Individual Projects

WWOX gene expression in Human Hepatocellular Carcinoma

Ileana (Sandra) Aderca
aderca.ileana@mayo.edu
Senior Research Technologist

The WW domain-containing oxidoreductase gene (or WWOX) is a candidate tumor suppressor gene which is located in the 16q23.1- 24.1 region on chromosome 16, within the common fragile site, FRA16D, which is the second most active fragile site in the human genome. Common fragile sites are regions of relative genomic instability which are frequent sites of deletions, breaks, and rearrangment of the genome.

A high frequency of loss of heterozygosity and a number of homozygous genomic deletions have been found in this region in various cancers, including prostate, lung, breast, ovarian, and hepatocellular cancer. Deletions or mutations in the coding region are rarely found in the WWOX gene. A number of research groups have identified the presence of multiple aberrant splice variants of the gene. This project is pursuing the hypothesis that the study of the splice variants will provide novel insights into aspects of human WWOX function in benign and malignant liver cells.

The role of SULF1 in hepatocellular carcinogenesis

Jinping Lai M.D., Ph.D.
lai.jinping@mayo.edu
Research Associate

SULF1 is a recently-described human sulfatase gene which is down-regulated in human cancer cell lines and a proportion of cancer tissues ( Lai, et al. JBC 2003, Gastroenterology 2004 and Oncogene 2004).

The heparin-binding growth factors fibroblast growth factor (FGF) and hepatocyte growth factor (HGF) are potent mitogens for hepatocytes. Heparin-binding growth factor signaling is dependent on the specific sulfation state of cell-surface heparan sulfate proteoglycans (HSPGs). Jin-Ping is exploring the hypothesis that SULF1 regulates growth signaling in hepatocytes by desulfating HSPGs and thus inhibiting cell growth. Downregulation of hSulf1 contributes to the development of liver cancer by enhancing heparin-binding growth factor signaling and resistance to apoptosis.

Finding Epigenetic Markers for Cholangiocarcinoma (CC)

Abdirashid Shire, Ph.D.
shire.abdirashid@mayo.edu
Research Associate

DNA hypermethylation is an epigenetic event that inactivates gene expression through addition of a methyl group at the 5’ carbon position of the cytosine base, and is catalyzed by DNA methyltransferases (DNMTs). In cancer, promoter hypermethylation is important mechanism for transcriptional silencing of tumor suppressor genes. Additionally, chromatin modifications, such as histone deacetylation, affect local chromatin structure and, together with DNA hypermethylation, contribute to inactivation of gene expression. Therefore, histone deacetylation is also important in cancer. In this project, we are identifying novel epigenetic targets that may potentially be useful markers for CC.

Characterization of Heparan Sulfate Glycosaminoglycans (HSGAGs) in Hepatocellular Carcinoma (HCC)

Dr. Roberts’ group recently found that the Sulfatase 1 (SULF1) gene is downregulated in a significant proportion of human HCCs and HCC cell lines. SULF1 is a plasma membrane associated sulfatase. HCC cell lines lacking SULF1 expression are more resistant to induction of apoptosis. Conversely, forced expression of SULF1 significantly decreases cell growth and increases the sensitivity of HCC cell lines to pro-apoptotic agents. SULF1 therefore may either inactivate a cell survival pathway or activate a cell death pathway. Cell survival signaling by a number of growth factors, particularly fibroblast growth factor (FGF), is dependent on the sulfation state of cell surface heparan sulfate glycosaminoglycans (HSGAGs). In this project, we are working on a methodology for the quantitative characterization of HSGAGs purified from hepatocellular carcinoma (HCC) using mass spectrometry techniques. This will allow us to carefully examine the effects of SULF1 on the structure of cell surface HSGAGs from cancer cell lines.