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RUNX3 has an oncogenic role in head and neck cancer.

Tsunematsu T, Kudo Y, Iizuka S, Ogawa I, Fujita T, Kurihara H, Abiko Y, Takata T - PLoS ONE (2009)

Bottom Line: These findings were confirmed by RUNX3 knockdown.Moreover, RUNX3 expression was low due to the methylation of its promoter in normal oral epithelial cells.Our findings suggest that i) RUNX3 has an oncogenic role in HNSCC, ii) RUNX3 expression observed in HNSCC may be caused in part by demethylation during cancer development, and iii) RUNX3 expression can be a useful marker for predicting malignant behavior and the effect of chemotherapeutic drugs in HNSCC.

View Article: PubMed Central - PubMed

Affiliation: Division of Frontier Medical Science, Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

ABSTRACT

Background: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor of cancer and appears to be an important component of the transforming growth factor-beta (TGF-ss)-induced tumor suppression pathway. Surprisingly, we found that RUNX3 expression level in head and neck squamous cell carcinoma (HNSCC) tissues, which is one of the most common types of human cancer, was higher than that in normal tissues by a previously published microarray dataset in our preliminary study. Therefore, here we examined the oncogenic role of RUNX3 in HNSCC.

Principal findings: Frequent RUNX3 expression and its correlation with malignant behavior were observed in HNSCC. Ectopic RUNX3 overexpression promoted cell growth and inhibited serum starvation-induced apoptosis and chemotherapeutic drug induced apoptosis in HNSCC cells. These findings were confirmed by RUNX3 knockdown. Moreover, RUNX3 overexpression enhanced tumorsphere formation. RUNX3 expression level was well correlated with the methylation status in HNSCC cells. Moreover, RUNX3 expression was low due to the methylation of its promoter in normal oral epithelial cells.

Conclusions/significance: Our findings suggest that i) RUNX3 has an oncogenic role in HNSCC, ii) RUNX3 expression observed in HNSCC may be caused in part by demethylation during cancer development, and iii) RUNX3 expression can be a useful marker for predicting malignant behavior and the effect of chemotherapeutic drugs in HNSCC.

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RUNX3 overexpression inhibited chemotherpeutic drug induced apoptosis.A: Adriamycin (Dox, 0, 0.5 and 1 µg/ml) was treated for 72 hours in control and RUNX3 overexpressing HSC3 cells. Cell cycle distribution was determined by DNA content analysis after propidium iodide staining using a flow cytometer. For each sample, 20,000 events were stored. Percentage of sub-G1 population is indicated. We performed two independent experiments with triplicate wells per condition. Representative data is shown. B: Flow cytometric analysis of Annexin V and propidium iodide staining in control and RUNX3 overexpressing cells after DOX treatment for 72 h at the indicated doses. C: Flow cytometric analysis of Annexin V and propidium iodide staining in control and RUNX3 knockdown cells after DOX treatment for 72 h at the indicated doses. We performed two independent experiments.
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pone-0005892-g006: RUNX3 overexpression inhibited chemotherpeutic drug induced apoptosis.A: Adriamycin (Dox, 0, 0.5 and 1 µg/ml) was treated for 72 hours in control and RUNX3 overexpressing HSC3 cells. Cell cycle distribution was determined by DNA content analysis after propidium iodide staining using a flow cytometer. For each sample, 20,000 events were stored. Percentage of sub-G1 population is indicated. We performed two independent experiments with triplicate wells per condition. Representative data is shown. B: Flow cytometric analysis of Annexin V and propidium iodide staining in control and RUNX3 overexpressing cells after DOX treatment for 72 h at the indicated doses. C: Flow cytometric analysis of Annexin V and propidium iodide staining in control and RUNX3 knockdown cells after DOX treatment for 72 h at the indicated doses. We performed two independent experiments.

Mentions: In addition, we examined the inhibition of apoptosis after treatment with chemotherapeutic drug in control and RUNX3 overexpressing HNSCC (Figure 6). Control and RUNX3 overexpressing HSC3 cells were exposed for 72 hours to adriamycin (DOX; 0.5 and 1 µg/ml), which is a chemotherapeutic agent commonly used in the treatment of HNSCC. The sub-G1 population of RUNX3 overexpressing HSC3 cells was 7.49%, while that of control cells was 44.76% after treatment with 1 µg/ml of DOX (Figure 6A). Moreover, after treatment with 1 µg/ml of DOX, Annexin V/propidium iodide double-positive cells were observed in 25.2% of control cells, while in 8.9% of RUNX3 overexpressing cells (Figure 6B). On the other hand, Annexin V/propidium iodide double-positive cells increased by RUNX3 knockdown (Figure 6C). Overall these suggest that RUNX3 overexpression may be involved in HNSCC development through promoting cell growth and inhibition of apoptosis.


RUNX3 has an oncogenic role in head and neck cancer.

Tsunematsu T, Kudo Y, Iizuka S, Ogawa I, Fujita T, Kurihara H, Abiko Y, Takata T - PLoS ONE (2009)

RUNX3 overexpression inhibited chemotherpeutic drug induced apoptosis.A: Adriamycin (Dox, 0, 0.5 and 1 µg/ml) was treated for 72 hours in control and RUNX3 overexpressing HSC3 cells. Cell cycle distribution was determined by DNA content analysis after propidium iodide staining using a flow cytometer. For each sample, 20,000 events were stored. Percentage of sub-G1 population is indicated. We performed two independent experiments with triplicate wells per condition. Representative data is shown. B: Flow cytometric analysis of Annexin V and propidium iodide staining in control and RUNX3 overexpressing cells after DOX treatment for 72 h at the indicated doses. C: Flow cytometric analysis of Annexin V and propidium iodide staining in control and RUNX3 knockdown cells after DOX treatment for 72 h at the indicated doses. We performed two independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2690822&req=5

pone-0005892-g006: RUNX3 overexpression inhibited chemotherpeutic drug induced apoptosis.A: Adriamycin (Dox, 0, 0.5 and 1 µg/ml) was treated for 72 hours in control and RUNX3 overexpressing HSC3 cells. Cell cycle distribution was determined by DNA content analysis after propidium iodide staining using a flow cytometer. For each sample, 20,000 events were stored. Percentage of sub-G1 population is indicated. We performed two independent experiments with triplicate wells per condition. Representative data is shown. B: Flow cytometric analysis of Annexin V and propidium iodide staining in control and RUNX3 overexpressing cells after DOX treatment for 72 h at the indicated doses. C: Flow cytometric analysis of Annexin V and propidium iodide staining in control and RUNX3 knockdown cells after DOX treatment for 72 h at the indicated doses. We performed two independent experiments.
Mentions: In addition, we examined the inhibition of apoptosis after treatment with chemotherapeutic drug in control and RUNX3 overexpressing HNSCC (Figure 6). Control and RUNX3 overexpressing HSC3 cells were exposed for 72 hours to adriamycin (DOX; 0.5 and 1 µg/ml), which is a chemotherapeutic agent commonly used in the treatment of HNSCC. The sub-G1 population of RUNX3 overexpressing HSC3 cells was 7.49%, while that of control cells was 44.76% after treatment with 1 µg/ml of DOX (Figure 6A). Moreover, after treatment with 1 µg/ml of DOX, Annexin V/propidium iodide double-positive cells were observed in 25.2% of control cells, while in 8.9% of RUNX3 overexpressing cells (Figure 6B). On the other hand, Annexin V/propidium iodide double-positive cells increased by RUNX3 knockdown (Figure 6C). Overall these suggest that RUNX3 overexpression may be involved in HNSCC development through promoting cell growth and inhibition of apoptosis.

Bottom Line: These findings were confirmed by RUNX3 knockdown.Moreover, RUNX3 expression was low due to the methylation of its promoter in normal oral epithelial cells.Our findings suggest that i) RUNX3 has an oncogenic role in HNSCC, ii) RUNX3 expression observed in HNSCC may be caused in part by demethylation during cancer development, and iii) RUNX3 expression can be a useful marker for predicting malignant behavior and the effect of chemotherapeutic drugs in HNSCC.

View Article: PubMed Central - PubMed

Affiliation: Division of Frontier Medical Science, Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

ABSTRACT

Background: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor of cancer and appears to be an important component of the transforming growth factor-beta (TGF-ss)-induced tumor suppression pathway. Surprisingly, we found that RUNX3 expression level in head and neck squamous cell carcinoma (HNSCC) tissues, which is one of the most common types of human cancer, was higher than that in normal tissues by a previously published microarray dataset in our preliminary study. Therefore, here we examined the oncogenic role of RUNX3 in HNSCC.

Principal findings: Frequent RUNX3 expression and its correlation with malignant behavior were observed in HNSCC. Ectopic RUNX3 overexpression promoted cell growth and inhibited serum starvation-induced apoptosis and chemotherapeutic drug induced apoptosis in HNSCC cells. These findings were confirmed by RUNX3 knockdown. Moreover, RUNX3 overexpression enhanced tumorsphere formation. RUNX3 expression level was well correlated with the methylation status in HNSCC cells. Moreover, RUNX3 expression was low due to the methylation of its promoter in normal oral epithelial cells.

Conclusions/significance: Our findings suggest that i) RUNX3 has an oncogenic role in HNSCC, ii) RUNX3 expression observed in HNSCC may be caused in part by demethylation during cancer development, and iii) RUNX3 expression can be a useful marker for predicting malignant behavior and the effect of chemotherapeutic drugs in HNSCC.

Show MeSH
Related in: MedlinePlus