Endothelin-1 Promotes Osteosarcoma Cell Invasion and Survival against Cisplatin-induced Apoptosis

Zhao, Yuan-Ting; Liao, Qiande; Zhu, Yong; Long, Haitao

doi:10.1007/s11999-011-1939-2

Cited by 26 publications

(45 citation statements)

References 25 publications

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“…2) in the present study, suggesting that ETAR does not play an important role in OS proliferation/viability. This is in agreement with our previous results that treatment with an ETAR antagonist alone would not significantly affect the viability of OS cells in vitro (9). The underlying mechanism is still unclear.…”

Section: Discussionsupporting

confidence: 93%

“…In vitro studies suggest that ETAR is a potential therapeutic target for OS metastasis (8,9). In the present study, we showed in an orthotopic xenograft OS mouse model that ETAR is critical for OS pulmonary metastasis, but not for tumor growth.…”

Section: Discussionsupporting

confidence: 49%

“…Our previous study showed that ETAR blockade inhibits OS cell invasion in vitro (9). In the present study, instead of blocking ETAR with an antagonist, we knocked down endogenous ETAR expression in xenograft OS cells to provide more direct evidence for the in vivo role of ETAR in OS proliferation and pulmonary metastasis.…”

Section: Discussionmentioning

confidence: 96%

“…In the present study, instead of blocking ETAR with an antagonist, we knocked down endogenous ETAR expression in xenograft OS cells to provide more direct evidence for the in vivo role of ETAR in OS proliferation and pulmonary metastasis. We used the MG-63 human osteosarcoma cell line in this study, since it constitutively expresses ET-1 and ETAR and has been used in previous in vitro studies (8,9) on OS cell invasion.…”

Section: Discussionmentioning

confidence: 99%

“…ET-1 and ETAR are expressed in OS tissue and cells (8,9). A few in vitro studies have reported that ETAR blockade could inhibit OS cell invasion, suggesting that ETAR could be a potential therapeutic target for OS metastasis (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of endothelin A receptor expression inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model

Yong

Liao

et al. 2012

Mol Med Report

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Abstract.Previous in vitro studies suggest that the endothelin A receptor (ETAR) could be a potential therapeutic target for osteosarcoma (OS) metastasis. In the present study, we assessed for the first time the role of ETAR in OS proliferation and pulmonary metastasis in vivo. MG-63 human OS cells were stably transduced with ETAR shRNA or scramble control shRNA and injected into the tibia of nude mice to generate an orthotopic xenograft OS model. The mice were divided into three groups (n=10 each group): i) the untransduced control group, where the mice were injected with untransduced MG-63 cells; ii) the scramble control group, where the mice were injected with cells stably transduced with the scramble control shRNA; iii) the ETAR-shRNA group, where the mice were injected with cells stably transduced with ETAR shRNA. The ETAR shRNA knocked down more than 75% of endogenous ETAR expression and significantly inhibited invasion, but not proliferation/viability of MG-63 cells in vitro. In the orthotopic xenograft OS mouse model, no significant difference in the tumor volume was observed over time among the untransduced control, the scramble control and the ETAR-shRNA groups. However, a combination of clinical signs, organ examinations and quantitative clonogenic lung metastasis assays showed that lung metastasis in the ETAR-shRNA group was significantly lower than that in the control groups. Immunohistochemical analyses revealed that the matrix metalloproteinase-2 (MMP-2) expression was significantly reduced in the ETAR-shRNA group compared with the control groups. The results were confirmed with western blot analyses using primary tumor tissues or the stably transduced MG-63 cells. In conclusion, we demonstrated in an orthotopic xenograft OS model that ETAR is critical for OS pulmonary metastasis, but not for tumor growth. This study provides the first in vivo evidence suggesting an important role for ETAR in OS pulmonary metastasis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Knockdown of endothelin A receptor expression inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model

Yong

Liao

et al. 2012

Mol Med Report

Self Cite

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Role of endothelin a receptor in colon cancer metastasis: In vitro and in vivo evidence

Nie

Zhou

Bai

et al. 2013

Molecular Carcinogenesis

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The endothelin (ET)-1/endothelin A receptor (ETAR) axis is reportedly involved in tumor cell invasion, survival, and metastasis. However, the role of ETAR in colon cancer metastasis and the underlying mechanisms have not been defined. In the present study, we assessed the role of ETAR in colon cancer metastasis in vitro and in vivo. Overexpression and knockdown of ETAR were respectively performed in SW480 and SW620 human colon cancer cells. Overexpression of ETAR in SW480 cells significantly increased cell survival against cisplatin, cell invasion, and matrix metalloproteinase (MMP)-2 expression, which was strengthened by exogenous ET-1 and abolished by selective ETAR antagonist BQ123 and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Knockdown of ETAR in SW620 cells markedly decreased cell survival against cisplatin, cell invasion, and MMP-2 expression, which was strengthened by BQ123 and LY294002, and partially rescued by exogenous ET-1. In a colon cancer liver metastasis mouse model, while ETAR overexpression promoted colon cancer liver metastases, ETAR knockdown markedly decreased liver metastases. In conclusion, our in vitro data demonstrate that ETAR mediates the promoting effects of ET-1 on colon cancer cell survival, invasion and MMP-2 expression by a PI3K-mediated mechanism. Our in vivo data indicate that ETAR markedly promotes colon cancer liver metastasis. This study provides direct evidence for a critical role of ETAR in colon cancer metastasis, which suggests that ETAR antagonism could benefit patients with metastatic colon cancer.

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Endothelin‐1 gene polymorphisms and risk of chemoresistant pediatric osteosarcoma

Zhou

Liu

Wang

et al. 2013

Pediatric Blood & Cancer

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Background Osteosarcoma (OS) is the most common childhood bone cancer. Chemoresistance is the principal reason for poor survival and disease recurrence in OS patients, and ET‐1 reportedly plays an important role in the development of chemoresistance in OS cells. In the present study, we for the first time explored the association of endothelin‐1 (ET‐1) SNPs and haplotypes with the risk of chemoresistant pediatric OS. Procedure We genotyped three SNPs (rs1800541, rs2070699, and rs5370) in the ET‐1 gene in a case–control study, using 350 pairs of age, sex, and tumor location and stage matched pediatric patients with OS. Patients who showed <90% tumor necrosis after neochemotherapy were defined as poor responders (cases), and those who showed ≥90% tumor necrosis were defined as good responders (controls). Results The G allele at rs1800541 and the G allele at rs2070699 were associated with reduced and increased risk of chemoresistant OS, respectively. The rs1800541–rs2070699 haplotypes TG and GT were respectively associated with increased (P = 0.012; adjusted OR, 1.82; 95% CI, 1.10–5.65) and reduced (P = 0.009; adjusted OR, 0.25; 95% CI, 0.14–0.84) risk of chemoresistant OS. The TG and the GT haplotypes have a gene‐dosage effect on increasing and decreasing the ET‐1 expression in primary OS tumor cells from chemoresistant pediatric OS subjects, respectively. Conclusions This study provides the first evidence of an association between the ET‐1 gene SNPs and haplotypes and the risk of chemoresistant pediatric OS, potentially adding new insights into the pathophysiology and treatment of chemoresistant OS. Pediatr Blood Cancer 2014;61:612–617. © 2013 Wiley Periodicals, Inc.

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Endothelin-1 Promotes Osteosarcoma Cell Invasion and Survival against Cisplatin-induced Apoptosis

Abstract: The ET-1/ET(A) pathway may represent an important target for treating OS, because blocking the ET(A) receptor with a selective antagonist can inhibit OS cell invasion and potentiate a chemotherapeutic agent's effect on OS.

Cited by 26 publications

References 25 publications

Knockdown of endothelin A receptor expression inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model

Knockdown of endothelin A receptor expression inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model

Role of endothelin a receptor in colon cancer metastasis: In vitro and in vivo evidence

Endothelin‐1 gene polymorphisms and risk of chemoresistant pediatric osteosarcoma

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