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Significance of the granulin-epithelin precursor (GEP) gene in hepatocellular carcinoma

by Wong, San-yu

Abstract (Summary)
(Uncorrected OCR) Abstract of thesis entitled

"Significance ofthe Granulin-Epithelin Precursor (GEP) gene in Hepatocellular Carcinoma"

Submitted by

Wong San Yu, Ashley

for the degree of Master of Philosophy at The University of Hong Kong

in August 2003

Hepatocellular carcinoma (HCe) is one of the most common malignancies worldwide, and the annual incidence is estimated as 1 million globally. There is an urgent need for understanding the molecular mechanism for HCC development and progression for better disease management. From our earlier global gene expression studies, the granulin-epithelin precursor (GEP) gene has shown frequent up-regulation in tumor compared to their paralleled non-tumor liver tissues. GEP was investigated in the present study for its clinical significance and functional role.

GEP protein expression pattern in various human liver samples was examined by immunohistochemistry method. The study included 110 pairs of HCC tumor tissues and their paralleled non-tumor liver samples, 20 cirrhotic liver specimens from non-cancer patients, and 22 normal livers from healthy individuals. Overexpression of GEP protein was frequently detected in HCCs (85/110, 77.3%), but it was rarely detected in the adjacent non-tumor liver tissues, cirrhotic liver and normal liver. Strong GEP over-expression was associated with the tumors that demonstrated presence of venous infiltration, large tumor size (~ 5 cm), absence of tumors capsule, and high serum alpha fetoprotein (AFP) level (~ 100ng/ml). All of

the correlations were statistically significant (chi-squared test, P < 0.05).

Functional role of GEP was evaluated by in vitro and in vivo assays using stable transfection approach in human HCC cell lines. The parental cell lines Hep3B and Huh-7, which expressed high level of endogenous GEP, were transfected with the GEP anti-sense cDNA. The transfectants demonstrated 2.5 to 6.0-fold reduction in GEP protein expression. Decreased GEP level led to the decreased cell proliferation rate as revealed by cell count and MTT assay, decreased cell invasion ability as shown by Matrigel invasion assay, decreased anchorage-independency as demonstrated by soft agar assay. Furthermore, reduction of GEP expression also led to reduced incidence of tumor formation and decreased growth rate of the xenograft tumor(s) in athymic nude mice. Therefore, GEP expression was important in controlling the growth, invasion and tumorigenic properties ofHCC.

The GEP associated genes and pathways were examined. In human HCC samples, strong GEP expression was significantly correlated with p53 overexpression (chi-squared test P

In conclusion, overexpression of GEP was common in tumor, but not in adjacent non-tumor liver, benign diseased liver nor normal liver. Strong GEP expression was associated with more aggressive tumors. The current study indicates that GEP plays

an important role in HCC development and progressiOn by controlling cell proliferation, invasion and tumorigenicity. The cell proliferation controlled by GEP in HCC may act through MAPK pathway and/or p53. Further investigation into the mechanism of GEP overexpression and its associated pathways would definitely help to elucidate the mystery of hepatocarcinogenesis and reveal potential targets for disease diagnosis and treatment.

(word count: 500)

Bibliographical Information:

Advisor:

School:The University of Hong Kong

School Location:China - Hong Kong SAR

Source Type:Master's Thesis

Keywords:liver cancer genetic aspects granulocytes epithelium gene expression

ISBN:

Date of Publication:01/01/2003

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