Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:Q86TM3 (
cage
)
29,987
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Objectives:
Integrins, the coordinator of extracellular and intracellular signaling, are often found to be aberrant in tumors and can reshape the tumor microenvironment. Although previous studies showed that
integrin beta 2
(
ITGB2
) is important for host defense, its expression profile and role in tumors, especially in
cancer associated
fibroblasts (CAFs) are still unknown.
Methods:
Immunofluorescence stain and fluorescence activated cell sorting were used to analyze the
ITGB2
expression profile in oral squamous cell carcinoma (OSCC). RT-PCR and western blot were used to compare
ITGB2
expression in normal fibroblasts (NFs) and
cancer associated
fibroblasts (CAFs). Clinical data and function-based experiments were used to investigate the promoting tumor growth ability of
ITGB2
expressing CAFs. Enhanced glycolysis activity was identified by using bioinformatics analyses and GC/MS assays. MCT1 knockdown OSCC cell lines were constructed to explore the pro-proliferative mechanisms of
ITGB2
expressing CAFs in multiple
in vitro
and
in vivo
assays.
Results:
We found that CAFs exhibited significantly higher
ITGB2
expression than the matched NFs. In addition, higher
ITGB2
expression in CAFs was correlated with higher TNM stages and more Ki67+ tumor cells, indicating its ability to promote OSCC proliferation. Further, co-culture assay demonstrated that
ITGB2
-mediated lactate release in CAFs promoted OSCC cell proliferation. Mechanically,
ITGB2
regulated PI3K/AKT/mTOR pathways to enhance glycolysis activity in CAFs. Accordingly, lactate derived from
ITGB2
-expressing CAFs was absorbed and metabolized in OSCC to generate NADH, which was then oxidized in the mitochondrial oxidative phosphorylation system (OXPHOS) to produce ATP. Notably, inhibiting the OXPHOS system with metformin delayed the proliferative capacity of OSCC cells cultured in the
ITGB2
-expressing CAFs medium.
Conclusions:
Our study uncovered the
ITGB2
high
pro-tumoral CAFs that activated the PI3K/AKT/mTOR axis to promote tumor proliferation in OSCC by NADH oxidation in the mitochondrial oxidative phosphorylation system.
...
PMID:ITGB2-mediated metabolic switch in CAFs promotes OSCC proliferation by oxidation of NADH in mitochondrial oxidative phosphorylation system. 3320 28
