Smoothened as a new therapeutic target for human osteosarcoma

Hirotsu, Masataka; Setoguchi, Takao; Sasaki, Hiromi; Matsunoshita, Yukihiro; Gao, Hui; Nagao, Hiroshi; Kunigou, Osamu; Komiya, Setsuro

doi:10.1186/1476-4598-9-5

Cited by 97 publications

(98 citation statements)

References 66 publications

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“…We had previously reported that 20 µM cyclopamine effectively inhibits Hedgehog pathway and osteosarcoma growth (13). The WST assay showed that 20 µM cyclopamine slowed the growth of KYM-1 (p<0.01), RMS-YM (p<0.01), and RD (p<0.05) cells in a dose-dependent manner ( Fig.…”

Section: Pharmacological Inhibition Of the Hedgehog Pathway Prevents mentioning

confidence: 87%

Pharmacological inhibition of the Hedgehog pathway prevents human rhabdomyosarcoma cell growth

Kawabata

Ijiri²,

Ishidou³

et al. 2011

Int J Oncol

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Abstract. The Hedgehog pathway functions as an organizer in embryonic development. Recent studies have shown that mutation of the PTCH1 gene involved in the Hedgehog pathway affects rhabdomyosarcoma development. However, the expression of Hedgehog pathway molecules in human rhabdomyosarcoma cells has not been well clarified. In addition, the effect of pharmacological inhibition of the Hedgehog pathway is not known. We investigated the expression of the genes involved in the Hedgehog pathway using human rhabdomyosarcoma cell lines and biopsy specimens. Further, we evaluated the effect of pharmacological inhibition of the Hedgehog pathway using cyclopamine or GANT61 by WST assay, cell proliferation assay and cell death detection assay. Real-time PCR revealed that human rhabdomyosarcoma cell lines and biopsy specimens overexpressed the following genes: Sonic hedgehog, Indian hedgehog, Desert hedgehog, PTCH1, SMO, GLI1, GLI2 and ULK3. Immunohistochemistry revealed that rhabdomyosarcoma cell lines and biopsy specimens expressed SMO and GLI2. Inhibition of SMO by cyclopamine slowed the growth of human rhabdomyosarcoma cell lines. Similarly, inhibition of GLI by GANT61 slowed the growth of human rhabdomyosarcoma cell lines. Inhibition of cell proliferation and apoptotic cell death together prevented the growth of rhabdomyosarcoma cells by cyclopamine and GANT61 treatment. Our findings suggest that pharmacological inhibition of the Hedgehog pathway may be a useful approach for treating rhabdomyosarcoma patients.

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Section: Pharmacological Inhibition Of the Hedgehog Pathway Prevents mentioning

confidence: 87%

Pharmacological inhibition of the Hedgehog pathway prevents human rhabdomyosarcoma cell growth

Kawabata

Ijiri²,

Ishidou³

et al. 2011

Int J Oncol

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“…The GLI transcription factors exist as three separate zinc-finger proteins, GLI 1 and GLI 2 functioning as transcriptional activators and GLI 3 as a transcriptional repressor (Ruiz, 1997). GLI2 was aberrantly over-expressed in human OSA biopsy specimens (Hirotsu et al, 2010;Nagao et al, 2011). GLI2 knockdown by RNA interferences prevented OSA growth and anchorage-independent growth (Hirotsu et al, 2010;Nagao et al, 2011).…”

Section: Gli2 Transcription Factor Accelerated the Progression Of Osamentioning

confidence: 98%

“…Knockdown of GLI2 promoted the arrest of OSA cells in G (1) phase and was accompanied by reduced protein expression of the cell cycle accelerators cyclin D1, SKP2 and phosphorylated Rb (Nagao et al, 2011). On the other hand, knockdown of GLI2 increased the expression of p21 (cip1) ( Hirotsu et al, 2010). In addition, over-expression of GLI2 promoted mesenchymal stem cell proliferation and accelerated their cell cycle progression.…”

Section: Gli2 Transcription Factor Accelerated the Progression Of Osamentioning

confidence: 99%

“…GLI2 was aberrantly over-expressed in human OSA biopsy specimens (Hirotsu et al, 2010;Nagao et al, 2011). GLI2 knockdown by RNA interferences prevented OSA growth and anchorage-independent growth (Hirotsu et al, 2010;Nagao et al, 2011). Knockdown of GLI2 promoted the arrest of OSA cells in G (1) phase and was accompanied by reduced protein expression of the cell cycle accelerators cyclin D1, SKP2 and phosphorylated Rb (Nagao et al, 2011).…”

Section: Gli2 Transcription Factor Accelerated the Progression Of Osamentioning

confidence: 99%

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Review of the Molecular Pathogenesis of Osteosarcoma

Hao²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

123

109

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Treating the osteosarcoma (OSA) remains a challenge. Current strategies focus on the primary tumor and have limited efficacy for metastatic OSA. A better understanding of the OSA pathogenesis may provide a rational basis for innovative treatment strategies especially for metastases. The aim of this review is to give an overview of the molecular mechanisms of OSA tumorigenesis, OSA cell proliferation, apoptosis, migration, and chemotherapy resistance, and how improved understanding might contribute to designing a better treatment target for OSA.

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“…It has been shown to mediate the Hedgehog signaling pathway during embryonic development and may initiate ligand independent pathway activation in tumorigenesis (41). The inactivation of SMO has been suggested as a potential target for the treatment of patients with OS (42). EWSR1 represents one of the most commonly involved genes in sarcoma translocations (43), and in a study regarding a fusion transcript in osteogenic sarcoma, it was shown to be closely associated with the molecular mechanisms of small cell osteogenic and Ewing sarcomas (44).…”

Section: Discussionmentioning

confidence: 99%

Regulatory network of differentially expressed genes in metastatic osteosarcoma

Peng

Wang

Ding

et al. 2014

Molecular Medicine Reports

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Abstract. The present study aimed to investigate the possible molecular mechanisms underlying the pathogenesis of metastatic osteosarcoma (OS), by examining the microarray expression profiles of normal samples, and metastatic and non-metastatic OS samples. The GSE9508 gene expression profile was downloaded from the Gene Expression Omnibus database, which included 11 human metastatic OS samples, seven non-metastatic OS samples and five normal samples. Pretreatment of the data was performed using the BioConductor package in R language, and the differentially expressed genes (DEGs) were identified by a t-test. Furthermore, function and pathway enrichment analyses of the DEGs were conducted using a molecule annotation system. A differential co-expression network was also constructed, and the submodules were screened using MCODE in Cytoscape. A total of 965 genes were identified as DEGs in metastatic OS. The DEGs were shown to participate in the regulation of DNA-dependent transcription, the composition of the nucleus, cytoplasm and membrane, and protein and nucleotide binding. Furthermore, the screened DEGs were significantly associated with the ribosome, axon guidance and the cytokine-cytokine receptor interaction pathway. Certain hub genes were identified in the constructed differential co-expression network, including matrix metalloproteinase 1 (MMP1), smoothened (SMO), ewing sarcoma breakpoint region 1 (EWSR1) and fasciculation and elongation protein ζ-1 (FEZ1). Brain selective kinase 2 (BRSK2) and aldo-keto reductase family 1 member B10 (AKRIB10) were present in the screened submodules. The results of the present study suggest that genes, including MMP1, SMO, EWSR1, FEZ1, BRSK2 and AKRIB10, may be potential targets for the diagnosis and treatment of metastatic OS. IntroductionOsteosarcomas (OS) are among the most frequently occurring secondary malignancies in childhood cancer (1). OS most often originates in the metaphyses of long bones in adolescents and young adults (2). During the past 30 years, an optimal treatment strategy for OS has been developed, which consists of multi-agent chemotherapy and aggressive surgical resection of all sites of disease involvement (3). However, ~80% of patients with localized OS develop metastatic disease following surgical resection (4). Patients with primary metastatic OS are a heterogeneous group, and a five-year event-free survival rate of up to 75% is reported for patients presenting with unilateral lung metastases (5). Furthermore <20% of patients with high-grade osteosarcoma are clinically diagnosed with metastatic disease at the initial diagnosis, and long-term survival rates of patients with metastatic OS range between 10-40% (6,7). Therefore, due to the high rate of systemic spread, complete recovery following surgical treatment alone is rare (8).Recently, microarray analysis (9) has been widely used in screening for differentially expressed genes (DEGs), in order to identify potential genes that may be investigated for the treatment of various human diseases (10,11)...

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Smoothened as a new therapeutic target for human osteosarcoma

Cited by 97 publications

References 66 publications

Pharmacological inhibition of the Hedgehog pathway prevents human rhabdomyosarcoma cell growth

Pharmacological inhibition of the Hedgehog pathway prevents human rhabdomyosarcoma cell growth

Review of the Molecular Pathogenesis of Osteosarcoma

Regulatory network of differentially expressed genes in metastatic osteosarcoma

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