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Human Osteosarcoma Transcriptome

ABSTRACT: Osteosarcoma (OS) is one of the most aggressive bone malignancy. Sub-optimal therapy has irretrievably compromised chances of survival of OS patients for years. Also lack of extensive research on this rare disease has hindered its therapeutic development. Cisplatin (CDDP) is an integral part of current treatment regime for OS. However, despite the proven benefits of CDDP, acquisition of resistance impedes therapy. Also, the molecular effects post CDDP insult in OS cells is poorly understood. Hence, we characterized molecular alterations associated with CDDP-exposure and resistance in OS cells. Resistance to CDDP in OS cells was developed and deep sequencing of mRNA was performed. It depicted an altered transcriptomic signature of resistant cells with enrichment of pathways regulating proliferation. Overall, a significant up-regulation of coding-RNAs and down-regulation of non-coding-RNAs were obtained. Further, analysis of immediate effect of CDDP-shock showed an increase in autophagy and JNK signaling, acting as a pro-survival strategy. Regulatory connections between MAPK signaling and autophagy favoring survival under CDDP-shock was elucidated. Taken together, this is the first study portraying not only global transcriptomic alterations in resistant OS cells but also showing key molecular changes associated with CDDP-insult in OS cells. Our results can be better utilized for future therapeutic benefit.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86053 | GEO | 2016/08/26

SECONDARY ACCESSION(S): PRJNA340140

REPOSITORIES: GEO

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Project description:The emergence of cisplatin (CDDP) resistance is the main cause of treatment failure and death in patients with testicular germ cell tumors (TGCT), but its biologic background is poorly understood. To study the molecular basis of CDDP resistance in TGCT we prepared and sequenced CDDP-exposed TGCT cell lines as well as 31 primary patients’ samples. Long-term exposure to CDDP increased the CDDP resistance 10 times in the NCCIT cell line, while no major resistance was achieved in Tera-2. Development of CDDP resistance was accompanied by changes in the cell cycle (increase in G1 and decrease in S-fraction), increased number of acquired mutations, of which 3 were present within ATRX gene, as well as changes in gene expression pattern. Copy number variation analysis showed, apart from obligatory gain of 12p, several other large-scale gains (chr 1, 17, 20, 21) and losses (chr X), with additional more CNVs found in CDDP-resistant cells (e.g., further losses on chr 1, 4, 18, and gain on chr 8). In the patients’ samples, those who developed CDDP resistance and died of TGCT (2/31) showed high numbers of acquired aberrations, both SNPs and CNVs, and harbored mutations in genes potentially relevant to TGCT development (e.g., TRERF1, TFAP2C in one patient, MAP2K1 and NSD1 in another one). Among all primary tumor samples, the most commonly mutated gene was NSD1, affected in 9/31 patients. This gene encoding histone methyl transferase was also downregulated and identified among the 50 most differentially expressed genes in CDDP-resistant NCCIT cell line. Interestingly, 2/31 TGCT patients harbored mutations in the ATRX gene encoding a chromatin modifier that has been shown to have a critical function in sexual differentiation. Our research newly highlights its probable involvement also in testicular tumors. Both findings support the emerging role of altered epigenetic gene regulation in TGCT and CDDP resistance development. This submission includes complete cell lines sequencing data and processed files. The patients data are available from the authors on request.

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Human Osteosarcoma Transcriptome

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