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

Kundu, Snehangshu (författare): Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab

Ali, Muhammad Akhtar (författare): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi

Padhan, Narendra (författare): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Vaskulärbiologi

Larsson, Jimmy, 1977- (författare): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Karoutsou, Maria (författare): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Ban, Kenneth (författare): Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, 8 Med Dr,02-06, Singapore 117597, Singapore.;ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore.

Wisniewski, Jacek R. (författare): Max Planck Inst Biochem, Dept Prote & Signal Transduct, Biochem Prote Grp, D-82152 Martinsried, Germany.

He, Liqun (författare): Uppsala universitet,Vaskulärbiologi,Science for Life Laboratory, SciLifeLab,Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China

Hellström, Mats (författare): Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab

Sjöblom, Tobias (författare): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi

(creator_code:org_t)

2018-01-04
2018
Engelska.
Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 10

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Abstract Ämnesord

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Background:The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in similar to 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.

Av författaren/redakt...: Kundu, Snehangsh ...; Ali, Muhammad Ak ...; Handin, Niklas; Padhan, Narendra; Larsson, Jimmy, ...; Karoutsou, Maria; visa fler...; Ban, Kenneth; Wisniewski, Jace ...; Artursson, Per; He, Liqun; Hellström, Mats; Sjöblom, Tobias; visa färre...

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