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Pan Chen,
Xiaofang Guo,
Houde Zhou,
Wenling Zhang,
Zhaoyang Zeng,
Qianjin Liao,
Xiayu Li,
Bo Xiang, Jianbo Yang,
Jian Ma,
Ming Zhou,
Shuping Peng,
Juanjuan Xiang,
Xiaoling Li,
Colvin Wanshura LE,
Wei Xiong,
James B McCarthy,
Guiyuan Li
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ABSTRACT: Little is known about the role of the host defensive protein short palate, lung and nasal epithelium clone 1 (SPLUNC1) in the carcinogenesis of nasopharyngeal carcinoma (NPC). Here we report that SPLUNC1 plays a role at a very early stage of NPC carcinogenesis. SPLUNC1 regulates NPC cell proliferation, differentiation and apoptosis through miR-141, which in turn regulates PTEN and p27 expression. This signaling axis is negatively regulated by the EBV-coded gene LMP1. Therefore we propose that SPLUNC1 suppresses NPC tumor formation and its inhibition by LMP1 provides a route for NPC tumorigenesis.
PLoS ONE 01/2013; 8(3):e56929. · 4.09 Impact Factor
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Wenling Zhang,
Zhaoyang Zeng,
Songqing Fan,
Jieru Wang, Jianbo Yang,
Yanhong Zhou,
Xiayu Li,
Donghai Huang,
Fang Liang,
Minghua Wu,
Ke Tang,
Li Cao,
Xiaoling Li,
Wei Xiong,
Guiyuan Li
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ABSTRACT: Gene expression profiling had revealed that TGF-β superfamily type I receptor (also known as activin receptor-like kinase-1, ALK1) and TGFβR2 (TGF-β type II receptor) were down-regulated in nasopharyngeal carcinoma (NPC) (P < 0.05, respectively). However, no study with significantly large clinical samples to address the relevance of ALK1 and TGFβR2 in NPC progression or in patient outcomes has been reported. This study aims to assess the possible correlations of ALK1 and TGFβR2 expression with NPC progression and their potential prognostic predictive ability in NPC outcomes. ALK1 and TGFβR2 mRNA and protein levels were detected by qRT-PCR and NPC tissue microarray (TMA), which included 742 tissue cores. Both mRNA and protein levels of ALK1 and TGFβR2 were significantly lower in the cancer tissues compared with the non-cancerous tissues (P < 0.05). Epstein-Barr virus small RNA (EBER-1) hybridization signals in NPC showed significant associations with ALK1 and TGFβR2 proteins (P = 0.000 and 0.003, respectively). In the final logistic regression analysis model, the abnormal expression of ALK1 and TGFβR2 were found to be independent contributors to nasopharyngeal carcinogenesis (P = 0.000 and 0.000, respectively). A survival analysis revealed that ALK1 (Disease Free Survival (DFS): P = 0.002, Overall Survival (OS): P = 0.007) and TGFβR2 (DFS: P = 0.072, OS: P = 0.045) could predict the prognosis of NPC patients. The positive expression of ALK1 and TGFβR2 were independent risk factors for DFS and OS in multivariate analyses (DFS: P = 0.001 and 0.420, respectively; OS: P = 0.018 and 0.047, respectively). These results suggest that ALK1 and TGFβR2 may be useful prognostic biomarkers in NPC.
Journal of molecular histology 03/2012; 43(3):297-306. · 1.75 Impact Factor
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ABSTRACT: Chondroitin sulfate proteoglycan 4 (CSPG4), a transmembrane proteoglycan originally identified as a highly immunogenic tumor antigen on the surface of melanoma cells, is associated with melanoma tumor formation and poor prognosis in certain melanomas and several other tumor types. The complex mechanisms by which CSPG4 affects melanoma progression have started to be defined, in particular the association with other cell surface proteins and receptor tyrosine kinases (RTKs) and its central role in modulating the function of these proteins. CSPG4 is essential to the growth of melanoma tumors through its modulation of integrin function and enhanced growth factor receptor-regulated pathways including sustained activation of ERK 1,2. This activation of integrin, RTK, and ERK1,2 function by CSPG4 modulates numerous aspects of tumor progression. CSPG4 expression has further been correlated to resistance of melanoma to conventional chemotherapeutics. This review outlines recent advances in our understanding of CSPG4-associated cell signaling, describing the central role it plays in melanoma tumor cell growth, motility, and survival, and explores how modifying CSPG4 function and protein-protein interactions may provide us with novel combinatorial therapies for the treatment of advanced melanoma.
Pigment Cell & Melanoma Research 12/2011; 24(6):1148-57. · 5.06 Impact Factor
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Mei Yi, Jianbo Yang,
Xiang Chen,
Ji Li,
Xiayu Li,
Li Wang,
Yixin Tan,
Wei Xiong,
Ming Zhou,
James B McCarthy,
Guiyuan Li,
Bo Xiang,
Hongfu Xie
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ABSTRACT: The tumor suppressor candidate gene Ras association domain family 1, isoform A (RASSF1A) encodes a microtubule-associated protein that is implicated in the regulation of cell proliferation, migration, and apoptosis. Several studies indicate that down-regulation of RASSF1A resulting from promoter hypermethylation is a frequent epigenetic abnormality in malignant melanoma. In this study, we report that compared with melanocytes in normal skins or benign skin lesions, RASSF1A is down-regulated in melanoma tissues as well as cell lines, and its expression negatively correlates with lymph node metastasis. Following ectopic expression in RASSF1A-deficient melanoma A375 cell line, RASSF1A reduces cell viability, suppresses cell-cycle progression but enhances apoptotic cell death. In vivo, RASSF1A expression inhibits the tumorigenic potential of A375 cells in nude mice, which also correlates with decreased cell proliferation and increased apoptosis. On the molecular level, ectopic RASSF1A expression leads to differential expression of 209 genes, including 26 down-regulated and 183 up-regulated ones. Among different signaling pathways, activation of the apoptosis signal-regulating kinase 1 (ASK1)/p38 MAP kinase signaling is essential for RASSF1A-induced mitochondrial apoptosis, and the inhibition of the Akt/p70S6 kinase/eIF4E signaling is also important for RASSF1A-mediated apoptosis and cell-cycle arrest. This is the first study exploring the biological functions and the underlying mechanisms of RASSF1A during melanoma development. It also identifies potential targets for further diagnosis and clinical therapy.
Journal of Cellular Physiology 09/2011; 226(9):2360-9. · 3.87 Impact Factor
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Wenjuan Li,
Xiaoling Li,
Wei Wang,
Xiayu Li,
Yixin Tan,
Mei Yi, Jianbo Yang,
James B McCarthy,
Wei Xiong,
Minghua Wu,
Jian Ma,
Bo Su,
Zuping Zhang,
Qianjin Liao,
Bo Xiang,
Guiyuan Li
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ABSTRACT: Promoter hypermethylation-mediated silencing of tumor suppressor genes (TSGs) is a hallmark of oncogenesis. Oxidored-nitro domain-containing protein 1 (NOR1) is a candidate TSG that is downregulated in nasopharyngeal carcinoma (NPC). In the present study, we identified a functional NOR1 promoter that is regulated by heat shock factor 1 and nuclear respiratory factor 1. The promoter is located within a CpG island. Hypermethylation of this CpG island was found in NPC tissue samples and cancer cell lines, whereas no aberrant promoter methylation was detected in non-cancerous nasopharyngeal tissue samples or normal nasopharyngeal epithelial cells. Treatment of NPC 6-10B cells and leukemia HL60 cells with 5'-aza-2'-deoxycytidine increased endogenous levels of NOR1 messenger RNA. Ectopic expression of NOR1 in NPC HNE1 cells inhibited tumor cell colony formation and viability. These findings suggest that promoter hypermethylation may participate in transcriptional inactivation of the NOR1 gene in NPC. Frequent epigenetic inactivation of the NOR1 gene in NPC suggests that it may be a critical tumor suppressor involved in the development of NPC.
Carcinogenesis 07/2011; 32(9):1305-14. · 5.70 Impact Factor
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ABSTRACT: Past studies on β-catenin in cancer cells focused on nuclear localized β-catenin and its involvement in the Wnt pathway. Our goal here was to investigate the function of β-catenin in both the cytoplasm and nucleus on the regulation of MT1-MMP expression and activity. We found that β-catenin in MDCK non-cancer cells inhibited the cell surface localization of MT1-MMP, and thus its proteolytic activity on pro-MMP2 activation, via direct interaction with the 18-amino-acid cytoplasmic tail of MT1-MMP in the cytoplasm. In contrast, β-catenin in HT1080 cancer cells enhanced the activity of MT1-MMP by entering the nucleus and activating transcription factor Tcf-4/Lef, and elevating the level of MT1-MMP protein. We also found that enhancement of cell growth in three-dimensional (3-D)/two-dimensional (2-D) type I collagen gels and of cell migration by MT1-MMP were inhibited by β-catenin in MDCK cells, whereas these functions were enhanced in HT1080 cells. In addition, regulation of MT1-MMP by β-catenin involved E-cadherin in MDCK cells and Wnt-3a in HT1080 cells. Taken together, our results present a differential effect of cytoplasmic and nuclear β-catenin on MT1-MMP activity in non-cancer cells versus cancer cells. These differences were most probably due to different subcellular locations and different involved pathways of β-catenin in these cells.
Journal of Cellular Physiology 11/2010; 225(3):810-21. · 3.87 Impact Factor
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ABSTRACT: Melanoma chondroitin sulfate proteoglycan (MCSP) is a plasma membrane-associated proteoglycan that facilitates the growth, motility, and invasion of tumor cells. MCSP expression in melanoma cells enhances integrin function and constitutive activation of Erk1,2. The current studies were performed to determine the mechanism by which MCSP expression promotes tumor growth and motility. The results show that MCSP expression in radial growth phase, vertical growth phase, or metastatic cell lines causes sustained activation of Erk1,2, enhanced growth, and motility which all require the cytoplasmic domain of the MCSP core protein. MCSP expression in a radial growth phase cell line also promotes an epithelial-to-mesenchymal transition based on changes in cell morphology and the expression of several epithelial-to-mesenchymal transition markers. Finally, MCSP enhances the expression of c-Met and hepatocyte growth factor, and inhibiting c-Met expression or activation limits the increased growth and motility of multiple melanoma cell lines. The studies collectively show the importance of MCSP in promoting progression by an epigenetic mechanism and they indicate that MCSP could be targeted to delay or inhibit tumor progression in patients.
Cancer Research 10/2009; 69(19):7538-47. · 7.86 Impact Factor
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Lili Wang,
Jian Ma,
Jiang Li,
Xiaoling Li,
Qiuhong Zhang,
Shuping Peng,
Cong Peng,
Ming Zhou,
Wei Xiong, Jianbo Yang,
Jie Zhou,
Songqing Fan,
Chen Tan,
Qun Yan,
Shourong Shen,
Guiyuan Li
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ABSTRACT: Nasopharyngeal carcinoma (NPC) is a common cancer in South China but is rare in other parts of the world. A novel NPC-related gene was isolated by location candidate cloning strategy, whose expression was down-regulated in NPC. This gene was designated human NGX6 (Genbank accession AF188239) and encoded a predicted protein of 338 amino acids that harbors an EGF-like domain. The effects of NGX6 on cells from human NPC cell line HNE1 were investigated. The cells transfected with NGX6 had a markedly high expression of NGX6, leading to significant decrease in cell proliferation and the capability to form colonies in soft agar, delaying the G0-G1 cell cycle progression. Flow cytometry assay indicated that the expression of cyclin D1 significantly decreased in NGX6-transfected HNE1 cells as well as cyclin A and E. There was a delay in tumor formation and a dramatic reduction in tumor size when cells transfected with NGX6 were injected into nude mice. In another way, we found NGX6 played a negative role in EGFR Ras/Mek/MAPK pathway. We propose that NGX6, as an EGF-like domain gene, could delay cell cycle G0-G1 progression and thus inhibit cell proliferation by negatively regulating EGFR pathway in NPC cells and down-regulating the expression of cyclin D1 and E.
Journal of Cellular Biochemistry 06/2005; 95(1):64-73. · 2.87 Impact Factor
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Jian Ma,
Jie Zhou,
Songqing Fan,
Lili Wang,
Xiaoling Li,
Qun Yan,
Ming Zhou,
Huaying Liu,
Qiuhong Zhang,
Houde Zhou,
Kai Gan,
Zheng Li,
Cong Peng,
Wei Xiong,
Chen Tan,
Shourong Shen, Jianbo Yang,
Jiang Li,
Guiyuan Li
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ABSTRACT: The epidermal growth factor (EGF)-like domain is involved in receptor-ligand interactions, extracellular matrix formation, cell adhesion and chemotaxis. Nasopharyngeal carcinoma associated gene 6 (NGX6) is a novel EGF-like domain-containing gene located at the high frequent loss of heterozygosity (LOH) region 9p21-22 associated with nasopharyngeal carcinoma (NPC). It is down-regulated in NPC and its over-expression can delay the cell cycle G(0)-G(1) progression in NPC cells. In the present study, in situ hybridization analysis, using NPC tissue microarrays, showed that loss of NGX6 expression was associated with NPC lymph node metastasis. The Tet-on gene expression system and cDNA array techniques were used to profile the potential targets of NGX6. We found that NGX6 can influence the expression of some cell adhesion molecules in NPC cells. NGX6 can associate with ezrin, a linkage between the cell membrane and cytoskeleton. The NGX6 protein was expressed on the cell surface as a glycoprotein. Ectopic induction of NGX6 can impair NPC cell migration and invasive ability as well as improve cell adhesion and gap junctional intercellular communication, and can suppress tumor formation in vivo. The data revealed that NGX6 plays a role in cell adhesion modulation in NPC cells.
Carcinogenesis 03/2005; 26(2):281-91. · 5.70 Impact Factor
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ABSTRACT: Melanoma chondroitin sulfate proteoglycan (MCSP) is an early cell surface melanoma progression marker implicated in stimulating tumor cell proliferation, migration, and invasion. Focal adhesion kinase (FAK) plays a pivotal role in integrating growth factor and adhesion-related signaling pathways, facilitating cell spreading and migration. Extracellular signal-regulated kinase (ERK) 1 and 2, implicated in tumor growth and survival, has also been linked to clinical melanoma progression. We have cloned the MCSP core protein and expressed it in the MCSP-negative melanoma cell line WM1552C. Expression of MCSP enhances integrin-mediated cell spreading, FAK phosphorylation, and activation of ERK1/2. MCSP transfectants exhibit extensive MCSP-rich microspikes on adherent cells, where it also colocalizes with alpha4 integrin. Enhanced activation of FAK and ERK1/2 by MCSP appears to involve independent mechanisms because inhibition of FAK activation had no effect on ERK1/2 phosphorylation. These results indicate that MCSP may facilitate primary melanoma progression by enhancing the activation of key signaling pathways important for tumor invasion and growth.
The Journal of Cell Biology 07/2004; 165(6):881-91. · 10.26 Impact Factor
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ABSTRACT: Etk/Bmx is a member of the Btk family tyrosine kinase, which contains an N-terminal pleckstrin homology domain. Etk has been shown to play a pivotal role in the regulation of various cellular processes including differentiation, apoptosis, and cell motility. Here we present evidence that Etk is a modulator of the small GTPase RhoA. Etk and RhoA both are translocated to the plasma membrane and can form a complex upon serum stimulation in C2C12 cells. Etk interacts with RhoA but not other closely related small GTPases such as Cdc42 and Rac1, suggesting a specific modulation of RhoA by Etk. Our results demonstrate that Etk activates RhoA and enhances Rho-mediated stress fiber formation and transcription activity in a pleckstrin homology domain-dependent manner. Furthermore, Etk disrupts the interaction between RhoA and Rho-GDI (guanine nucleotide dissociation inhibitor) and promotes the membrane translocation of RhoA. Our data suggest that Etk plays an important role in regulation of RhoA-mediated signaling.
Journal of Biological Chemistry 09/2002; 277(33):30066-71. · 4.77 Impact Factor
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ABSTRACT: Etk/BMX tyrosine kinase is involved in regulation of various cellular processes including proliferation, differentiation, motility, and apoptosis. Through a yeast two-hybrid screening for the effectors of Etk, a new gene family designated as RUFY was identified. The RUFY gene family (RUFY1 and RUFY2) contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between. They appear to be homologues of a recently identified mouse Rabip4 (Cormant, M., Mari, M., Galmiche, A., Hofman, P., and Le Marchand-Brustel, Y. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 1637-1642). RUFY proteins are localized predominantly to endosomes as evidenced by their co-localization with early endosome antigen marker (EEA1). Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. The RUFY1 mutant lacking the phosphorylation sites failed to go to the endosomes. Furthermore, overexpression of Etk in COS-1 and B82L cells resulted in increased plasma membrane localization of the epidermal growth factor receptor and delayed its induced endocytosis in COS-1 cells. The effects of Etk were blocked by the FYVE domain of RUFY1. Interestingly, the FYVE domain of RUFY1 is targeted to the plasma membrane through an interaction between its proline-rich motif and the SH3 domain of Etk or possibly some other membrane-associated SH3 domain-containing protein(s), whereas the lipid binding activity of the FYVE domain is not required. Our data suggest that Etk may be involved in regulation of endocytosis through its interaction with an endosomal protein RUFY1.
Journal of Biological Chemistry 09/2002; 277(33):30219-26. · 4.77 Impact Factor
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Jiang Li,
Chen Tan,
Qiu Xiang,
Xiaomei Zhang,
Jian Ma,
Jie-ru Wang, Jianbo Yang,
Wei-fang Li,
Shou-rong Shen,
Songping Liang,
Guiyuan Li
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ABSTRACT: In the previous study, we cloned a new gene, named NGX6, related to nasopharyngeal carcinoma (NPC) at 9p. To study its function in the pathogenesis of NPC, we have investigated changes in protein synthesis between NPC cell line HNE1 and that transfected with the gene. Using high-resolution two-dimensional electrophoresis, we found that 22 protein spots showed variations that were significant and reproducible. Analysis of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and database searches identified seven proteins that were upregulated and seven proteins that were downregulated. These proteins included Fas, zinc-finger protein (ZNF), RAB, and Ah receptor-interacting protein (AIP). The functional implications of the identified proteins are discussed.
Journal of Protein Chemistry 02/2001; 20(3):265-271.
