M.D. National Defense Medical Center
Ph.D. University of Texas-Houston M.D Anderson Cancer Center
1. Adenovirus type 5 E1A-mediated tumor suppression in hepatocellular carcinoma (HCC) HCC is resistant to conventional chemotherapy. We examined the synergistic effect of adenovirus type 5 E1A (abbreviated E1A) and gemcitabine on HCC and found that E1A sensitized J5, J7, Huh7, and HepG2 HCC cells to gemcitabine. E1A clearly sensitizes HCC cells to gemcitabine through induction of apoptosis. NF-kB is activated in HCC cells treated with gemcitabine but not in HCC cells that expressed E1A. Occurrence of apoptosis entails cleavage of poly (ADP-ribose) polymerase (PARP), a nuclear protein involved in DNA repair, genome stability, and maintenance of telomere length. Our study also shows that gemcitabine enhanced PARP expression. However, E1A does not induce PARP cleavage but rather suppresses PARP expression at the transcriptional level. Further study shows that both NF-kB and PARP play protective roles in the prevention of E1A+gemcitabine-induced apoptosis.
2. X protein of hepatitis B virus (HBx)-mediated carcinogenesis in hepatocellular carcinoma. It has been known from published reports that HBx up- and down-regulates a lot of genes involved in cell cycle regulation, cell growth and differentiation, apoptosis. Therefore, HBx may also function as a transcriptional co-repressor. We have recently found that HBx resulted in reduced binding of a transcriptional complex to DNA sequence containing a GGCC motif. We have searched the NCBI gene bank and found that promoters of a lot of genes possess the GGCC motif upstream the TATA box. Based on the published reports and our preliminary data, we hypothesize that HBx modulates expression of certain genes by suppressing binding of a transcriptional protein complex to a DNA sequence containing GGCC motif. The major aim of this project is to identify proteins bound to the GGCC motif and determine their function.
3. Cytokine gene polymorphism and gastric cancer. Interleukin-8 (IL-8) is a potent chemokine in attraction of neutrophils and lymphocytes to the sites of inflammation. High local IL-8 contributes to chronic inflammation in tissues insulted by intrinsic or extrinsic factors. Gastric carcinoma is related to Helicobacter pylori infection, which induces IL-8 secretion, gastric ulcer, and carcinoma. We aim to determine whether polymorphism of the IL-8 promoter is related to the development of gastric carcinoma. The –251T allele has stronger promoter activity than the –251A allele by change of a single nucleotide in the IL-8 promoter and is a risk factor for diffuse- and atypical-type gastric carcinoma. Since IL-8 is a potent stimulator of angiogenesis, it may assist diffuse spreading of carcinoma cells in patients with the –251T allele