The LBX2‐AS1–miR‐491‐5p–PKM2 Positive Feedback Loop Promotes Radiation Resistance of Esophageal Cancer by Enhancing Glycolysis

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‐1 α , 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‐1 α , 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‐1 α , 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.