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Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
Published on: March 10, 2023
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MTH1 expression is required for effective transformation by oncogenic HRAS
Maria G Giribaldi1,2, Anisleidys Munoz1, Katherine Halvorsen1,3
1Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
Oncotarget
|April 21, 2015
Summary
MutT Homolog 1 (MTH1) is crucial for RAS-driven tumor development. Suppressing MTH1 before transformation hinders cancer cell growth and progression, indicating its essential role in nucleotide pool sanitization for tumor cells.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Oncogenic RAS transformation elevates reactive oxygen species (ROS), leading to upregulation of redox-protective genes like MutT Homolog 1 (MTH1).
- MTH1 has been shown to abrogate RAS oncogene-induced senescence (OIS) and its inhibition compromises tumorigenicity in established RAS-harboring cancer cells.
Purpose of the Study:
- To investigate the influence of pre-transformation MTH1 levels on HRASV12-induced oncogenic transformation in immortalized cells.
- To determine if MTH1 is required for the accumulation of RAS oncoprotein and subsequent tumor development.
Main Methods:
- HRASV12 transduction into BEAS2B immortalized epithelial cells with suppressed MTH1 levels.
- Assessment of RASV12 and ROS-expressing cell populations, soft agar colony formation, and epithelial-mesenchymal transition (EMT).
Main Results:
- MTH1 suppression prior to HRASV12 transduction compromised the maintenance of high RASV12 and ROS-expressing cell populations.
- Pre-transformation MTH1 levels modulated HRASV12-mediated soft agar colony formation and EMT.
- Effects were more pronounced in cells with higher RASV12 levels, suggesting MTH1's role in RAS oncoprotein accumulation.
Conclusions:
- Nucleotide pool sanitization by MTH1 is a critical transformation-promoting requirement.
- Compromising MTH1 pre-transformation cannot be adequately compensated post-transformation, impacting RAS-driven tumor development and progression.
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