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Kwan Ho Tang,
Yongdong Dai,
Man Tong,
Yuen-Piu Chan,
Pak Shing Kwan,
Li Fu,
Yan-Ru Qin,
Sai Wah Tsao, Hong Lok Lung,
Maria Li Lung,
Daniel K Tong,
Simon Law,
Kwok Wah Chan,
Stephanie Ma,
Xin-Yuan Guan
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ABSTRACT: Tumor-initiating cells (TICs), also known as cancer stem cells, are regarded widely as a specific subpopulation of cells needed for cancer initiation and progression. TICs have yet to be identified in esophageal tumors that have a rising incidence in developed countries. Here we report a CD90+ cell population found in esophageal squamous cell carcinoma (ESCC) which is endowed with stem cell-like properties and high tumorigenic and metastatic potential. mRNA profiling of these cells suggested pathways through which they drive tumor growth and metastasis, with deregulation of an Ets1-MMP signaling pathway and epithelial-mesenchymal transition figuring prominently. These cells possessed higher self-renewal activity and were sufficient for tumor growth, differentiation, metastasis and chemotherapeutic resistance. CD90+ TICs were isolated and characterized from ESCC clinical specimens as well as ESCC cell lines. In freshly resected clinical specimens, they represented a rare cell population the levels of which correlated with strong family histories and lymph node metastasis. Our results prompt further study of this CD90+ population of esophageal TICs as potential therapeutic targets.
Cancer Research 02/2013; · 7.86 Impact Factor
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02/2012; , ISBN: 978-953-307-879-3
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ABSTRACT: The identification of cancer genes in sporadic cancers has been recognized as a major challenge in the field. It is clear that deletion mapping, genomic sequencing, comparative genomic hybridization, or global gene expression profiling alone would not have easily identified candidate tumor suppressor genes (TSGs) from the huge array of lost regions or genes observed in nasopharyngeal carcinoma (NPC). In addition, the epigenetically silenced genes would not have been recognized by the mapping of deleted regions. In this review, we describe how functional approaches using monochromosome transfer may be used to circumvent the above problems and identify TSGs in NPC. A few examples of selected NPC TSGs and their functional roles are reviewed. They regulate a variety of gene functions including cell growth and proliferation, adhesion, migration, invasion, epithelial-mesenchymal transition, metastasis, and angiogenesis. These studies show the advantages of using functional approaches for identification of TSGs.
Seminars in Cancer Biology 12/2011; 22(2):87-95. · 6.47 Impact Factor
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Arthur Kwok Leung Cheung,
Josephine M Y Ko, Hong Lok Lung,
Kwok Wah Chan,
Eric J Stanbridge,
Eugene Zabarovsky,
Takashi Tokino,
Lisa Kashima,
Toshiharu Suzuki,
Dora Lai-Wan Kwong,
Daniel Chua,
Sai Wah Tsao,
Maria Li Lung
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ABSTRACT: Chromosome 14 was transferred into tumorigenic nasopharyngeal carcinoma and esophageal carcinoma cell lines by a microcell-mediated chromosome transfer approach. Functional complementation of defects present in the cancer cells suppressed tumor formation. A candidate tumor-suppressor gene, cysteine-rich intestinal protein 2 (CRIP2), located in the hot spot for chromosomal loss at 14q32.3, was identified as an important candidate gene capable of functionally suppressing tumor formation. Previous studies have shown that CRIP2 is associated with development. To date, no report has provided functional evidence supporting a role for CRIP2 in tumor development. The present study provides unequivocal evidence that CRIP2 can functionally suppress tumorigenesis. CRIP2 is significantly down-regulated in nasopharyngeal carcinoma cell lines and tumors. CRIP2 reexpression functionally suppresses in vivo tumorigenesis and angiogenesis; these effects are induced by its transcription-repressor capability. It interacts with the NF-κB/p65 to inhibit its DNA-binding ability to the promoter regions of the major proangiogenesis cytokines critical for tumor progression, including IL6, IL8, and VEGF. In conclusion, we provide compelling evidence that CRIP2 acts as a transcription repressor of the NF-κB-mediated proangiogenic cytokine expression and thus functionally inhibits tumor formation and angiogenesis.
Proceedings of the National Academy of Sciences 05/2011; 108(20):8390-5. · 9.68 Impact Factor
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Victor Chun Lam Wong,
Han Chen,
Josephine Mun Yee Ko,
Kwok Wah Chan,
Yuen Piu Chan,
Simon Law,
Daniel Chua,
Dora Lai-Wan Kwong, Hong Lok Lung,
Gopesh Srivastava,
Johnny Cheuk On Tang,
Sai Wah Tsao,
Eugene R Zabarovsky,
Eric J Stanbridge,
Maria Li Lung
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ABSTRACT: Suppressive effects of DUSP6 in tumorigenesis and EMT-associated properties were observed. Dual-specificity phosphatase (DUSP6) is a MAP kinase phosphatase (MKP) negatively regulating the activity of ERK, one of the major molecular switches in the MAPK signaling cascade propagating the signaling responses during malignancies. The impact of DUSP6 in EMT and its contribution to tumor dissemination has not yet been characterized. Due to differences in tumor microenvironments affecting cell signaling during cancer progression, DUSP6 may play varying roles in tumor development. We sought to examine the potential role of DUSP6-mediated tumorigenesis and EMT-associated properties in two aerodigestive tract cancers, namely, esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC). Significant loss of DUSP6 was observed in 100% of 11 ESCC cell lines and 71% of seven NPC cell lines. DUSP6 expression was down-regulated in 40% of 30 ESCC tumor tissues and 75% of 20 NPC tumor tissues compared to their respective normal counterparts. Suppressive effects of DUSP6 in tumor formation and cancer cell mobility are seen in in vivo tumorigenicity assay and in vitro colony formation, three-dimensional Matrigel culture, cell migration and invasion chamber tests. Notably, overexpression of DUSP6 impairs EMT-associated properties. Furthermore, tissue microarray analysis reveals a clinical association of DUSP6 expression with better patient survival. Taken together, our study provides a novel insight into understanding the functional impact of DUSP6 in tumorigenesis and metastasis of ESCC and NPC.
International Journal of Cancer 02/2011; 130(1):83-95. · 5.44 Impact Factor
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King Chi Chan,
Josephine Mun Yee Ko, Hong Lok Lung,
Radislav Sedlacek,
Zeng-Feng Zhang,
Dian-Zhong Luo,
Zhen-Bo Feng,
Shuang Chen,
Honglin Chen,
Kwok Wah Chan,
Sai Wah Tsao,
Daniel Tsin-Tien Chua,
Eugene R Zabarovsky,
Eric J Stanbridge,
Maria Li Lung
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ABSTRACT: The association of Matrix metalloproteinase-19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down-regulated in the NPC cell lines. In this study, quantitative RT-PCR and Western blot analysis showed MMP19 was down-regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down-regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down-regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild-type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild-type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony-forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC-1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube-forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme-linked immunosorbent assay (ELISA). The anti-angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti-angiogenic functions in NPC.
International Journal of Cancer 12/2010; 129(8):1826-37. · 5.44 Impact Factor
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Paulisally Hau Yi Lo, Hong Lok Lung,
Arthur Kwok Leung Cheung,
Suneel S Apte,
Kwok Wah Chan,
Fung Mei Kwong,
Josephine Mun Yee Ko,
Yue Cheng,
Simon Law,
Gopesh Srivastava,
Eugene R Zabarovsky,
Sai Wah Tsao,
Johnny Cheuk On Tang,
Eric J Stanbridge,
Maria Li Lung
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ABSTRACT: ADAMTS metalloprotease family member ADAMTS9 maps to 3p14.2 and shows significant associations with the aerodigestive tract cancers esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC). However, the functional impact of ADAMTS9 on cancer development has not been explored. In this study, we evaluated the hypothesized antiangiogenic and tumor-suppressive functions of ADAMTS9 in ESCC and NPC, in stringent tumorigenicity and Matrigel plug angiogenesis assays. ADAMTS9 activation suppressed tumor formation in nude mice. Conversely, knockdown of ADAMTS9 resulted in clones reverting to the tumorigenic phenotype of parental cells. In vivo angiogenesis assays revealed a reduction in microvessel numbers in gel plugs injected with tumor-suppressive cell transfectants. Similarly, conditioned medium from cell transfectants dramatically reduced the tube-forming capacity of human umbilical vein endothelial cells. These activities were associated with a reduction in expression levels of the proangiogenic factors MMP9 and VEGFA, which were consistently reduced in ADAMTS9 transfectants derived from both cancers. Taken together, our results indicate that ADAMTS9 contributes an important function in the tumor microenvironment that acts to inhibit angiogenesis and tumor growth in both ESCC and NPC.
Cancer Research 07/2010; 70(13):5567-76. · 7.86 Impact Factor
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Hong Lok Lung,
Arthur Kwok Leung Cheung,
Yue Cheng,
Fung Mei Kwong,
Paulisally Hau Yi Lo,
Evan Wai Lok Law,
Daniel Chua,
Eugene R Zabarovsky,
Nancy Wang,
Sai Wah Tsao,
Eric J Stanbridge,
Maria Li Lung
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ABSTRACT: THY1 was previously identified as a candidate tumor suppressor gene (TSG) associated with lymph node metastases in nasopharyngeal carcinoma (NPC) through functional studies. It was identified by oligonucleotide microarray analysis as an interesting differentially expressed gene. However, direct functional evidence is still lacking for THY1 being a TSG in NPC, as in vivo tumorigenicity assays have not been previously reported in our last study of THY1. In this study, a tetracycline-inducible expression vector, pETE-Bsd, was used to obtain stable transfectants of THY1. The stringent in vivo tumorigenicity assay results show that the activation of THY1 suppresses tumor formation of HONE1 cells in nude mice, and the tumor formation ability was restored in the presence of doxycycline (a tetracycline analog), when the gene is shut off. Functional inactivation of this gene is observed in all the tumors derived from the tumorigenic transfectant. The tumor suppressive effect could be repressed by knockdown of THY1 expression in nontumorigenic microcell hybrids. Further studies indicate that expression of THY1 inhibits HONE1 cell growth in vitro by arresting cells in G(0)/G(1) phase. It greatly reduces the ability for anchorage-independent growth. The invasiveness of HONE1 cells was also inhibited by the expression of THY1. These findings suggest that THY1 is a TSG in NPC, which is involved in invasion and shows an association with tumor metastasis. Taken together, THY1 clearly plays an important functional role in tumor suppression in NPC.
International Journal of Cancer 11/2009; 127(2):304-12. · 5.44 Impact Factor
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Arthur Kwok Leung Cheung, Hong Lok Lung,
Josephine Mun Yee Ko,
Yue Cheng,
Eric J Stanbridge,
Eugene R Zabarovsky,
John M Nicholls,
Daniel Chua,
Sai Wah Tsao,
Xin-Yuan Guan,
Maria Li Lung
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ABSTRACT: Chromosome 14 allelic loss is common in nasopharyngeal carcinoma (NPC) and may reflect essential tumor suppressor gene loss in tumorigenesis. An intact chromosome 14 was transferred to an NPC cell line using a microcell-mediated chromosome transfer approach. Microcell hybrids (MCHs) containing intact exogenously transferred chromosome 14 were tumor suppressive in athymic mice, demonstrating that intact chromosome 14 NPC MCHs are able to suppress tumor growth in mice. Comparative analysis of these MCHs and their derived tumor segregants identified 4 commonly eliminated tumor-suppressive CRs. Here we provide functional evidence that a gene, Mirror-Image POLydactyly 1 (MIPOL1), which maps within a single 14q13.1-13.3 CR and that hitherto has been reported to be associated only with a developmental disorder, specifically suppresses in vivo tumor formation. MIPOL1 gene expression is down-regulated in all NPC cell lines and in approximately 63% of NPC tumors via promoter hypermethylation and allelic loss. SLC25A21 and FOXA1, 2 neighboring genes mapping to this region, did not show this frequent down-regulated gene expression or promoter hypermethylation, precluding possible global methylation effects and providing further evidence that MIPOL1 plays a unique role in NPC. The protein localizes mainly to the nucleus. Re-expression of MIPOL1 in the stable transfectants induces cell cycle arrest. MIPOL1 tumor suppression is related to up-regulation of the p21(WAF1/CIP1) and p27(KIP1) protein pathways. This study provides compelling evidence that chromosome 14 harbors tumor suppressor genes associated with NPC and that a candidate gene, MIPOL1, is associated with tumor development.
Proceedings of the National Academy of Sciences 09/2009; 106(34):14478-83. · 9.68 Impact Factor
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Arthur Kwok Leung Cheung, Hong Lok Lung,
Siu Chun Hung,
Evan Wai Lok Law,
Yue Cheng,
Wing Lung Yau,
Dhinoth Kumar Bangarusamy,
Lance D Miller,
Edison Tak-Bun Liu,
Jian-Yong Shao,
Chang-Wei Kou,
Daniel Chua,
Eugene R Zabarovsky,
Sai Wah Tsao,
Eric J Stanbridge,
Maria Li Lung
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ABSTRACT: Functional studies to identify the potential role of a chromosome 3p14-21 gene, protein tyrosine phosphatase receptor type G (PTPRG), were performed. PTPRG was identified as a candidate tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC) by differential gene profiling of tumorigenic and nontumorigenic NPC chromosome 3 microcell hybrids (MCH). Down-regulation of this gene was found in tumor segregants when compared with their corresponding tumor-suppressive MCHs, as well as in NPC cell lines and tumor biopsies. Promoter hypermethylation and loss of heterozygosity were found to be important mechanisms contributing to PTPRG silencing. PTPRG overexpression in NPC cell lines induces growth suppression and reduced anchorage-independent growth in vitro. This is the first study to use a tetracycline-responsive vector expression system to study PTPRG stable transfectants. Results indicate its ability to induce significant tumor growth suppression in nude mice under conditions activating transgene expression. These studies now provide functional evidence indicating critical interactions of PTPRG in the extracellular matrix milieu induce cell arrest and changes in cell cycle status. This is associated with inhibition of pRB phosphorylation through down-regulation of cyclin D1. These novel findings enhance our current understanding of how PTPRG may contribute to tumorigenesis.
Cancer Research 11/2008; 68(19):8137-45. · 7.86 Impact Factor
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Hong Lok Lung,
Paulisally Hau Yi Lo,
Dan Xie,
Suneel S Apte,
Arthur Kwok Leung Cheung,
Yue Cheng,
Evan Wai Lok Law,
Daniel Chua,
Yi-Xin Zeng,
Sai Wah Tsao,
Eric J Stanbridge,
Maria Li Lung
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ABSTRACT: By using a functional complementation approach, suppression of tumorigenicity was observed after transfer of intact or truncated copies of chromosome 3 into a nasopharyngeal carcinoma (NPC) HONE1 cell line. The extra exogenous chromosome 3 in the microcell hybrids (MCHs) significantly extended the lag period of tumor formation, which may be associated with loss or inactivation of wild type alleles from the normal donor chromosome 3. Representative tumors, which grew in nude mice were reconstituted into culture and expanded as tumor segregants (TSs). In our study, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9 (ADAMTS9), a gene mapping to 3p14.2, was identified to be critically associated with tumor suppression in NPC. Gene expression analysis showed that ADAMTS9 was either not expressed or was downregulated in HONE1 cells, TSs and NPC cell lines. The mechanism of ADAMTS9 gene inactivation in the NPC cell lines and tissues was attributed to promoter hypermethylation. Using a tissue microarray and immunohistochemical staining, 31 of 66 (47%) of the NPC cases showed downregulated or absence of ADAMTS9 expression. ADAMTS9 expression was downregulated or lost in 17 of 23 (73.9%) lymph node metastatic NPC specimens, which was significantly higher than in 14 of 43 (32.6%) primary tumors. After transfection of the ADAMTS9 gene into 7 NPC cell lines, a dramatic reduction of colony forming ability was observed. These findings support ADAMTS9 as a putative tumor suppressor gene in vivo in NPC that is significantly associated with lymph node metastases.
International Journal of Cancer 08/2008; 123(2):401-8. · 5.44 Impact Factor
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Hong Lok Lung,
Cathy Carfield Lo,
Carmen Chak Lui Wong,
Arthur Kwok Leung Cheung,
Ka Fu Cheong,
Nathalie Wong,
Fung Mei Kwong,
King Chi Chan,
Evan Wai Lok Law,
Sai Wah Tsao,
Daniel Chua,
Jonathan Shuntong Sham,
Yue Cheng,
Eric J Stanbridge,
Gavin P Robertson,
Maria Li Lung
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ABSTRACT: In previous studies, we successfully refined nasopharyngeal carcinoma (NPC) critical regions (CRs) mapping to chromosome 11q13 and 11q22-23. The chromosome 11 fragment containing the 1.8 Mb NPC CR at 11q13 (CR1), the CR at 11q22.3 mapped near D11S2000 (CR2), part of the CR at 11q23.1-11q23.2 overlapping with D11S1300 and D11S1391 (CR3), and the CR at cell adhesion molecule 1 (CADM1) locus (CR4), was chosen as the chromosome 11 donor cell line for the present study. Gamma irradiation was applied to cleave this truncated chromosome into smaller fragments and a new panel of donor cells containing further deleted fragments was produced. Subclones XMCH3.2 and XMCH3.4 were chosen for subsequent transfer to HONE1 cells; each contains a single copy of deleted chromosome 11 fragment with or without CR2 and the THY1 locus, previously shown to be involved in NPC. Both resultant chromosome 11 fragments in XMCH3.2 and XMCH3.4 caused tumor suppression. The association of alpha B-crystallin (CRYAB), a gene identified as being differentially expressed by gene profiling of NPC and an immortalized nasopharyngeal epithelial cell line, and which is located near CR3, was found to be associated with tumor suppression in all the tumor-suppressive hybrids. In addition, the expression level of this gene was down-regulated in the 7 NPC cell lines and in 5 out of 14 normal/tumor tissue pairs in the present study. Both promoter hypermethylation and allelic loss may be involved in the inactivation of this gene, suggesting its possible role in NPC development.
International Journal of Cancer 04/2008; 122(6):1288-96. · 5.44 Impact Factor
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ABSTRACT: Vimentin is one of the intermediate filaments that functions in structural support, signal transduction and organelle positioning of a cell. In the present study, we report the contribution of vimentin in mitochondrial morphology and organization. Using subcellular fractionation, immunoprecipitation and fluorescence microscopy analyses, we found that vimentin was associated with mitochondria. Knockdown of vimentin resulted in mitochondrial fragmentation, swelling and disorganization. We further demonstrated that the vimentin cytoskeleton co-localized and interacted with mitochondria to a greater extent than other cytoskeletal components known to support mitochondria. Our results also suggest that vimentin could participate in the mitochondrial association of microtubules. As mitochondrial morphologies determine mitochondrial function, our findings revealed a potentially important relationship between the vimentin-based intermediate filaments and the regulation of mitochondria.
Biochemical Journal 03/2008; 410(1):141-6. · 4.90 Impact Factor
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ABSTRACT: Chromosome 3p plays an important role in tumorigenesis in many cancers, including nasopharyngeal carcinoma (NPC). We have previously shown chromosome 3p can suppress tumor growth in vivo by using the monochromosome transfer approach, which indicated the chromosome 3p21.3 region was critical for tumor suppression. BLU/ZMYND10 is one of the candidate tumor suppressor genes mapping in the 3p21.3 critical region and is a candidate TSG for NPC. By quantitative RT-PCR, it is frequently downregulated in NPC cell lines (83%) and NPC biopsies (80%). However, no functional studies have yet verified the functional role of BLU/ZMYND10 as a tumor suppressor gene. In the current study, a gene inactivation test (GIT) utilizing a tetracycline regulation system was used to study the functional role of BLU/ZMYND10. When BLU/ZMYND10 is expressed in the absence of doxycycline, the stable transfectants were able to induce tumor suppression in nude mice. In contrast, downregulation of BLU/ZMYND10 in these tumor suppressive clones by doxycycline treatment restored the tumor formation ability. This study provides the first significant evidence to demonstrate BLU/ZMYND10 can functionally suppress tumor formation in vivo and is, therefore, likely to be one of the candidate tumor suppressor genes involved in NPC.
International Journal of Cancer 01/2007; 119(12):2821-6. · 5.44 Impact Factor
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Hong Lok Lung,
Arthur Kwok Leung Cheung,
Dan Xie,
Yue Cheng,
Fung Mei Kwong,
Yoshinori Murakami,
Xin-Yuan Guan,
Jonathan Shuntong Sham,
Daniel Chua,
Alexey I Protopopov,
Eugene R Zabarovsky,
Sai Wah Tsao,
Eric J Stanbridge,
Maria Li Lung
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ABSTRACT: In up to 87% of nasopharyngeal carcinoma (NPC) clinical tumor specimens, there was either down-regulation or loss of TSLC1 gene expression. Using a tissue microarray and immunohistochemical staining, the frequency of down-regulated or loss of expression of TSLC1 in metastatic lymph node NPC was 83% and the frequency of loss of expression of TSLC1 was 35%, which was significantly higher than that in primary NPC (12%). To examine the possible growth-suppressive activity of TSLC1 in NPC, three NPC cell lines, HONE1, HNE1, and CNE2, were transfected with the wild-type TSLC1 gene cloned into the pCR3.1 expression vector; a reduction of colony formation ability was observed for all three cell lines. A tetracycline-inducible expression vector, pETE-Bsd, was also used to obtain stable transfectants of TSLC1. There was a dramatic difference between colony formation ability in the presence or absence of doxycycline when the gene is shut off or expressed, respectively, with the tetracycline-inducible system. Tumorigenicity assay results show that the activation of TSLC1 suppresses tumor formation in nude mice and functional inactivation of this gene is observed in all the tumors derived from tumorigenic transfectants. Further studies indicate that expression of TSLC1 inhibits HONE1 cell growth in vitro by arresting cells in G(0)-G(1) phase in normal culture conditions, whereas in the absence of serum, TSLC1 induced apoptosis. These findings suggest that TSLC1 is a tumor suppressor gene in NPC, which is significantly associated with lymph node metastases.
Cancer Research 11/2006; 66(19):9385-92. · 7.86 Impact Factor
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ABSTRACT: Accumulating evidence indicates the potential role of actin cytoskeleton in facilitating the mitochondrial recruitment of various pro-apoptotic proteins from the cytosol to initiate apoptosis. In the present paper, we report the observation of the increase in mitochondrial association of actin in early apoptosis. Using cell fractionation and Western blot analysis, we found that mitochondrial accumulation of beta-actin occurred before the mitochondrial insertion of Bax and release of cytochrome c in apoptosis. The mitochondrial accumulation of beta-actin was observed with various apoptotic stimuli in various cell lines, suggesting that this is a general apoptotic phenomenon in mammalian systems. Using fluorescence microscopy, we have shown that an apoptotic induction triggered the reorganization of the F-actin (filamentous actin) network with an increase in the association with mitochondria, which was observed before mitochondrial fission and nuclear condensation. Perhaps actin could contribute to the initiation of apoptosis by enabling cytosolic pro-apoptotic proteins to be carried to mitochondria by the cytoskeleton-driven trafficking system.
Biochemical Journal 06/2006; 396(1):1-5. · 4.90 Impact Factor
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ABSTRACT: In the present study, we observed that isoproterenol, a beta-adrenergic receptor (beta-AR) agonist, stimulated rat C6 glioma cell proliferation, while propranolol, a beta-AR blocker, greatly reduced the proliferative effect of TNF-alpha on C6 cells. The gene and protein expressions of both beta1- and beta2-ARs were enhanced in C6 cells after TNF-alpha treatment, and the increase in beta-AR was due to an increased number of binding sites and not due to increase in receptor affinity. We further showed that protein kinase C (PKC) was involved in the TNF-alpha-induced beta-AR expression. Collectively, our results indicate that TNF-alpha-induced proliferation in C6 glioma cells might be via the induction and activation of beta-ARs.
Journal of Neuroimmunology 10/2005; 166(1-2):102-12. · 2.96 Impact Factor
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Hong Lok Lung,
Dhinoth Kumar Bangarusamy,
Dan Xie,
Arthur Kwok Leung Cheung,
Yue Cheng,
Mande Kuppusamy Kumaran,
Lance Miller,
Edison Tak-Bun Liu,
Xin-Yuan Guan,
Jonathan Shuntong Sham,
Yan Fang,
Liqiong Li,
Nancy Wang,
Alexey I Protopopov,
Eugene R Zabarovsky,
Sai Wah Tsao,
Eric J Stanbridge,
Maria Li Lung
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ABSTRACT: Using oligonucleotide microarray analysis, THY1, mapping close to a previously defined 11q22-23 nasopharyngeal carcinoma (NPC) critical region was identified as showing consistent downregulated expression in the tumour segregants, as compared to their parental tumour-suppressing microcell hybrids (MCHs). Gene expression and protein analyses show that THY1 was not expressed in the NPC HONE1 recipient cells, tumour segregants, and other NPC cell lines; THY1 was exclusively expressed in the non-tumourigenic MCHs. The mechanism of THY1 gene inactivation in these cell lines was attributed to hypermethylation. Clinical study showed that in 65% of NPC specimens there was either downregulation or loss of THY1 gene expression. Using a tissue microarray and immunohistochemical staining, 44% of the NPC cases showed downregulated expression of THY1 and 9% lost THY1 expression. The frequency of THY1 downregulated expression in lymph node metastatic NPC was 63%, which was significantly higher than in the primary tumour (33%). After transfection of THY1 gene into HONE1 cells, a dramatic reduction of colony formation ability was observed. These findings suggest that THY1 is a good candidate tumour suppressor gene in NPC, which is significantly associated with lymph node metastases.
Oncogene 10/2005; 24(43):6525-32. · 6.37 Impact Factor
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ABSTRACT: Despite the abundant evidence of high allelic loss of chromosome arm 14q in human cancers, tumor-suppressor genes mapped to this chromosome have yet to be identified. To narrow the search for candidate genes, we performed monochromosome transfer of chromosome 14 into an esophageal carcinoma cell line, SLMT-1 S1. Statistically significant suppression of the tumorigenic potential of microcell hybrids containing the transferred chromosome 14 provided functional evidence that tumor-suppressive regions of chromosome 14 are essential for esophageal cancer. Tumor segregants emerging in nude mice during the tumorigenicity assay were analyzed by detailed PCR-microsatellite typing to identify critical nonrandomly eliminated regions (CRs). A 680-kb CR mapped to 14q32.13 and an approximately 2.2-Mb CR mapped to 14q32.33 were delineated. Dual-color BAC FISH analysis of microcell hybrids and tumor segregants verified the selective loss of the 14q32.13 region. In contrast, similar transfers of an intact chromosome 11 into SLMT-1 S1 did not significantly suppress tumor formation. These functional complementation studies showing the correlation of tumorigenic potential with critical regions of chromosome 14 validated the importance of the 14q32 region in tumor suppression in esophageal cancer. The present study also paved the path for further identification of novel tumor-suppressor genes that are relevant to the molecular pathogenesis of esophageal cancer.
Genes Chromosomes and Cancer 08/2005; 43(3):284-93. · 3.31 Impact Factor
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ABSTRACT: Previous studies transferring an intact chromosome 11 into HONE1 cells demonstrated the functional significance of chromosome regions, 11q13 and 11q22-23, in nasopharyngeal carcinoma (NPC) development. In our study the 11q22-23 region was comprehensively re-investigated by detailed microsatellite and single nucleotide polymorphism genotyping and by fluorescence in situ hybridization to map precisely the regions containing tumor suppressive activity. We observed 3 chromosomal intervals within 11q22-23 that were commonly lost in the tumor segregants derived from HONE1/chromosome 11 hybrids. One critical region of 0.36 Mb was mapped near the marker D11S2000 and a second 0.44 Mb region was located around the markers D11S1300 and D11S1391. In a third region high allelic loss was also observed at marker D11S4484, where a newly cloned tumor suppressor gene, TSLC1 (tumor suppressor in lung cancer 1), is located. The gene expression analysis showed absence or low expression levels of TSLC1 mRNA in 4 highly tumorigenic NPC cell lines. In addition, the methylation study results show that the TSLC1 promoter region was hypermethylated in all 4 NPC cell lines and re-expression of the gene occurs in HONE1 cells after 5-aza-2'-deoxycytidine treatment. Hence, the mode of silencing of this candidate TSG in NPC may be attributed to promoter hypermethylation. We have obtained functional evidence for multiple critical tumor suppressive regions in 11q22-23 by fine deletion mapping and for inactivation of TSLC1 being one of these candidate TSGs in NPC development.
International Journal of Cancer 12/2004; 112(4):628-35. · 5.44 Impact Factor
