Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines

Roversi, Gaia; Pfundt, Rolph; Moroni, Ramona Frida; Magnani, Ivana; Reijmersdal, S.V. van; Pollo, Bianca; Straatman, Huub; Larizza, Lidia; Schoenmakers, Eric

doi:10.1038/sj.onc.1209177

Cited by 101 publications

(78 citation statements)

References 56 publications

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“…In addition, human miR-21 is known to be localized on chromosome 17q23.2. Although amplification of this region has been observed in several cancers, many other cancers that exhibit high miR-21 expression, including gliomas, did not show any genetic amplification (Roversi et al, 2006). This observation implicates the aberrant expression of miR-21 in gliomas is due to deregulation of its biogenesis, but not by its genetic alterations.…”

Section: Discussionmentioning

confidence: 79%

Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas

et al. 2011

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Gliomas are associated with high mortality because of their exceedingly invasive character. As these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. We found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional phosphatase and tensin homolog (PTEN), but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the posttranscriptional regulation of Spry2 by miR-21 has an essential role on the malignant progression of human gliomas. Thus, Spry2 may be a novel therapeutic target for treating gliomas.

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Section: Discussionmentioning

confidence: 79%

Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas

et al. 2011

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“…25 These probes were chosen because loss of euploidy for chromosomes 10, 19, and 22 has been observed frequently in glioblastoma. 12,26,27 Briefly, for nuclei extraction, 40-lm-thick sections were dewaxed with xylene, manually disaggregated, and digested with freshly prepared 0.005% proteinase K in TRIS 0.05 M, pH 7, for 30 minutes at 37 C. To aid with enzymatic digestion, the samples were vortexed for 5 seconds at 5-minute intervals during this incubation. Nuclei were pelleted using a microcentrifuge (6000 rpm) for 10 minutes.…”

Section: Fluorescence In Situ Hybridizationmentioning

confidence: 99%

Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis

Pallini

Ricci–Vitiani²,

Montano

et al. 2010

Cancer

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BACKGROUND: Experimental data suggest that glioblastoma cells expressing the stem cell marker CD133 play a major role in radiochemoresistance and tumor aggressiveness. To date, however, there is no clinical evidence that the fraction of CD133-positive cells in glioblastoma that recurs after radiochemotherapy may be relevant for prognosis. METHODS: The authors used immunohistochemistry to assess CD133 expression in 37 paired glioblastoma samples, including 1 primary tumor sample and 1 recurrent tumor sample, after patients received adjuvant radiochemotherapy. To assess the actual composition of the CD133-positive glioblastoma cell population, fluorescence-associated cell sorting (FACS) analysis was used to sort CD133-positive/CD45-negative cells that were assayed for tumor-specific chromosomal aberrations using interphase fluorescence in situ hybridization. To rule out endothelial precursor cells, CD133-positive fractions also were assayed with anti-CD34 by FACS. RESULTS: In recurrent glioblastomas, the percentage of CD133-positive cells was increased by 4.6-fold compared with the percentage in primary glioblastomas, although, in some tumors, it increased up to 10-fold and 20-fold. Unexpectedly, the increase in CD133 expression was associated significantly with longer survival after tumor recurrence. An analysis of tumor-specific chromosomal aberrations and in vivo studies revealed that the CD133-positive cell compartment of recurrent glioblastoma was composed of both cancer stem cells and nontumor neural stem cells. The latter cells represented from 20% to 60% of the CD133-positive cell population, and their relative percentage favorably affected the survival of patients with recurrent glioblastoma. Endothelial CD133-positive/CD34-positive precursors did not contribute to the CD133-positive cell population. CONCLUSIONS: The authors hypothesized that, similar to the phenomenon described in glioblastoma models, neural stem/progenitor cells that are recruited by the tumor from surrounding brain may exert an antitumorigenic effect. Cancer 2011;117:162-74.

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“…(30,31) LRP1B is also a very large gene, containing 92 exons and spanning 1.9 Mb of genomic sequence within FRA2F (2q22.1, http://www.ncbi.nlm.nih.gov/). (17) Inactivation of this gene due to homozygous deletions or epigenetic events has been reported in various cancers (19)(20)(21)(22) and by us in ESCC. (16) Thus, LRP1B is another very large CFS gene that is inactivated in multiple tumors.…”

Section: Resultsmentioning

confidence: 99%

“…In view of previous reports of homozygous deletions of LRP1B in various types of tumors, (17,(19)(20)(21)(22) we screened a panel of OSCC cell lines for homozygous losses by genomic PCR using primers flanking exons 1, 5, 7 and 10 of LRP1B (GenBank accession number NM_018557 for cDNA sequence and NT_005058 for genomic sequence). All primer sequences used in this study are available on request.…”

Section: Screening Of Homozygous Deletions By Genomic Pcrmentioning

confidence: 99%

Genetic or epigenetic silencing of low density lipoprotein receptor‐related protein 1B expression in oral squamous cell carcinoma

Nakagawa

Pimkhaokham

Suzuki³

et al. 2006

Cancer Science

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Previously, we have reported frequent silencing of the expression of LRP1B by genetic and epigenetic mechanisms in esophageal squamous cell carcinoma. As the same events might be involved in the development/progression of OSCC, we examined intragenic homozygous deletions, expression levels, and methylation status in the CpG island of this gene. Homozygous deletion was detected in only 1 of 18 (5.6%) OSCC lines, whereas the expression of LRP1B mRNA was silenced in 8 of 17 (47.1%) OSCC lines without homozygous deletion. An inverse correlation between mRNA expression and methylation status of the LRP1B CpG island was clearly observed in OSCC lines, and LRP1B mRNA expression was restored by treatment with 5-aza-dCyd. Frequent methylation of the LRP1B promoter was also observed in primary OSCC. Taken O ral cancer, predominantly OSCC, is the most common head and neck neoplasm, affecting >400 000 people worldwide every year.(1,2) Despite advances in surgical techniques, chemotherapy, and radiation, 50% of patients die of the disease or complications from it within 5 years.(3) Moreover, OSCC has a severe impact on quality of life through impairments of swallowing and speaking or esthetic disorders. Despite recent progress in the diagnosis and therapeutic methods for OSCC, the prognosis has not improved, reflecting the ineffectiveness of current treatment regimens.(4) An improved understanding of the molecular pathogenesis of OSCC is urgently needed to identify new targets and strategies for effective therapy.(5,6) However, the molecular mechanisms of the progression of OSCC are still unknown.The carcinogenesis of OSCC is thought to be a multistep phenomenon in which a variety of genetic alterations can be segregated into early to late stages.(7) Recently, in addition, evidence has emerged that epigenetic mechanisms, such as altered DNA methylation patterns, play a significant role in the silencing of tumor suppressor genes and contribute to malignant transformation during carcinogenesis.(8) Although several genes, for example, p14, p15, p16, RASSF1A, VHL, hMLH1, and MGMT, have been reported to be silenced by aberrant DNA methylation, (9)(10)(11)(12)(13)(14)(15)(16) some of them were infrequently methylated in OSCC compared with other tumors. In order to create the b.est possible panel of markers for the prediction of outcome, sensitivity to chemotherapy and radiation, and disease status OSCC, more candidates for tumor-suppressor genes targeted by promoter methylation will no doubt be tested in this disease. (16) Recently, we have reported frequent inactivation of the LRP1B (2q22.1) through intragenic homozygous deletion or promoter hypermethylation in ESCC. (17) In the study reported here, homozygous deletion of LRP1B was observed in only 1 of 18 OSCC cell lines, whereas silencing of the expression of LRP1B mRNA through methylation of the promoter was observed in 8 of 18 OSCC cell lines, suggesting that LRP1B is mainly inactivated through an epigenetic mechanism in OSCC. Frequent hypermethylation of the LRP1B promote...

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Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines

Cited by 101 publications

References 56 publications

Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas

Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas

Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis

Genetic or epigenetic silencing of low density lipoprotein receptor‐related protein 1B expression in oral squamous cell carcinoma

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