, Jim Jinn-Chyuan; Choi, Jung Hye; Guan, Bin et al. (2013) Rsf-1, a chromatin remodelling protein, interacts with cyclin E1 and promotes tumour development. J Pathol 229:559-68
Gao, Min; Shih, Ie-Ming; Wang, Tian-Li (2012) The role of forkhead box Q1 transcription factor in ovarian epithelial carcinomas. Int J Mol Sci 13:13881-93
Kuhn, Elisabetta; Kurman, Robert J; Soslow, Robert A et al. (2012) The diagnostic and biological implications of laminin expression in serous tubal intraepithelial carcinoma. Am J Surg Pathol 36:1826-34
Thiaville, Michelle M; Stoeck, Alexander; Chen, Li et al. (2012) Identification of PBX1 target genes in cancer cells by global mapping of PBX1 binding sites. PLoS One 7:e36054

Showing the most recent 10 out of 70 publications