Mechanisms of Resistance to Interferon-γ-mediated Cell Growth Arrest in Human Oral Squamous Carcinoma Cells

Hiroi, Miki; Mori, Kensaku; Sekine, Keisuke; Sakaeda, Yoshiichi; Shimada, Jun; Ohmori, Yoshihiro

doi:10.1074/jbc.m109.025932

Cited by 11 publications

(7 citation statements)

References 50 publications

(64 reference statements)

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“…Local cytokine therapy with recombinant IFN-g administered into the pleural cavity induced some responses in patients with early disease but was ineffective in patients with advanced stage disease (35). The antiproliferative effect of IFN-g was also reported to be enhanced by the addition of chemotherapeutic agents or other cytokines, but the mechanism of tumor growth inhibition by IFN-g has not been fully elucidated and not all cell lines respond to IFN-g treatment (36,37).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts

Takenouchi

Hirai²,

Sakuragi³

et al. 2011

Clinical Cancer Research

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Purpose: The interleukin-13 receptor a2 (IL-13Ra2) is expressed by a variety of human malignant cells. Here, we have examined the constitutive surface expression and the epigenetic regulation of IL-13Ra2 by human mesothelioma. We have also investigated the therapeutic effect of the DNA methylation inhibitor 5-aza-2 0 -deoxycytidine (5-aza-dC) and anti-IL-13Ra2 monoclonal antibody on mesothelioma xenografts.Experimental Design: Cell surface expression of IL-13Ra2 by various lung carcinomas was analyzed using flow cytometry. Therapeutic effects of anti-IL-13Ra2 and 5-aza-dC were investigated using antibodydependent cellular cytotoxicity and proliferation assays and by monitoring the survival of mesotheliomabearing mice.Results: We found that human malignant mesotheliomas expressed surface IL-13Ra2 on their surface and that it was upregulated by treatment with 5-aza-dC. This augmented expression of IL-13Ra2 resulted in growth inhibition of the mesothelioma cells when cocultured with anti-IL-13Ra2 and effector cells, such as splenocytes and peritoneal exudate cells. The growth inhibition of mesothelioma cells was mediated by IFN-g that was only detected in the supernatant when effector cells were exposed to 5-aza-dC-treated tumors in the presence of anti-IL-13Ra2. Compared with the control or either regimen alone, in vivo administration of anti-IL-13Ra2 in combination with 5-aza-dC significantly prolonged the survival of mice with mesothelioma xenografts.Conclusions: These observations indicate a promising role for IL-13Ra2 as a target for antibody treatment in malignant mesothelioma, and, in combination with epigenetic regulation by a DNA methylation inhibitor, suggest the potential for a novel strategy to enhance therapeutic potency.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts

Takenouchi

Hirai²,

Sakuragi³

et al. 2011

Clinical Cancer Research

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“…In agreement with the results above, the fraction of proliferating cells having incorporated EdU was significantly lower in DLD-1-GBP-1 cells as compared with DLD-1-CV cells (Student's t-test, P ≤ 0.001) ( Figure 2B). IFN-γ is known to exert antiproliferative effects on various tumor cells including breast cancer, melanoma, CRC and oral squamous carcinoma (39)(40)(41)(42). GBP-1 is a major IFN-γ target gene and has been shown to mediate the antiproliferative effects of IFN-γ in endothelial cells (33).…”

Section: Gbp-1 Inhibits Proliferation Migration and Invasion Of Crc mentioning

confidence: 99%

GBP-1 acts as a tumor suppressor in colorectal cancer cells

et al. 2012

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The human guanylate-binding protein 1 (GBP-1) is among the proteins the most highly induced by interferon-γ (IFN-γ) in every cell type investigated as yet. In vivo, GBP-1 expression is associated with the presence of inflammation and has been observed in autoimmune diseases, inflammatory bowel diseases (IBD) and cancer. In colorectal carcinoma (CRC), the expression of GBP-1 in the desmoplastic stroma has been previously reported to correlate with the presence of an IFN-γ-dominated T helper type 1 (Th1) micromilieu and with an increased cancer-related 5-year survival. In the present study, the analysis of GBP-1 expression in a series of 185 CRCs by immunohistochemistry confirmed that GBP-1 is expressed in stroma cells of CRCs and revealed a significantly less frequent expression in tumor cells, which was contradictory with the broad inducibility of GBP-1. Furthermore, three of six CRC cell lines treated with IFN-γ were unable to express GBP-1 indicating that colorectal tumor cells tend to downregulate GBP-1. On the contrary, non-transformed colon epithelial cells strongly expressed GBP-1 in vitro in presence of IFN-γ and in vivo in inflammatory bowel diseases. Reconstitution of GBP-1 expression in a negative CRC cell line inhibited cell proliferation, migration and invasion. Using RNA interference, we showed that GBP-1 mediates the antitumorigenic effects of IFN-γ in CRC cells. In addition, GBP-1 was able to inhibit tumor growth in vivo. Altogether, these results suggested that GBP-1 acts directly as a tumor suppressor in CRC and the loss of GBP-1 expression might indicate tumor evasion from the IFN-γ-dominated Th1 immune response.

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“…In previous studies, OSCC-related genes among the selected genes were STAT1 [ 14 ], SKP2 [ 7 , 25 ], IFI16 [ 8 ], RHEB [ 9 ], IFI44 [ 64 ], SOD2 [ 10 - 12 ], and GREM1 [ 11 ]. The gene set, which has not been proven as OSCC-related genes until now, could be expected to be possibly proven as OSCC-related genes by biological evaluation.…”

Section: Discussionmentioning

confidence: 99%

Possibility of the Use of Public Microarray Database for Identifying Significant Genes Associated with Oral Squamous Cell Carcinoma

Kim

Cha

2012

Genomics Inform

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There are lots of studies attempting to identify the expression changes in oral squamous cell carcinoma. Most studies include insufficient samples to apply statistical methods for detecting significant gene sets. This study combined two small microarray datasets from a public database and identified significant genes associated with the progress of oral squamous cell carcinoma. There were different expression scales between the two datasets, even though these datasets were generated under the same platforms - Affymetrix U133A gene chips. We discretized gene expressions of the two datasets by adjusting the differences between the datasets for detecting the more reliable information. From the combination of the two datasets, we detected 51 significant genes that were upregulated in oral squamous cell carcinoma. Most of them were published in previous studies as cancer-related genes. From these selected genes, significant genetic pathways associated with expression changes were identified. By combining several datasets from the public database, sufficient samples can be obtained for detecting reliable information. Most of the selected genes were known as cancer-related genes, including oral squamous cell carcinoma. Several unknown genes can be biologically evaluated in further studies.

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Mechanisms of Resistance to Interferon-γ-mediated Cell Growth Arrest in Human Oral Squamous Carcinoma Cells

Cited by 11 publications

References 50 publications

Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts

Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts

GBP-1 acts as a tumor suppressor in colorectal cancer cells

Possibility of the Use of Public Microarray Database for Identifying Significant Genes Associated with Oral Squamous Cell Carcinoma

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