Inability of Transforming Growth Factor-β to Cause SnoN Degradation Leads to Resistance to Transforming Growth Factor-β–Induced Growth Arrest in Esophageal Cancer Cells

Edmiston, Jeffery; Yeudall, W. Andrew; Chung, Theodore D.; Lebman, Deborah A.

doi:10.1158/0008-5472.can-04-4354

Cited by 43 publications

(32 citation statements)

References 35 publications

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“…A further two complementary oligonucleotides were used to generate a nontargeting ''scrambled'' control (NTC; Table 1). Each complementary oligonucleotide pair, containing 5V phosphorylations, was diluted to 10 Amol/L, mixed, and denatured at 100jC for 5 minutes, incubated overnight at ambient temperature, then ligated into the retroviral plasmid pSIREN-Retro-Q as previously described (20). CXCL5 cDNA was obtained by reverse transcription PCR using HN12 RNA as a template.…”

Section: Methodsmentioning

confidence: 99%

Down-regulation of CXCL5 Inhibits Squamous Carcinogenesis

et al. 2006

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We report a novel role for the CXC-chemokine, CXCL5, in the proliferation and invasion of head and neck squamous cell carcinoma (HNSCC). Previously, we reported transcriptional up-regulation of CXCL5 in metastatic cells. In this study, we provide biological validation of these findings and show that CXCL5 is intimately involved in tumor cell proliferation, migration, and invasion. Cells derived from a lymph node metastasis, but not from a synchronous primary tumor, secreted CXCL5 as judged by Western blotting of conditioned media. We used RNA interference to generate cell lines (shL5) in which CXCL5 expression was greatly reduced, and tested whether this modulated the cell phenotype. shL5 cells showed decreased proliferation compared with cells harboring nontargeting control sequences. In addition, we found that the ability of shL5 cells to migrate and invade in vitro through a basement membrane substitute was greatly impaired compared with control cells. Finally, whereas control cells were highly tumorigenic in nude mice, the tumorigenic potential in vivo of shL5 cells was found to be ablated. Taken together, these data suggest that CXCL5 production contributes to both enhanced proliferation and invasion of squamous cell carcinomas and that targeting of chemokine pathways may represent a potential therapeutic modality for these lesions.

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Section: Methodsmentioning

confidence: 99%

Down-regulation of CXCL5 Inhibits Squamous Carcinogenesis

et al. 2006

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“…Consistent with its role as an oncoprotein, elevated SnoN expression has been observed in human carcinoma cells of the lung, breast, vulva, stomach, ovary, and thyroid (32,42,67). The increase in SnoN expression observed in human cancer cells can occur by one of several mechanisms, including gene amplification, transcriptional activation, and increased protein stability (11,24,32,55,56,68). However, it appears that SnoN can also act as a negative regulator of tumor progression.…”

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Dual Role of SnoN in Mammalian Tumorigenesis

Zhu

Krakowski

Dunham

et al. 2007

Molecular and Cellular Biology

137

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SnoN is an important negative regulator of transforming growth factor ␤ signaling through its ability to interact with and repress the activity of Smad proteins. It was originally identified as an oncoprotein based on its ability to induce anchorage-independent growth in chicken embryo fibroblasts. However, the roles of SnoN in mammalian epithelial carcinogenesis have not been well defined. Here we show for the first time that SnoN plays an important but complex role in human cancer. SnoN expression is highly elevated in many human cancer cell lines, and this high level of SnoN promotes mitogenic transformation of breast and lung cancer cell lines in vitro and tumor growth in vivo, consistent with its proposed prooncogenic role. However, this high level of SnoN expression also inhibits epithelial-to-mesenchymal transdifferentiation. Breast and lung cancer cells expressing the shRNA for SnoN exhibited an increase in cell motility, actin stress fiber formation, metalloprotease activity, and extracellular matrix production as well as a reduction in adherens junction proteins. Supporting this observation, in an in vivo breast cancer metastasis model, reducing SnoN expression was found to moderately enhance metastasis of human breast cancer cells to bone and lung. Thus, SnoN plays both protumorigenic and antitumorigenic roles at different stages of mammalian malignant progression. The growth-promoting activity of SnoN appears to require its ability to bind to and repress the Smad proteins, while the antitumorigenic activity can be mediated by both Smad-dependent and Smad-independent pathways and requires the activity of small GTPase RhoA. Our study has established the importance of SnoN in mammalian epithelial carcinogenesis and revealed a novel aspect of SnoN function in malignant progression.

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“…After 2 h, TGF-␤ elicits a marked increase in the levels of SnoN through transcriptional activation (10). In malignant cells, SnoN expression is often elevated because of increased transcription, gene amplification, and͞or protein stability (17)(18)(19). This elevated SnoN expression may be responsible for the resistance of malignant cancer cells to TGF-␤-induced growth arrest.…”

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confidence: 99%