Abstract
Background and objective:
Radioresistance is a significant factor affecting the therapeutic efficacy of radiotherapy. This study is aimed at investigating the molecular mechanism by which LBX2-AS1 regulates pyruvate kinase M2 (PKM2) to influence radioresistance and its potential as a biomarker for radioresistance in esophageal cancer.
Methods and key findings:
Radioresistant sub-cell lines, KYSE150R, were established in KYSE150 cells, and PKM2, cyclin D1, HIF-1α, and LBX2-AS1 levels were elevated in KYSE150R. Upregulated and downregulated PKM2 sub-cell lines were established. Upregulating PKM2 increased the PKM2 level in the nucleus and increased levels of HIF-1α, cyclin D1, and LBX2-AS1. The knockdown of PKM2 showed the opposite result. Downregulated LBX2-AS1 sub-cell lines were established. Downregulation of LBX2-AS1 decreased cell proliferation, glycolysis, cell cycle progression, and radioresistance, along with a reduction in cyclin D1, HIF-1α, and PKM2 levels. The dual-luciferase reporter system was used to verify that LBX2-AS1 directly binds to miR-491-5p, and miR-491-5p directly binds to the 3 'UTR of PKM2 mRNA. Downregulation of miR-491-5p in sh-LBX2-AS1 cells could increase cell proliferation, cell cycle, glycolysis, and radiation resistance. The LBX2-AS1 level in serum of patients with esophageal cancer was detected, and its clinical relevance was analyzed. Results showed that high LBX2-AS1 levels correlated with worse disease control, increased lymphatic metastasis, and poorer overall and progression-free survival.
Conclusion and clinical implications:
LBX2-AS1-miR-491-5p-PKM2 positive feedback loop enhances the radioresistance of esophageal cancer cells by altering the cell cycle and enhancing glycolysis. High level of LBX2-AS1 in serum was correlated with worse DCR, lymphatic metastasis, worse overall survival, and progression-free survival.
Keywords:
LBX2-AS1; PKM2; esophageal cancer; glycolysis; radiotherapy.