Lactate-associated transcriptomic alterations and malignant phenotypes in colorectal cancer

Area of Science:

• Oncology
• Metabolism
• Molecular Biology

Background:

• Lactate's role in cancer progression is recognized, but its specific impact on colorectal cancer (CRC) requires further elucidation.
• Understanding lactate's influence is crucial for developing targeted therapies against CRC.

Purpose of the Study:

• To investigate the clinical significance of lactate in colorectal cancer.
• To determine the biological effects of lactate on CRC cell behavior.
• To explore the transcriptomic and signaling pathway alterations induced by lactate in CRC cells.

Main Methods:

• Analysis of lactate levels in human CRC specimens.
• In vitro functional assays using SW480 and HCT116 CRC cell lines.
• RNA sequencing, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.
• Quantitative reverse transcription PCR (qRT-PCR) for gene expression validation.
• Flow cytometry to assess NF-κB and HIF-1α signaling activation.
• Pharmacological inhibition of NF-κB and HIF-1α pathways.

Main Results:

• Elevated lactate levels in CRC specimens correlated with advanced stage and reduced disease-free survival.
• Lactate treatment promoted malignant cellular behaviors in CRC cells, independent of extracellular acidification.
• RNA sequencing identified significant gene expression changes, implicating metabolic and signaling pathway alterations.
• Lactate activated NF-κB and HIF-1α signaling pathways.
• Inhibition of NF-κB or HIF-1α pathways reversed lactate-induced malignant phenotypes.

Conclusions:

• Lactate significantly contributes to colorectal cancer progression.
• Lactate promotes malignant phenotypes in CRC cells through the activation of NF-κB and HIF-1α signaling.
• These findings provide mechanistic insights into lactate's role in CRC and suggest potential therapeutic targets.