Invasiveness of Hepatocellular Carcinoma Cell Lines: Contribution of Hepatocyte Growth Factor, c-met, and Transcription Factor Ets-1

Jiang, Yan; Xu, Wenjian; Lü, Jun; He, Fuchu; Xiaoming, Yang

doi:10.1006/bbrc.2001.5521

Cited by 74 publications

(60 citation statements)

References 29 publications

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“…[15][16][17] Ets-1 expression is not restricted to the tumor cells since its mRNA is also found in the stromal fibroblasts of invasive tumors. 18,19 Ets-1 is not expressed in quiescent endothelial cells in adult tissues, but it is induced by proliferating and migrating endothelial cells but not after these cells have reached confluence.…”

Section: Discussionmentioning

confidence: 99%

Ets-1 transcription factor is widely expressed in benign and malignant melanocytes and its expression has no significant association with prognosis

et al. 2004

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Ets-1 transcription factor has been associated with tumor progression in various carcinomas, but its expression in malignant melanoma was only recently described. The study was conducted in two steps: exploratory and confirmatory. In the first step, we studied 69 primary melanomas, 28 metastatic melanomas, 10 usual intradermal nevi and 13 various melanocytic skin lesions. In the second step, an additional group of 98 patients with follow-up of up to 200 months was also evaluated. Immunohistochemical analysis of formalinfixed/paraffin-embedded tissues was performed using 1G11 antibody and polymer conjugate for visualization. While Ets-1 was variably expressed in 83% primary melanomas in exploratory and 69% in the confirmatory group, the expression of Ets-1 was also found in normal benign melanocytes and all nevi. Analysis of the exploratory group revealed lower expression of Ets-1 in primary melanomas than in common nevi (P ¼ 0.048, Mann-Whitney U-test) and metastatic melanomas expressed significantly less Ets-1 than primary melanomas (P ¼ 0.015, Mann-Whitney U-test). There was a negative correlation between Ets-1 expression and the largest dimension of the primary tumors (r ¼ 0.23, P ¼ 0.034, Spearman's correlation rank test), but no correlation with the depth of tumor invasion (Breslow thickness) or the presence of ulceration was found. Analyses of the confirmatory group revealed no association between Ets-1 expression with disease-specific survival or time to treatment failure. However, a statistical trend was found for worse outcome for those primary melanomas that had strong expression (H-score 4100) of Ets-1 (P ¼ 0.054). Ets-1 is expressed in benign melanocytes probably due to their neural crest origin. We conclude that Ets-1 expression cannot be used to differentiate between benign and malignant melanocytic lesions and it has no definite association with clinical outcome. At the same time, its role in tumor progression in some cases of malignant melanoma cannot be entirely excluded. Keywords: Ets-1; malignant melanoma; survival; neural crest Malignant melanoma originates from melanocytes derived from the neural crest. 1 It is the most deadly form of skin cancer, whose incidence is rapidly increasing worldwide. 2 To date the most reliable prognostic marker of malignant melanoma is the vertical thickness (Breslow thickness) of the primary tumor. 3,4 Although progression of malignant melanoma occurs through a series of well-defined steps, the knowledge of genetic and phenotypic background for the disease is still rather scarce. The proto-oncogene ETS-1 belongs to the ETS family of transcription factors that also include, among others, ets-2, elf-1, fli-1 and PU-1. 5-7 Ets-1 plays an important role in cancer progression due to its ability to activate transcription of metastasis-, angiogenesis-and invasion-associated genes. [8][9][10][11][12] In a limited study on 10 melanomas and 24 benign melanocytic lesions, Keehn et al 13 recently reported expression of the Ets-1 in melanocytic lesions and suggested that E...

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Section: Discussionmentioning

confidence: 99%

Ets-1 transcription factor is widely expressed in benign and malignant melanocytes and its expression has no significant association with prognosis

et al. 2004

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“…Ets-1 and activator protein-1; Johnson et al, 1995;Paumelle et al, 2002) leads to the expression of numerous target genes (e.g. MMPs and urokinase-type plasminogen activator (uPA); Sato et al, 1995;McCawley et al, 1998;Jiang et al, 2001;Monvoisin et al, 2002;Ozaki et al, 2003).…”

Section: Transforming Growth Factor B Signaling Axismentioning

confidence: 99%

Dysregulation of growth factor signaling in human hepatocellular carcinoma

2006

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“…Indeed, the overexpression of ets-1 found in different human cancers is associated with invasiveness and the degree of malignancy, thus defining ets-1 as a potential target in anticancer therapy (Watabe et al, 1998;Nakada et al, 1999;Kitange et al, 2000;Jiang et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

et al. 2003

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Cancer formation and progression is a complex process determined by several mechanisms that promote cell growth, invasiveness, neo-angiogenesis, and render neoplastic cells resistant to apoptosis. The tumor suppressor p53 and the proto-oncogenic factor ets-1 are important regulators of such mechanisms. While it is well established that p53 and ets-1 influence various aspects of cell behavior by regulating the transcription of specific genes, little is known about the functional relationship between these transcription factors. We found that the gene encoding thromboxane synthase (TXSA), which we recently identified as a factor promoting invasion and resistance to apoptosis in gliomas, is a novel target gene for both p53 and ets-1. We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and interrelated manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. Negative interference with ets-1 transcription requires functional p53 and is lost in mutant p53 proteins. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53. An important implication of our findings is that the loss of p53-mediated negative control over ets-1-dependent transcription may lead to the acquisition of an invasive phenotype in tumor cells.

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Invasiveness of Hepatocellular Carcinoma Cell Lines: Contribution of Hepatocyte Growth Factor, c-met, and Transcription Factor Ets-1

Cited by 74 publications

References 29 publications

Ets-1 transcription factor is widely expressed in benign and malignant melanocytes and its expression has no significant association with prognosis

Ets-1 transcription factor is widely expressed in benign and malignant melanocytes and its expression has no significant association with prognosis

Dysregulation of growth factor signaling in human hepatocellular carcinoma

Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

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