Project description:MicroRNAs (miRNAs) are small (21-25 nucleotide in length) non-coding RNA molecules that negatively regulate protein expression. They are linked to cancer development and maintenance. In this work, studying gene expression profiles of 340 mammalian miRNAs with DNA microarrays, we selected 10 miRNAs gene features able to distinguish primary from secondary glioblastoma type; furthermore we verified that miR-21 and miR-155 up-regulatation seems to characterize the glioblastoma tumour state since it was found up-regulated in all samples analyzed compared to adult brain noneoplastic tissue. Since miR-21 function in glioblastoma cells was addressed previously we concentrated our efforts on miR-155 function. We found that miR-155 levels were markedly elevated both in primary and secondary glioblastomas tumours, in glioblastoma cell cultures and in 4 glioblastoma cell lines (U87, A172, LN229, and LN308) compared with adult brain tissue, CHP212-neuroblastoma cell lines and DAOY-1-medulloblastoma cell line. Since one of the miR-155 target was gamma-aminobutyric acid (GABA) A receptor (GABRA1) we verified if there was a relation between miR-155 up-regulation and GABRA1 expression. We demonstrated that, in cultured glioblastoma cells, knockdown of miR-155, which lower miR-155 expression to normal level, restore the normal expression of the gamma-aminobutyric acid (GABA) A receptor (GABRA1), making glioblastoma cells responsive to GABA cell cycle inhibiting signals. Our data suggest that aberrantly over-expressed miR-155 contribute to the malignant phenotype of the glioblastoma cells, promoting their unlimited growth. Keywords: miRNA expression profile We studied the expression profiles of 340 miRNAs in 97 glioblastoma tissues, of which 66 were primary glioblastomas and 27 were secondary glioblastomas. We have 66 replicates of primary glioblastoma and 27 replicates of secondary glioblastoma, each hybridized with the respective adult non-neoplastic brain tissue as a control.

Project description:We report the results of a molecular study in thirty-seven cases of gliomatosis cerebri, correlating these results with prognosis. The well-known prognostic factors of gliomas, i.e., age, KPS, histology (Grade 2 vs. 3), or contrast enhancement, was predictive of response or outcome only in a percentage of patients but not in all patients. We identified an 8 miRNA signature able to predict patient prognosis with microarray gene expression profiling. The 8 gene features were used to built a prediction method able to distinguish patients with good prognosis (more likely to be responsive to therapy) from patients with a poor prognosis (less likely to be responsive to therapy). Keywords: miRNA expression profile Fifty-nine patients, between 12- and 73-years-old, with clinical signs of increased intracranial pressure were admitted to our institutions between January 2000 to September 2005. Pre-operative neuroradiological studies (CT scan and MRI) showed diffuse infiltrative processes involving more than two different lobes, no identifiable focal mass, and contrast enhancement absent or less than 1 cm in diameter. Written informed consent and tumour DNA were obtained for molecular analysis. Other eligibility criteria included a Karnofsky Performance Scale index (KPS) >50, normal bone marrow function (white blood cell count >3.0X109/l, neutrophil count >1.5X109/l, platelet count >100X109/l, and haemoglobin >10g/dL), normal liver function (aspartate aminotransferase or alanine aminotransferase <2 times the upper limit of laboratory normal, normal bilirubin, and alkaline phosphatase < 2 times the upper limit of normal), and normal renal function (serum creatinine <1.5 mg/dL). The patients received chemotherapy with temozolamide and radiotherapy. The TMZ schedule consisted of 150 to 200 mg/m2 was orally administered once daily on days 1 to 5. Treatment cycles were repeated every 28 days, with a maximum of 24 months. All patients had a monthly neurological and performance status evaluation and a radiological (MRI) evaluation every 2 to 3 months. Responses were evaluated according to previously described criteria (8): a clinical response was defined as an improvement of a neurological deficit or cognitive function evaluated by Mini-Mental Status Examination, an improvement of at least 75% in seizure frequency, or the disappearance of intracranial hypertension. When radiological MRI scans showed a reduction of more than 50% in the hyper intense area it was considered a partial response (PR), and a <50% regression or an objective regression of mass effect, was considered a minor response (MR). Disease was considered as stable when no clinical or radiological changes were seen for at least 6 months, whereas neurological deterioration, a need to increase corticosteroids, or evidence of tumour progression on MRI (an increase in the T2 or the appearance of contrast enhancement) indicated tumour progression.

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Human primary and secondary glioblastoma vs. non-neoplastic adult brain tissue

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