RNA sequencing of Cd44-positive and Cd44-negative primary osteosarcoma isolated from Nf2 - mutant mice
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ABSTRACT:
PROVIDER: PRJNA863460 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20706785.fastq.gz | Fastqsanger.gz | |||
| SRR20706786.fastq.gz | Fastqsanger.gz | |||
| SRR20706787.fastq.gz | Fastqsanger.gz | |||
| SRR20706788.fastq.gz | Fastqsanger.gz | |||
| SRR20706789.fastq.gz | Fastqsanger.gz |
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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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Project description:Primary liver cancer is the third leading cause of cancer related death worldwide. An increasing body of evidence suggests that the Hippo tumor suppressor pathway plays a critical role in restricting cell proliferation and determining cell fate during physiological and pathological processes in the liver. Merlin (Moesin-Ezrin-Radixin-likeprotein), encoded by the NF2 (neurofibromatosis type 2) gene is an upstream regulator of the Hippo signaling pathway. Targeting of Merlin to the plasma membrane seems to be critical for fulfilling its major tumor-suppressive functions; this is facilitated by interactions with membrane-associated proteins, including CD44 (clusterofdifferentiation44). Indeed, mutations within the CD44-binding domain of Merlin were reported in many human cancers. In this study, we evaluated the relative contribution of CD44- and Merlin-dependent processes to the development and progression of liver tumors. To this end, mice with liver-specific deletion of the Nf2 gene were crossed with Cd44-deleted mice, and subjected to extensive histological, biochemical and molecular analyses. In addition, cells were isolated from mutant livers and subjected to in vitro assays. Deletion of Nf2 in the liver led to substantial liver enlargement and generation of hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (iCCAs) as well as mixed hepatocellular cholangiocarcinomas. Deletion of Cd44 had no influence on liver size or primary liver tumor development but it significantly inhibited metastasis formation in Nf2-mutant mice. CD44 upregulates expression of integrin β2 and promotes transendothelial migration of liver cancer cells which may facilitate metastatic spreading. Altogether, our results suggest that CD44 may be a promising target for interfering with metastatic spreading of liver cancer.
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Project description:RNA sequencing of Cd44-positive and Cd44-negative livers isolated from Nf2 - mutant mice
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Project description:we used whole-genome microRNA microarray expression profiling as a discovery platform to identify a subset of miRNAs that were differently expressed in CD44-positive pediatric posterior fossa ependymoma compared with CD44-negative ones.
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Project description:Preferentially Expressed Antigen in Melanoma (PRAME) is frequently overexpressed in a wide variety of cancers and it has been proposed as prognostic marker for clinical outcome. It belongs to a class of non-mutated genes whose expression seems to be mostly restricted to tumor cells. Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Despite advances in the diagnosis and management of osteosarcoma, long-term survival has not envolved substantially in the past decades, justifying efforts in finding effective therapeutic targets. In order to assess transcriptome characteristics that could contribute to further comprehend PRAME association with cancer, the technique of gene expression profiling was used to compare PRAME-positive and PRAME-negative osteosarcoma samples. Keywords: disease state analysis Six tumor samples representing distinct histological classes of osteosarcoma (telangiectatic, giant cell, anaplastic, osteoblastic and chondroblastic) were included in this study. They were obtained from individual patients ranging from 5 to 29 years old. Microarray experiments were carried out using the microarray platform CodeLink (GE Healthcare). This platform utilizes bioarrays consisting of 30-base, single pre-validated oligonucleotide probe per gene target. CodeLink UniSet Human I bioarrays, containing 10,000 human transcripts, were used for all experiments. Hybridization procedures strictly followed protocols provided by the manufacturer (GE Healthcare). A total of 12 arrays were hybridized, including 6 tumor samples (3 PRAME-positive and 3 PRAME-negative) and their respective technical replicates. Arrays were scanned following the recommended scanning procedure and settings for use with CodeLink bioarrays (GE Healthcare) on GenePix 4000B Array Scanner/GenePix Pro 4.0 software (Axon Instruments).
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2016-09-01 | GSE84223 | GEO
Project description:To investigate the significance of CD44+ hepatocellular carcinoma (HCC) HuH7 cells, microRNA (miRNA) expression profiles of CD44-positive HuH7, CD44-negative HuH7, and human nomal hepatocyes were analyzed. Results provide the insight into the significance of CD44-positive HCC cells as the liver CSCs.
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Project description:We hypothesized that CD44+ tumor cells might have an increased capacity for reactive oxygen species (ROS) defense in the gastric tumors of K19-Wnt1/C2mE mice. To address this possibility, we examined the expression of antioxidant genes in tumor cells isolated from K19-Wnt1/C2mE mice by fluorescence-activated cell sorting (FACS). Lineage marker (Lin)–negative cells that were CD44+ or CD44– were thus isolated from the gastric tumors of 30-week-old K19-Wnt1/C2mE mice and subjected to cDNA microarray analysis. The expression of several key antioxidant genes, including those for glutathione peroxidase (GPX) and peroxiredoxin (PRDX) isoforms, was found to be increased in CD44+ tumor cells compared with that in CD44– cells.
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