Molecular characterization of a novel gene JK-1 for its roles of molecular pathogenesis in human esophageal squamous cell carcinoma (ESCC) and the anti-cancer effects of gleditsia sinensis extract (GSE) on ESCC cell lines

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Molecular characterization of a novel gene JK-1 for its roles of molecular pathogenesis in human esophageal squamous cell carcinoma (ESCC) and the anti-cancer effects of gleditsia sinensis extract (GSE) on ESCC cell lines

 

Author: Tang, Wing-ka
Title: Molecular characterization of a novel gene JK-1 for its roles of molecular pathogenesis in human esophageal squamous cell carcinoma (ESCC) and the anti-cancer effects of gleditsia sinensis extract (GSE) on ESCC cell lines
Degree: M.Phil.
Year: 2007
Subject: Hong Kong Polytechnic University -- Dissertations.
Esophagus -- Cancer.
Esophagus -- Cancer -- Genetic aspects.
Esophagus -- Cancer -- Treatments.
Department: Dept. of Applied Biology and Chemical Technology
Pages: xxiii, 223 leaves : ill. (some col.) ; 30 cm.
Language: English
InnoPac Record: http://library.polyu.edu.hk/record=b2116701
URI: http://theses.lib.polyu.edu.hk/handle/200/3353
Abstract: Esophageal squamous cell carcinoma (ESCC) has a high mortality rate and shows high frequency of occurrence in Asian regions, including China. Despite advances in multimodality treatments, the 5-year survival rate remains low. Previous analysis of genomic DNA of ESCC using comparative genomic hybridization indicated that amplification of chromosome 5p regions is a common event in ESCC cell lines and patient cases of Hong Kong Chinese origin, and the results suggest that the genes located in chromosome 5p regions may play crucial roles in molecular pathogenesis of ESCC. In the present study, a novel gene JK-1 which is located at 5p 15.1 and is downstream to d-catenin was characterized for its roles in the molecular pathogenesis of ESCC. Thirteen ESCC cell lines and 29 surgical specimens of ESCC were studied for the overexpression of JK-1 using multiplex RT-PCR analysis. The transforming capacity of overexpression of JK-1 was also investigated by transfecting NIH 3T3 and HEK 293 cells with the expression vector cloned with JK-1, followed by the soft agar and foci formation assays. JK-1 was overexpressed in 9/13 (69%) of ESCC cell lines and 9/29 (31%) of ESCC patient cases. Both NIH 3T3 and HEK 293 cells acquired anchorage independent growth in soft agar and properties of loss of contact inhibition when JK-1 was overexpressed. Most significantly, subcutaneous sarcomas were formed in all (3/3) the athymic nude mice after NIH 3T3 cells overexpressing JK-1 were injected subcutaneously. Our results thus indicated that JK-1 is commonly overexpressed in ESCC and has a prominent capacity to transform normal cells. Moreover, previous studies showed that the anomalous fruit extract of Gleditsia sinensis (GSE) exhibited the anti-cancer properties in various tumors in vitro. However, the other potential anti-cancer effects of GSE, including changes in oncogenic expression and telomerase activities, in ESCC have not been studied before. The anti-cancer effects of GSE were demonstrated in three ESCC cell lines (HKESC-1, HKESC-2 and SLMT-1) using MTS and anchorage-independent clongenicity assays, expression studies on commonly overexpressed oncogenes at 11q13 region in ESCC (CCND1, INT2, FGF4 and EMS1) and JK-1 by multiplex RT-PCR analysis, and real-time quantitative telomeric repeat amplification protocol assay to show the inhibitory effect on telomerase in ESCC. The means of MTS50 of GSE for the ESCC cell lines and non-tumor NIH 3T3 cells were 21ug/ml and 163ug/ml respectively. The anchorage-independent clongenicity assay showed that SLMT-1 cells lost their colony-forming potential which was dose-dependent to GSE. Moreover, GSE could demonstrate the dose-dependent suppression on the expressions of JK-1, INT2, EMS1 and FGF4, and inhibition of the telomerase activity in the ESCC cell lines. Our overall results thus provide the first evidence that the overexpression of JK-1 and its transforming capacity in normal cells may play a critical role in the molecular pathogenesis of ESCC and the anti-cancer effects of GSE on ESCC involve the suppression of oncogenic expression and inhibition of telomerase activity. Our studies also provide the foundation for the further development of GSE as a novel anti-cancer agent for ESCC and possibly for other cancers.

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