VEGF-C contributes to head and neck squamous cell carcinoma growth and motility

Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Oral Oncology (Impact Factor: 3.03). 03/2010; 46(4):e19-24. DOI: 10.1016/j.oraloncology.2010.02.006
Source: PubMed

ABSTRACT Previous work from our laboratory has demonstrated overexpression of chemokines in head and neck cancer and the utility of targeting these proteins for tumor therapy in a preclinical model. However, the mechanisms involved are unexplored. Through gene expression analysis, we found that expression of vascular endothelial growth factor (VEGF-C) was elevated in HN12 cells expressing high levels of CXCL5. In the present study, we have investigated the contribution of VEGF-C to tumor cell growth and motility. RNAi-mediated knockdown of VEGF-C expression in HN12 cells, which express high levels of CXCL5, resulted in a decrease in proliferation. Conversely, forced expression of VEGF-C in HN4 tumor cells with low endogenous CXCL5 levels increased cell growth. Suppression of VEGF-C inhibited migration of HN12 cells. Similarly, HN4 cells showed reduced migration towards conditioned media collected from HN12 cells with VEGF-C knockdown compared to controls, while HN4/VEGF-C conditioned media stimulated cell migration. Moreover, tumor growth in vivo was markedly reduced when VEGF-C expression was blocked by shRNA. Finally, determination of VEGF-C expression in squamous carcinoma cell lines revealed universal overexpression compared to normal keratinocytes. These findings support a role for VEGF-C in head and neck squamous cell carcinogenesis.

1 Follower
  • Source
    • "So doctors are aiming to find a new way of treatment, that is gene therapy (Tangney, 2010). VEGF-C is a specific lymphatic endothelial cell growth factor, its roles of promoting tumor cell growth and angiogenesis have been reported in more literatures( Mandriota et al., 2001; Benke et al., 2010) .In this study, VEGF-C ASODN was transfected into A-549 cell lines, its invasive ability and expression of VEGF-C were examined, maybe the gene VEGF-C will be a new target in treatment of lung cancer. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vascular endothelial growth factor C (VEGF-C), a member of the VEGF family, has been reported to promote angiogenesis and tumor cell growth. In this study, we analyzed inhibitory action of a VEGF-C antisense oligoxydeonucleotide (ASODN) on a lung carcinoma cell line A-549 and its invasive ability in vitro. Liposomes, liposome-mediated sense oligoxydeonucleotide (SODN) and ASODN were transfected into A-549 cells, with a blank control group. The expression of VEGF-C was examined by western blotting and invasive ability of cells was detected at four levels. Lower expression of VEGF-C and lower invasive ability to recombinate basal membranes were apparent in the ASOND group (P<0.01). However, there were no significant differences among the other three groups (P>0.05). In the invasion assay, the number of transmembrane cells was significantly reduced in the ASODN group after 48 hours (58.6±9.2 P<0.01), but there was no variation among control, LIP and SOND groups (132.5±15.6, 129.7±16.1, 118.2±12.5, P>0.05). VEGF-C ASODN can downregulate the expression of VEGF-C in cell lines and can obviously inhibit invasive ability in vitro.
    Asian Pacific journal of cancer prevention: APJCP 01/2011; 12(8):2097-9. · 2.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We designed an epidermal growth factor (EGF)-containing polyamidoamine (PAMAM) Generation 4 dendrimer vector labeled with quantum dots for targeted imaging and nucleic acid delivery. (1)H NMR, SDS-PAGE, and Western blotting were applied to characterize the synthesized G4.0-GGG-EGF nanoparticles. Targeting efficiency, cell viability, proliferation, and intracellular signal transduction were evaluated using HN12, NIH3T3, and NIH3T3/EGFR cells. We found that EGF-conjugated dendrimers did not stimulate growth of EGFR-expressing cells at the selected concentration. Consistent with this, minimal stimulation of post-receptor signaling pathways was observed. These nanoparticles can localize within cells that express the EGFR in a receptor-dependent manner, whereas uptake into cells lacking the receptor was low. A well characterized vimentin shRNA (shVIM) and yellow fluorescent protein (YFP) siRNA were used to test the delivery and transfection efficiency of the constructed targeted vector. Significant knockdown of expression was observed, indicating that this vector is useful for introduction of nucleic acids or drugs into cells by a receptor-targeted mechanism.
    Oral Oncology 09/2010; 46(9):698-704. DOI:10.1016/j.oraloncology.2010.07.001 · 3.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of dominant transforming p53 in carcinogenesis is poorly understood. Our previous data suggested that aberrant p53 proteins can enhance tumorigenesis and metastasis. Here, we examined potential mechanisms through which gain-of-function (GOF) p53 proteins can induce motility. Cells expressing GOF p53 -R175H, -R273H and -D281G showed enhanced migration, which was reversed by RNA interference (RNAi) or transactivation-deficient mutants. In cells with engineered or endogenous p53 mutants, enhanced migration was reduced by downregulation of nuclear factor-kappaB2, a GOF p53 target. We found that GOF p53 proteins upregulate CXC-chemokine expression, the inflammatory mediators that contribute to multiple aspects of tumorigenesis. Elevated expression of CXCL5, CXCL8 and CXCL12 was found in cells expressing oncogenic p53. Transcription was elevated as CXCL5 and CXCL8 promoter activity was higher in cells expressing GOF p53, whereas wild-type p53 repressed promoter activity. Chromatin immunoprecipitation assays revealed enhanced presence of acetylated histone H3 on the CXCL5 promoter in H1299/R273H cells, in agreement with increased transcriptional activity of the promoter, whereas RNAi-mediated repression of CXCL5 inhibited cell migration. Consistent with this, knockdown of the endogenous mutant p53 in lung cancer or melanoma cells reduced CXCL5 expression and cell migration. Furthermore, short hairpin RNA knockdown of mutant p53 in MDA-MB-231 cells reduced expression of a number of key targets, including several chemokines and other inflammatory mediators. Finally, CXCL5 expression was also elevated in lung tumor samples containing GOF p53, indicating relevance to human cancer. The data suggest a mechanistic link between GOF p53 proteins and chemokines in enhanced cell motility.
    Carcinogenesis 11/2011; 33(2):442-51. DOI:10.1093/carcin/bgr270 · 5.27 Impact Factor
Show more