Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells

Autor:	Kundu, S., Ali, M., Handin, N., Padhan, N., Larsson, J., Karoutsou, M., Ban, K., Wiśniewski, J., Artursson, P., He, L., Hellstrom, M., Sjoblom, T.
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	Proteomics lcsh:QH426-470 Cetuximab Forward genetics lcsh:Medicine Nuclear Receptor Coactivator 3 Cell Line Tumor Humans Genetic Testing Phosphorylation RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Cell Proliferation Glucose Transporter Type 1 Genome Human Research Forkhead Box Protein O3 lcsh:R Ras pathway piggyBac transposon Colorectal cancer Gene Expression Regulation Neoplastic lcsh:Genetics Phenotype Drug Resistance Neoplasm Gene Knockdown Techniques DNA Transposable Elements ras Proteins Colorectal Neoplasms Transcription Factor 7-Like 2 Protein Signal Transduction
Zdroj:	Genome Medicine, Vol 10, Iss 1, Pp 1-13 (2018) Genome Medicine
Popis:	Background The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in ~ 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway. Methods To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted. Results Of the 163 recurrently targeted genes in the two different genetic backgrounds, one-third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, nine genes also mutated in human colorectal cancers were identified. Among these, stable knockdown of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knockdown of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells. Conclusions This work establishes a proof-of-concept that human cell-based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0511-4) contains supplementary material, which is available to authorized users.
Databáze:	OpenAIRE
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