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The Lysyl Oxidase G473A Polymorphism Exacerbates Oral Cancer Development in Humans and Mice
Yaser Peymanfar1, Faranak Mahjour2, Neha Shrestha2
1The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.
International Journal of Molecular Sciences
|June 10, 2023
Summary
A genetic variant in the Lysyl oxidase (LOX) gene (rs1800449) is linked to increased oral cancer risk. This variant impairs a tumor-suppressive pathway, suggesting its potential as an oral cancer biomarker.
Area of Science:
- Oncology
- Genetics
- Biochemistry
Background:
- Oral squamous cell carcinoma (OSCC) has a poor prognosis, with a 5-year survival rate around 50%.
- Lysyl oxidase (LOX) is crucial for extracellular matrix maturation, and its propeptide (LOX-PP) exhibits tumor-inhibitory effects.
- A specific polymorphism in the LOX propeptide region (rs1800449, G473A) alters amino acid sequence and may impact LOX function.
Purpose of the Study:
- To investigate the frequency of the rs1800449 polymorphism in OSCC patients using TCGA data.
- To evaluate the impact of this polymorphism on oral lesion development in a mouse model.
- To elucidate the underlying molecular mechanisms, including LOX regulation and immune response.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) database for rs1800449 frequency in OSCC.
- Generation and chemical carcinogen (4-nitroquinoline oxide) exposure of wildtype and LOX rs1800449 knockin mice.
- Immunohistochemistry for LOX expression in mouse tissues and in vitro studies.
- Flow cytometry to analyze T cell phenotypes.
Main Results:
- The rs1800449 variant was more frequent in human OSCC patients compared to the wildtype.
- Knockin mice exhibited increased susceptibility to precancerous oral lesion development.
- A deficiency in the negative feedback loop of wildtype LOX-PP on LOX expression was observed in knockin mice.
- Knockin mice displayed a T cell phenotype shift towards a more tumor-permissive state.
Conclusions:
- The rs1800449 polymorphism is associated with increased oral cancer susceptibility in humans.
- This genetic variant promotes oral lesion development and alters immune cell profiles, contributing to a pro-tumorigenic environment.
- rs1800449 serves as a potential biomarker for oral cancer risk, and LOX-PP's tumor-inhibitory mechanisms warrant further investigation.
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