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ABSTRACT: Metastatic cancer is one of the main causes of cancer-related death since they rarely respond to available treatments. Recently, certain compounds isolated from the dietary supplement, garlic, have shown anti-proliferation effect on cancer cells. The aim of this study was to investigate whether certain garlic derivatives had any effect on the potentially invasive androgen-independent prostate cancer (PCa) cells. Using colony-forming, wound-closure as well as matrigel-invasion assays, we found that two main water-soluble constituents of the garlic, S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC), were able to suppress PCa cell proliferation and invasive abilities. This inhibitory effect was associated with induction of mesenchymal to epithelial transition. Most importantly, the SAC and SAMC treatment led to restoration of E-cadherin expression at transcription and protein levels. In contrast, the expression of E-cadherin repressor, Snail, was reduced in the SAC- and SAMC-treated cells. Furthermore, examination of cell lines from other types of cancer (ovarian, nasopharyngeal and esophageal carcinomas) also confirmed that the effect of SAC and SAMC on activation of E-cadherin might be a general effect on human cancer cells. Our results demonstrate a novel anticancer effect of garlic and suggest that certain garlic-derived compounds may be potential agents for suppression of invasive growth through restoration of E-cadherin expression in cancer cells.
Carcinogenesis 12/2006; 27(11):2180-9. · 5.70 Impact Factor
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Hing Lok Wong,
Xianghong Wang,
Raymond Chuen-Chung Chang,
Dong-Yan Jin, Huichen Feng,
Qi Wang,
Kwok-Wai Lo,
Dolly P Huang,
Po Wing Yuen,
Kenzo Takada,
Yong Chuan Wong,
Sai Wah Tsao
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ABSTRACT: Epstein-Barr virus (EBV) infection is closely associated with the development of nasopharyngeal carcinoma (NPC). The EBV-encoded RNAs (EBERs) are the most abundant EBV transcripts (about 10(7) copies per cell) in EBV infected cells. However, the cellular function of EBER expression, particularly in nasopharyngeal epithelial cells, remains poorly understood. EBERs acquire secondary structures analogous to double-stranded RNA (dsRNA) and may bind to the double-stranded RNA-dependent protein kinase (PKR) and interfere with its function. Activation of PKR involves autophosphorylation resulting in protein synthesis inhibition and cellular apoptosis. Induction of cellular apoptosis by activation of PKR may be an antiviral response adopted by virally infected cells. We have examined the functional properties of EBER expression in an immortalized nasopharyngeal epithelial cell line (NP69). Expression of EBERs was achieved by transfecting the NP69 cells with an EBER-expressing plasmid, pESK10. The EBER-expressing NP69 cells attained a higher growth rate compared to cells transfected with control plasmid (pcDNA3). However, the EBER-expressing NP69 cells did not form colonies in soft agar and were non-tumorigenic in nude mice. To investigate if EBERs may protect the nasopharyngeal epithelial cells from apoptotic insults, we treated the EBER-expressing NP69 cells with a dsRNA analogue, poly(I).poly(C) (pIC), to activate PKR in cells and examined for their responses. Lower level of PKR phosphorylation and elevation of Bcl-2 were observed in EBER-expressing NP69 cells. In addition, other apoptotic markers including the cleaved forms of caspase-3 and poly(ADP)ribose polymerase (PARP) were found to be lower in EBER-expressing NP69 cells after treatment with pIC. Lower phosphorylation levels of p38 MAPK (mitogen-activated protein kinase) and c-jun were also observed in EBER-expressing NP cells. Our results suggest that EBER expression may confer an apoptotic-resistant phenotype in immortalized nasopharyngeal epithelial cells.
Molecular Carcinogenesis 11/2005; 44(2):92-101. · 3.16 Impact Factor
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ABSTRACT: To assess the differential gene expression in neoplastic and normal trophoblastic cells and evaluate the effect of methylation on tissue inhibitor of metalloproteinase 3 (TIMP3) expression in choriocarcinoma (CCA) cells.
The Atlas Human Cancer 1.2 Array (Clontech) was used to compare differential gene expression in a trophoblastic cell line (B6) established from first term placenta with two choriocarcinoma cell lines (JAR and JEG-3). The differentially expressed candidate genes in the placental and malignant trophoblastic cells in these cell lines were confirmed by real-time polymerase chain reaction (PCR), Western blotting and immunohistochemistry. Differential expression of a specific gene, TIMP3, was confirmed by immunohistochemistry using clinical specimens of choriocarcinoma and placenta. The involvement of promoter methylation in suppression of TIMP3 expression in choriocarcinoma was examined using methylation-specific PCR (MSP) and demethylation treatment.
Differential expression of 23 genes was observed in choriocarcinoma cell lines compared to the placental trophoblastic cells using the cDNA array analysis (Atlas Human Cancer Array, Clontech). Among these differentially expressed genes, down-regulation of TIMP3, PLAB, IGFBP3 and up-regulation of CCNB1 were confirmed by real-time PCR determination. Reduced expression of TIMP3 was further confirmed in clinical samples of choriocarcinoma by immunohistochemical staining. Methylation of TIMP3 promoter was detected in choriocarcinoma cell lines and clinical samples of choriocarcinoma. Treatment with a demethylation drug, 5-aza-2'-deoxycytidine, in choriocarcinoma cell lines restored TIMP3 expression.
Down-regulation of TIMP3, PLAB, IGFBP3 and up-regulation of CCNB1 were observed in choriocarcinoma cells compared to placental trophoblasts. Down-regulation of TIMP3 expression was confirmed in clinical specimens of choriocarcinoma and may play a role in its pathogenesis. Promoter methylation of the TIMP3 is involved in suppression of TIMP3 expression. Differentiation expression of TIMP3 in choriocarcinoma may have potential application in clinical diagnosis and patient treatment.
Gynecologic Oncology 09/2004; 94(2):375-82. · 3.89 Impact Factor
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ABSTRACT: To investigate the correlation between BRI gene expression and the metastatic potential in human non small cell lung cancer cell lines.
BRI gene differential expression was detected between human lung adenocarcinoma cell lines AGZY83-a and Anip973 by RT-PCR and Northern blot. Anip973 was isolated from AGZY83-a with a higher metastatic potential than its parent line. Other 6 human non small cell lung cancer cell lines, A549, TKB-18, SPC-A-1, GLC-82, 95D and PAa, were also detected for the relationship between BRI expression and metastatic potential.
There was a significant difference in BRI gene expression between AGZY83-a and Anip973 cell lines. BRI was overexpressed in Anip973 cells comparing to AGZY83-a cells. Up regulation of BRI gene was also observed in other 6 lung cancer cell lines, and partly correlated with their metastatic potential. Furthermore, there were two mRNA transcripts in the lung cancer cells, in which the 1.6 kb transcript was the major one.
The up-regulated expression of BRI 1.6 kb mRNA transcript may indicate the formation of metastatic potential of NSCLC. BRI is possibly a metastasis related gene.
Zhongguo fei ai za zhi = Chinese journal of lung cancer 02/2004; 7(1):12-5.
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ABSTRACT: To search the candidate gene in the development and metastasis of lung adenocarcinoma and shed light on the possible molecular mechanism of the development of lung carcinoma.
Using methods of cell culture, reverse transcription-PCR, RH gene mapping and RNA in situ hybridization.
The cDNA fragment named OPB7-1 was mapped at 1p31-1p34 by RH gene mapping method. The fragment sequences obtained from lung cDNA library of normal person and cell line of AGZY83-a were similar in length but showed individual base difference. For OPB7-1, there is a low homogeneity to known gene by analysis in GenBank, but 3 contigs homologous to OPB7-1 were located at chromosome 1(1p31-1p34). Different degrees of expression were noted in tumor tissues from 24 cases of lung carcinoma, however no significant expression was found in their corresponding normal tissues. And high expression was found in the lung tissues of cases with lymph node metastasis.
OPB7-1 may be a novel gene. It may be a tumor related gene in occurrence and metastasis of lung carcinoma.
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 05/2003; 20(2):156-9.
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ABSTRACT: Mitotic arrest deficient 2 (MAD2) is thought to be a key component of the mitotic checkpoint, which ensures accurate chromosome segregation. Reduced expression of MAD2 protein is associated with mitotic checkpoint abrogation and chromosomal instability in certain types of human cancers. To explore the possibility of developing a novel strategy for the treatment of cancer based on selective killing of mitotic checkpoint-defective or -competent cells, here we have investigated the effect of MAD2 expression on cellular sensitivity to checkpoint-targeting anticancer drugs. We reintroduced MAD2 protein in a mitotic checkpoint-defective nasopharyngeal carcinoma cell line, CNE2, using an inducible expression vector. We found that overexpression of MAD2 led to an increased sensitivity to vincristine, which was accompanied by increased mitotic index and G2/M cell cycle arrest. In addition, increased phosphorylation of Raf, MEK1/2 and Bcl-2 was observed in MAD2-overexpressing cells in response to vincristine. Furthermore, inhibition of phosphorylation of MEK1/2 by its inhibitor PD098059 led to reduced sensitivity to vincristine, which was associated with decreased Bcl-2 phosphorylation. Our data suggest a role for MAD2 in the sensitization of cancer cells to certain mitotic checkpoint-targeting anticancer drugs.
Oncogene 02/2003; 22(1):109-16. · 6.37 Impact Factor
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Sai Wah Tsao,
Xianghong Wang,
Yu Liu,
Yuk Chun Cheung, Huichen Feng,
Zhong Zheng,
Natalie Wong,
P W Yuen,
Angela K F Lo,
Y C Wong,
D P Huang
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ABSTRACT: Nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia, especially in southern China. One of the most striking features of this disease is its close relationship with Epstein-Barr Virus (EBV). However, to date there is no direct study on the mechanisms involved in the role of EBV in the tumorigenesis of NPC, largely due to lack of an experimental model. Available hypotheses on the association between EBV and NPC are generated from non-nasopharyngeal epithelial cell systems such as human keratinocytes or mouse epithelial cells, which may not truly represent the biological properties of nasopharyngeal epithelial (NP) cells. In this study, we report the establishment of two immortalized NP cell lines, NP69SV40T and NP39E6/E7, using SV40T and HPV16E6/E7 oncogenes. We found that NP60SV40T and NP39E6/E7 cell lines not only maintained many characteristics of normal NP cells (i.e. keratin profile and responsive to TGFbeta inhibition) but also highly responsive to one of the EBV encoded genes, LMP1. Comparative genome hybridization (CGH) analysis showed that these two cell lines contained multiple genetic alterations, some of which have been described in NPC. The immortalized NP cell lines are non-tumorigenic and exhibit anchorage-dependent growth. These cell lines may provide a possible cell model system for studying the mechanisms involved in the tumorigenesis of NPC.
Biochimica et Biophysica Acta 07/2002; 1590(1-3):150-8. · 4.66 Impact Factor
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ABSTRACT: Chromosome instability is a commonly observed feature in ovarian carcinoma. Mitotic checkpoint controls are thought to be essential for accurate chromosomal segregation, and MAD2 is a key component of this checkpoint. In this study, we investigated the competence of the mitotic checkpoint and its relationship to the expression of MAD2 protein in seven ovarian cancer cell lines. We found that a significant number (43%, three of seven cell lines) of the tested ovarian cancer cells failed to arrest in the G(2)-M phase of the cell cycle in response to microtubule disruption. This loss of mitotic checkpoint control was associated with reduced expression of the MAD2 protein. To additionally understand the significance of the MAD2 to mitotic checkpoint control, we established an inducible expression system in which MAD2 was induced by the addition of ponasterone A. Notably, the induced expression of MAD2 in two checkpoint-defective ovarian cancer cell lines led to the restoration of mitotic checkpoint response to spindle-disrupting agents. Taken together, our findings suggest that the steady-state amount of MAD2 inside cells may represent a molecular switch for mitotic checkpoint control. This provides a novel insight into the molecular basis of CIN in ovarian carcinoma and has implications for effective use of checkpoint-targeting drugs.
Cancer Research 04/2002; 62(6):1662-8. · 7.86 Impact Factor
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ABSTRACT: Gastric cancer is the second most common cause of cancer-related death worldwide and the highest incidence of this cancer has been reported in Asia, especially in China. Identification of early stage lesions is vital in achieving high survival rate. However, due to the lack of reliable biomarkers, the majority of gastric cancer is presented at an advanced stage. Recently, it has been reported that Id-1, a helix-loop-helix protein, may be a valuable diagnostic marker in many types of human cancer. In this study, we evaluated Id-1 protein expression in gastric cancer specimens and compared it with non-malignant tissues. In addition, to investigate whether Id-1 expression levels were associated with the aggressiveness of this disease as implicated in other cancer types, we also assessed Id-1 expression levels in primary tumours and their lymph node metastasized lesions. Our results indicate that up-regulation of Id-1 is a frequent event in gastric cancer but its expression levels are not associated with tumour metastasis. Our evidence provides a possible novel marker for the diagnosis of gastric cancer.
Anticancer research 24(2B):881-6. · 1.73 Impact Factor
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Sai Wah Tsao,
Xianghong Wang,
Yu Liu,
Yuk Chun Cheung, Huichen Feng,
Zhong Zheng,
Natalie Wong,
P.W Yuen,
Angela K.F Lo,
Y.C Wong,
D.P Huang
[show abstract]
[hide abstract]
ABSTRACT: Nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia, especially in southern China. One of the most striking features of this disease is its close relationship with Epstein–Barr Virus (EBV). However, to date there is no direct study on the mechanisms involved in the role of EBV in the tumorigenesis of NPC, largely due to lack of an experimental model. Available hypotheses on the association between EBV and NPC are generated from non-nasopharyngeal epithelial cell systems such as human keratinocytes or mouse epithelial cells, which may not truly represent the biological properties of nasopharyngeal epithelial (NP) cells. In this study, we report the establishment of two immortalized NP cell lines, NP69SV40T and NP39E6/E7, using SV40T and HPV16E6/E7 oncogenes. We found that NP60SV40T and NP39E6/E7 cell lines not only maintained many characteristics of normal NP cells (i.e. keratin profile and responsive to TGFβ inhibition) but also highly responsive to one of the EBV encoded genes, LMP1. Comparative genome hybridization (CGH) analysis showed that these two cell lines contained multiple genetic alterations, some of which have been described in NPC. The immortalized NP cell lines are non-tumorigenic and exhibit anchorage-dependent growth. These cell lines may provide a possible cell model system for studying the mechanisms involved in the tumorigenesis of NPC.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.
