Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness

Hypercholesterolemia is a prevalent metabolic disorder that has been implicated in the development of steroid-targeted cancers. However, the link between hypercholesterolemia and urinary bladder cancer (UBC), a non-steroid-targeted cancer, remains unresolved. Here we show that diet-induced and Ldlr deficiency-induced hypercholesterolemia enhances both UBC stemness and progression. Inhibition of intestinal cholesterol absorption by ezetimibe reversed diet-induced hypercholesterolemia and cancer stemness. As a key component in hypercholesterolemic sera, oxidized low-density lipoprotein (ox-LDL), but not native low-density lipoprotein-cholesterol or metabolite 27-hydroxycholesterol, increased cancer stemness through its receptor CD36. Depletion of CD36, ectopic expression of an ox-LDL binding-disabled mutant form of CD36(K164A), and the neutralization of ox-LDL and CD36 via neutralizing antibodies all reversed ox-LDL-induced cancer stemness. Mechanistically, ox-LDL enhanced the interaction of CD36 and JAK2, inducing phosphorylation of JAK2 and subsequently activating STAT3 signaling, which was not mediated by JAK1 or Src in UBC cells. Finally, ox-LDL levels in serum predicted poor prognosis, and the ox-LDLhigh signature predicted worse survival in patients with UBC. These findings indicate that ox-LDL links hypercholesterolemia with UBC progression by enhancing cancer stemness. Lowering serum ox-LDL or targeting the CD36/JAK2/STAT3 axis might serve as a potential therapeutic strategy for UBCs with hypercholesterolemia. Moreover, elevated ox-LDL may serve as a biomarker for UBC. SIGNIFICANCE: This study demonstrates how hypercholesterolemia-induced oxidized LDL promotes urinary bladder cancer stemness via a CD36/STAT3 signaling axis, highlighting these factors as biomarkers and potential therapeutic targets of aggressive disease.