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Genes involved in doxorubicin drug resistance in 143b osteosarcoma cell line

ABSTRACT: The study was done to identify the differentially expressed genes in response to Doxorubicin drug resistance in the 143B human osteosarcoma cell line, using the Microarray technology. Keywords: drug resistance; dual channel; cell line based; doxorubicin resistance; Human osteosarcoma cell line

ORGANISM(S): Homo sapiens

PROVIDER: GSE3362 | GEO | 2007/03/01

SECONDARY ACCESSION(S): PRJNA93491

REPOSITORIES: GEO

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Project description:Osteosarcoma is the most common type of pediatric bone tumor. Despite great advances in chem-otherapy during the past decades the survival rates of osteosarcoma patients remains usatisfacto-ry. Drug resistance is one of the main reasons leading to treatment failure and poor progno-sis. Previous reports correlated expression of cluster of differentiation 44 (CD44) with drug re-sistance and poor survival of osteosarcoma patients, however the underlying mechanisms are poorly defined. Here, we investigated the role of CD44 in the regulation of drug chemoresistance using osteosarcoma cells isolated from mice carrying a mutation of the tumor suppressor neurofi-bromatosis type 2 (Nf2) gene. CD44 expression was knocked-down in the cells using CRISPR/Cas9 approach. Subsequently, CD44 isoforms and mutants were re-introduced to investigate CD44-dependent processes. Sensitivity to doxorubicin was analyzed in the osteosarcoma cells with modified CD44 expression by immunoblot, colony formation- and WST-1 assay. To dissect the molecular alterations induced by deletion of Cd44, RNA sequencing was performed on Cd44-positive and Cd44-negative primary osteosarcoma tissues isolated from Nf2-mutant mice. Subsequently, expression of candidate genes was evaluated by quantitative reverse transcription PCR (qRT-PCR). Our results indicate that CD44 increases the resistance of osteosarcoma cells to doxorubicin by up-regulating the levels of multidrug resistance (MDR) 1 protein expression, and suggest the role of proteolytically released CD44 intracellular domain, and hyaluronan interac-tions in this process. Moreover, high throughput sequencing analysis identified differential regula-tion of several apoptosis-related genes in Cd44-positive and -negative primary osteosarcomas, in-cluding p53 apoptosis effector related to PMP-22 (Perp). Deletion of CD44 in osteosarcoma cells led to doxorubicin-dependent p53 activation and a profound increase in Perp mRNA expression. Overall, our results suggest that CD44 might be an important regulator of drug resistance and suggest that targeting CD44 can sensitize osteosarcoma to standard chemotherapy.

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Genes involved in doxorubicin drug resistance in 143b osteosarcoma cell line

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