CYP genes in osteosarcoma: Their role in tumorigenesis, pulmonary metastatic microenvironment and treatment response

CYP genes in osteosarcoma: Their role in tumorigenesis, pulmonary metastatic microenvironment and treatment response

Author Trujillo-Paolillo, Alini Autor UNIFESP Google Scholar
Tesser-Gamba, Francine Autor UNIFESP Google Scholar
Petrilli, Antonio Sergio Autor UNIFESP Google Scholar
de Seixas Alves, Maria Teresa Autor UNIFESP Google Scholar
Garcia Filho, Reynaldo Jesus Autor UNIFESP Google Scholar
de Oliveira, Renato Autor UNIFESP Google Scholar
Caminada de Toledo, Silvia Regina Autor UNIFESP Google Scholar
Abstract Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The present study investigated the expression of Cytochrome P-450 (CYP) genes: CYP1A2, CYP3A4 and CYP3A5 by qRT-PCR in 135 specimens obtained from OS patients, including biopsy (pre-chemotherapy), tumor resected in surgery (post-chemotherapy), adjacent bone to tumor (nonmalignant tissue), pulmonary metastasis and adjacent lung to metastasis (nonmalignant tissue). Normal bone and normal lung tissues were used as control. We also investigated in five OS cell lines the modulation of CYPs expression by cisplatin, doxorubicin and methotrexate. As result, the adjacent lung specimens presented CYP1A2 overexpression compared to the normal lung (p=0.0256). Biopsy specimens presented lower CYP3A4 expression than normal bone (p=0.0314). The overexpression of both CYP1A2 and CYP3A4 in post-chemotherapy specimens were correlated with better event free-survival (p=0.0244) and good response (p=0.0484), respectively. Furthermore, in vitro assays revealed that CYP1A2 was upregulated by doxorubicin (p=0.0034)

CYP3A4 was upregulated by cisplatin, doxorubicin and methotrexate (p=0.0004, p=0.0024, p<0.0001, respectively)

and CYP3A5 was downregulated by doxorubicin (p=0.0285) and upregulated in time-dependent manner by methotrexate (p=0.0239). In conclusion, our findings suggest that CYP genes play an important role in OS tumorigenesis, at primary and metastatic sites, as well in treatment response.
Keywords osteosarcoma
cytochrome P-450
osteosarcoma cell line
tumor microenvironment
treatment response
xmlui.dri2xhtml.METS-1.0.item-coverage Orchard Park
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
Grupo de Apoio ao Adolescente e a Crianca com Cancer (GRAACC/UNIFESP)
Grant number FAPESP: 2013/19166-6
Grupo de Apoio ao Adolescente e a Crianca com Cancer (GRAACC/UNIFESP)
Date 2017
Published in Oncotarget. Orchard Park, v. 8, n. 24, p. 38530-38540, 2017.
ISSN 1949-2553 (Sherpa/Romeo, impact factor)
Publisher Impact Journals Llc
Extent 38530-38540
Origin http://dx.doi.org/10.18632/oncotarget.15869
Access rights ACESSO ABERTO
Type Article
Web of Science ID WOS:000403311900040
URI https://repositorio.unifesp.br/handle/11600/53660

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