Lactate-sensitive response elements in genes involved in hyaluronan catabolism

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Tissue anoxia is an early event in wound healing, leading to lactate production.
• Increased hyaluronan and CD44 expression accompany lactate production, suggesting a causal link.
• Hyaluronan catabolism involves CD44, caveolin-1, Hyal-1, and Hyal-2, with lactate potentially influencing these pathways.

Purpose of the Study:

• To investigate the cause-and-effect relationship between lactate and hyaluronan/CD44 expression in wound healing.
• To identify the molecular mechanisms, including gene activation, underlying lactate-induced changes in fibroblasts.
• To explore potential shared mechanisms between wound healing and tumor progression (Warburg effect).

Main Methods:

• Fibroblast cultures were treated with lactate.
• Hyaluronan and CD44 expression and deposition were analyzed.
• Gene promoter regions (CD44, caveolin-1, Hyal-1, Hyal-2) were analyzed for transcription factor binding sites (AP-1, ets-1).
• Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to quantify mRNA levels of specific genes (c-fos, c-jun, c-ets, Hyal-1, Hyal-2, CD44, caveolin-1).

Main Results:

• Lactate addition to fibroblast cultures increased hyaluronan and CD44 expression and deposition.
• Analysis revealed AP-1 and ets-1 response elements in the promoter regions of genes involved in hyaluronan metabolism.
• RT-PCR confirmed increased transcripts for c-fos, c-jun, c-ets, Hyal-1, Hyal-2, CD44, and caveolin-1 in lactate-treated fibroblasts.

Conclusions:

• Lactate activates specific genes (c-fos, c-jun, c-ets, Hyal-1, Hyal-2, CD44, caveolin-1) in fibroblasts, contributing to hyaluronan metabolism during wound healing.
• The identified lactate-activated genes and pathways are crucial for wound healing responses.
• Similar molecular mechanisms may underlie lactate-driven processes in tumor progression, such as the Warburg effect.