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Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression.

Tsuru A, Setoguchi T, Matsunoshita Y, Nagao-Kitamoto H, Nagano S, Yokouchi M, Maeda S, Ishidou Y, Yamamoto T, Komiya S - Br. J. Cancer (2015)

Bottom Line: In addition, lung metastases were significantly inhibited by the knockdown of HEY1.We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells.Knockdown of HEY1 decreased the expression of MMP9.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.

ABSTRACT

Background: Activation of the Notch pathway has been reported in various types of cancers. However, the role of the hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) in osteosarcoma is unknown. We examined the function of HEY1 in osteosarcoma.

Methods: Expression of HEY1 was studied in human osteosarcoma. The effects of HEY1 in osteosarcoma were evaluated in vitro and in a xenograft model. Moreover, we examined the function of matrix metallopeptidase 9 (MMP9) as a downstream effector of HEY1.

Results: HEY1 was upregulated in human osteosarcoma. Knockdown of HEY1 inhibited the invasion of osteosarcoma cell lines. In contrast, the forced expression of HEY1 increased the invasion of mesenchymal stem cell. In addition, lung metastases were significantly inhibited by the knockdown of HEY1. We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells. Knockdown of HEY1 decreased the expression of MMP9. Addition of MMP9 rescued the invasion of osteosarcoma cells that had been rendered less invasive by knockdown of HEY1 expression.

Conclusions: Our findings suggested that HEY1 augmented the metastasis of osteosarcoma via upregulation of MMP9 expression. Therefore, inhibition of HEY1 may be a novel therapeutic strategy for preventing osteosarcoma metastasis.

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Related in: MedlinePlus

Knockdown of HEY1 prevents osteosarcoma cells from metastasising to the lung. Stably GFP-expressing control shRNA/143B or HEY1 shRNA/143B cells were inoculated into the left knee joint of nude mice (n=7 for control, n=6 for HEY1 shRNA group). Seven and a half weeks post inoculation, the mice were sacrificed. Lung metastases were evaluated by using fluorescence microscopy, and the number of metastatic tumours was calculated by using Image J software. Photographs show lung metastases for each group. Knockdown of HEY1 decreased the percentage of mice with lung metastases (A), the number of lung metastases (B), and the area of lung metastases (C). *P<0.05, **P<0.01, Mann–Whitney U test and Student's t-test.
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fig4: Knockdown of HEY1 prevents osteosarcoma cells from metastasising to the lung. Stably GFP-expressing control shRNA/143B or HEY1 shRNA/143B cells were inoculated into the left knee joint of nude mice (n=7 for control, n=6 for HEY1 shRNA group). Seven and a half weeks post inoculation, the mice were sacrificed. Lung metastases were evaluated by using fluorescence microscopy, and the number of metastatic tumours was calculated by using Image J software. Photographs show lung metastases for each group. Knockdown of HEY1 decreased the percentage of mice with lung metastases (A), the number of lung metastases (B), and the area of lung metastases (C). *P<0.05, **P<0.01, Mann–Whitney U test and Student's t-test.

Mentions: We evaluated the role of HEY1 in lung metastasis in a mouse xenograft model. Knockdown of HEY1 did not affect the growth of original site osteosarcoma in knee joints (data not shown). The percentage and number of lung metastases in mice inoculated with HEY1 shRNA/143B-GFP was significantly less than in control mice inoculated with shRNA/143B-GFP (Figures 4A and B). In addition, the area of lung metastasis in mice inoculated with HEY1 shRNA/143B-GFP was significantly smaller than in control mice inoculated with shRNA/143B-GFP (Figure 4C). These findings suggest that knockdown of HEY1 inhibits osteosarcoma lung metastasis.


Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression.

Tsuru A, Setoguchi T, Matsunoshita Y, Nagao-Kitamoto H, Nagano S, Yokouchi M, Maeda S, Ishidou Y, Yamamoto T, Komiya S - Br. J. Cancer (2015)

Knockdown of HEY1 prevents osteosarcoma cells from metastasising to the lung. Stably GFP-expressing control shRNA/143B or HEY1 shRNA/143B cells were inoculated into the left knee joint of nude mice (n=7 for control, n=6 for HEY1 shRNA group). Seven and a half weeks post inoculation, the mice were sacrificed. Lung metastases were evaluated by using fluorescence microscopy, and the number of metastatic tumours was calculated by using Image J software. Photographs show lung metastases for each group. Knockdown of HEY1 decreased the percentage of mice with lung metastases (A), the number of lung metastases (B), and the area of lung metastases (C). *P<0.05, **P<0.01, Mann–Whitney U test and Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385965&req=5

fig4: Knockdown of HEY1 prevents osteosarcoma cells from metastasising to the lung. Stably GFP-expressing control shRNA/143B or HEY1 shRNA/143B cells were inoculated into the left knee joint of nude mice (n=7 for control, n=6 for HEY1 shRNA group). Seven and a half weeks post inoculation, the mice were sacrificed. Lung metastases were evaluated by using fluorescence microscopy, and the number of metastatic tumours was calculated by using Image J software. Photographs show lung metastases for each group. Knockdown of HEY1 decreased the percentage of mice with lung metastases (A), the number of lung metastases (B), and the area of lung metastases (C). *P<0.05, **P<0.01, Mann–Whitney U test and Student's t-test.
Mentions: We evaluated the role of HEY1 in lung metastasis in a mouse xenograft model. Knockdown of HEY1 did not affect the growth of original site osteosarcoma in knee joints (data not shown). The percentage and number of lung metastases in mice inoculated with HEY1 shRNA/143B-GFP was significantly less than in control mice inoculated with shRNA/143B-GFP (Figures 4A and B). In addition, the area of lung metastasis in mice inoculated with HEY1 shRNA/143B-GFP was significantly smaller than in control mice inoculated with shRNA/143B-GFP (Figure 4C). These findings suggest that knockdown of HEY1 inhibits osteosarcoma lung metastasis.

Bottom Line: In addition, lung metastases were significantly inhibited by the knockdown of HEY1.We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells.Knockdown of HEY1 decreased the expression of MMP9.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.

ABSTRACT

Background: Activation of the Notch pathway has been reported in various types of cancers. However, the role of the hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) in osteosarcoma is unknown. We examined the function of HEY1 in osteosarcoma.

Methods: Expression of HEY1 was studied in human osteosarcoma. The effects of HEY1 in osteosarcoma were evaluated in vitro and in a xenograft model. Moreover, we examined the function of matrix metallopeptidase 9 (MMP9) as a downstream effector of HEY1.

Results: HEY1 was upregulated in human osteosarcoma. Knockdown of HEY1 inhibited the invasion of osteosarcoma cell lines. In contrast, the forced expression of HEY1 increased the invasion of mesenchymal stem cell. In addition, lung metastases were significantly inhibited by the knockdown of HEY1. We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells. Knockdown of HEY1 decreased the expression of MMP9. Addition of MMP9 rescued the invasion of osteosarcoma cells that had been rendered less invasive by knockdown of HEY1 expression.

Conclusions: Our findings suggested that HEY1 augmented the metastasis of osteosarcoma via upregulation of MMP9 expression. Therefore, inhibition of HEY1 may be a novel therapeutic strategy for preventing osteosarcoma metastasis.

Show MeSH
Related in: MedlinePlus