基于c-Myc/HIF1α/多胺途径探讨结直肠癌进程中肠黏膜屏障功能紊乱的发生机制OA

Objective To explore the molecular mechanism by which human colon cancer cell line HCT116 deprives normal intestinal mucosal tissue of polyamines to meet its energy needs through activating the c-Myc/HIF1α pathway,ultimately leading to intestinal epithelial barrier dysfunction in colon cancer.Methods HCT116 cells with different levels of HIF1α expression were co-cultured with IEC6 cells for 24,48,72,and 96 hours.The intestinal mucosal barrier function was assessed by measuring transepithelial electrical resistance(TEER),FD4 permeability,and tight junction proteins(ZO-1,Occludin).Intracellular polyamine content was detected using HPLC.The effect of exogenous spermidine on HCT116 proliferation was analyzed using the CCK8 method.Interventions with DFMO,2DG,and c-Myc inhibitors were conducted to examine glycolysis indicators(glucose consumption,lactate production,lactate dehydrogenase(LDH)activity,ATP levels)and the expression of key proteins(HK2,GLUT1,LDHA,PKM2,HIF1α,c-Myc,ODC,SLC22A1),aiming to elucidate the molecular mechanism.Results Upregulation of HIF1α exacerbated the polyamine deprivation of HCT116 cells from IEC6,leading to impaired intestinal barrier function(decreased TEER,increased FD4,and downregulation of ZO-1/Occludin).Exogenous spermidine promoted HCT116 proliferation and glycolysis through the c-Myc/HIF1α pathway.Hypoxia-induced HIF1α inhibited ODC expression and reduced polyamine synthesis within the tumor,forcing HCT116 to deprive IEC6 of polyamines to maintain energy metabolism.Conclusion The c-Myc/HIF1α signaling axis in HCT116 cells drives tumor glycolysis,disrupts the intestinal mucosal barrier,and promotes colorectal cancer progression by depriving the gut of polyamines.This discovery provides a new strategy for targeting the polyamine metabolism pathway to prevent and treat colorectal cancer.