Regulation of genes involved in cell migration and invasion by Class IA hosphatidylinositol 3-kinase p110{463} isoform in glioblastoma multiforme

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Regulation of genes involved in cell migration and invasion by Class IA hosphatidylinositol 3-kinase p110{463} isoform in glioblastoma multiforme

 

Author: Lau, Ka Yee
Title: Regulation of genes involved in cell migration and invasion by Class IA hosphatidylinositol 3-kinase p110{463} isoform in glioblastoma multiforme
Degree: M.Sc.
Year: 2014
Subject: Glioblastoma multiforme.
Genetic regulation.
Hong Kong Polytechnic University -- Dissertations
Department: Dept. of Health Technology and Informatics
Pages: xiv, 95 leaves : illustrations (some color) ; 30 cm
Language: English
InnoPac Record: http://library.polyu.edu.hk/record=b2759006
URI: http://theses.lib.polyu.edu.hk/handle/200/7588
Abstract: Glioblastoma multiforme (GBM) is the most common and aggressive malignant tumour originated from central nervous system. GBM can be divided into primary (de novo) glioblastoma, which composed of around 90% of GBM cases, and secondary glioblastoma arises from low grade astrocytoma. Primary glioblastoma patients are usually associated with poor prognosis and short median survival time due to poor response to surgery, radiotherapy and chemotherapy. Recurrence always occurs within 2 cm from the resection margin in a short period of time because of the highly infiltrative nature of GBM cells. Moreover, GBM is one of the most vascularised solid tumour which also enhances its invasiveness as angiogenesis is an important factor for tumour invasion. In the past decade, common genetic alterations were reported in primary glioblastoma, like EGFR amplification and PTEN mutation. Among them, phosphatidylinositol 3-kinase (PI3K) comes in the limelight as mutation of PIK3CA gene and overexpression of PIK3CB and PIK3CD genes are frequently noted in many cancers, such as breast cancer, colorectal cancer, glioblastoma and prostate cancer. Besides, its central position in the PI3K/Akt/mTOR signaling pathways also allows it to regulate cellular processes like cell survival, proliferation, migration and invasion.
In this study, effect of Class IA PI3K p110δ isoform on the regulation of genes involved in tumour migration and invasion was evaluated using RNA interference technology. GBM cell line SK-MG3 cells were transfected with siRNA for the knockdown of PIK3CD gene together with control transfection. Gene expression analysis of ECM and adhesion molecules on both samples were performed using TaqMan(R) array plates. By calculating the relative quantity of each gene, the effect of PIK3CD knockdown on the gene expression can be evaluated as up-or down-regulation. A total of 14 genes were identified with fold change greater than 4.0 when comparing PIK3CD knockdown sample with control. Four genes (CTNNA1, LAMC1, TIMP-1 and TIMP-2) were upregulated while ten genes (COL11A1, COL6A1, COL7A1, ITGA4, ITGA6, ITGB1, ITGB3, MMP2, MMP14 and PECAM-1) were downregulated. Most of the affected genes have well-defined functions in cell migration and invasion, such as ECM degradation and cytoskeleton reorganization. When compared with results using other GBM cell lines, discrepancies were observed which might be due to heterogeneity of GBM cells. This also suggests PI3K p110δ isoform can be a possible target for new treatment as knockdown of PIK3CD (1) regulate genes involved in cell migration pathway, (2) does not affect many cell types like that of p110α isoform as it is not expressed ubiquitously and (3) theoretically inhibits migration regardless of different gene expression patterns for different cell lines.

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