The Lysyl Oxidase G473A Polymorphism Exacerbates Oral Cancer Development in Humans and Mice.

Autor: Peymanfar Y; The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA., Mahjour F; Department of Translational Dental Medicine, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, Boston, MA 02118, USA., Shrestha N; Department of Translational Dental Medicine, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, Boston, MA 02118, USA., de la Cueva A; Department of Biochemistry, School of Medicine, Boston University, 72 East Concord Street, Boston, MA 02118, USA., Chen Y; The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA., Huang S; Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA., Kirsch KH; Department of Biochemistry, School of Medicine, Boston University, 72 East Concord Street, Boston, MA 02118, USA., Han X; Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA., Trackman PC; The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.; Department of Translational Dental Medicine, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, Boston, MA 02118, USA.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 May 28; Vol. 24 (11). Date of Electronic Publication: 2023 May 28.
DOI: 10.3390/ijms24119407
Abstrakt: Oral cancer is primarily squamous-cell carcinoma with a 5-year survival rate of approximately 50%. Lysyl oxidase (LOX) participates in collagen and elastin maturation. The propeptide of LOX is released as an 18 kDa protein (LOX-PP) in the extracellular environment by procollagen C-proteinases and has tumor-inhibitory properties. A polymorphism in the propeptide region of LOX (rs1800449, G473A) results in a single amino acid substitution of Gln for Arg. Here we investigated the frequency of rs1800449 in OSCC employing TCGA database resources and determined the kinetics and severity of precancerous oral lesion development in wildtype and corresponding knockin mice after exposure to 4-nitroquinoline oxide (4 NQO) in drinking water. Data show that the OSCC is more common in humans carrying the variant compared to the wildtype. Knockin mice are more susceptible to lesion development. The immunohistochemistry of LOX in mouse tissues and in vitro studies point to a negative feedback pathway of wildtype LOX-PP on LOX expression that is deficient in knockin mice. Data further demonstrate modulations of T cell phenotype in knockin mice toward a more tumor-permissive condition. Data provide initial evidence for rs1800449 as an oral cancer susceptibility biomarker and point to opportunities to better understand the functional mechanism of LOX-PP cancer inhibitory activity.
Databáze: MEDLINE
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