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Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
2012 (Engelska)Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, nr Suppl.5, s. S118-S118Artikel i tidskrift, Meeting abstract (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
2012. Vol. 48, nr Suppl.5, s. S118-S118
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-194476DOI: 10.1016/S0959-8049(12)71162-0ISI: 000313036501006OAI: oai:DiVA.org:uu-194476DiVA, id: diva2:605891
Konferens
22nd Biennial Congress of the European-Association-for-Cancer-Research, JUL 07-10, 2012, Barcelona, SPAIN
Tillgänglig från: 2013-02-15 Skapad: 2013-02-14 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Ingår i avhandling
1. Understanding Cancer Mutations by Genome Editing
Öppna denna publikation i ny flik eller fönster >>Understanding Cancer Mutations by Genome Editing
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Mutational analyses of cancer genomes have identified novel candidate cancer genes with hitherto unknown function in cancer. To enable phenotyping of mutations in such genes, we have developed a scalable technology for gene knock-in and knock-out in human somatic cells based on recombination-mediated construct generation and a computational tool to design gene targeting constructs. Using this technology, we have generated somatic cell knock-outs of the putative cancer genes ZBED6 and DIP2C in human colorectal cancer cells. In ZBED6-/- cells complete loss of functional ZBED6 was validated and loss of ZBED6 induced the expression of IGF2. Whole transcriptome and ChIP-seq analyses revealed relative enrichment of ZBED6 binding sites at upregulated genes as compared to downregulated genes. The functional annotation of differentially expressed genes revealed enrichment of genes related to cell cycle and cell proliferation and the transcriptional modulator ZBED6 affected the cell growth and cell cycle of human colorectal cancer cells. In DIP2C-/-cells, transcriptome sequencing revealed 780 differentially expressed genes as compared to their parental cells including the tumour suppressor gene CDKN2A. The DIP2C regulated genes belonged to several cancer related processes such as angiogenesis, cell structure and motility. The DIP2C-/-cells were enlarged and grew slower than their parental cells. To be able to directly compare the phenotypes of mutant KRAS and BRAF in colorectal cancers, we have introduced a KRASG13D allele in RKO BRAFV600E/-/-/ cells. The expression of the mutant KRAS allele was confirmed and anchorage independent growth was restored in KRASG13D cells. The differentially expressed genes both in BRAF and KRAS mutant cells included ERBB, TGFB and histone modification pathways. Together, the isogenic model systems presented here can provide insights to known and novel cancer pathways and can be used for drug discovery.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 37
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1054
Nyckelord
Genome editing, rAAV, ZBED6, DIP2C, KRAS, BRAF, colorectal cancer, tumor driver genes, cancer pathways
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-235680 (URN)978-91-554-9106-2 (ISBN)
Disputation
2014-12-19, Rudbeck Salen, Uppsala University, Rudbeck Laboratory SE-751 85, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-11-27 Skapad: 2014-11-07 Senast uppdaterad: 2018-01-11

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Förlagets fulltexthttp://dx.doi.org/10.1016/S0959-8049(12)71162-0

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Ali, Muhammad AkhtarSjöblom, Tobias

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