Activation of Tyrosine Metabolism in CD13+ Cancer Stem Cells DrivesRelapse in Hepatocellular Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

ABSTRACT

Purpose@#Cancer stem cells (CSCs) are naturally resistant to chemotherapy, explaining why tumorrelapse frequently occurs after initial regression upon administration of chemotherapeuticagents in most cases. A CSC population characterized by CD13 expression has been identifiedin hepatocellular carcinoma (HCC). In the current study, we aimed to clarify the molecularmechanism by which it escapes conventional therapies. @*Materials and Methods@#Here, we used flow cytometry to examine the percentage of CD13+ CSCs in HepG2 andHuH7 cells after chemotherapy. Using in vitro isotope labeling technique, we comparedmetabolic pathways between CD13+ and CD13– subpopulations. Using co-immunoprecipitationand western blotting, we determined the target expressions in protein levels underdifferent conditions. We also performed immunohistochemistry to detect the target proteinsunder different conditions. Animal models were constructed to verify the potential role oftyrosine metabolism in post-chemotherapeutic relapse in vivo. @*Results@#We observed that quiescent CD13+ CSCs are enriched after chemotherapy in HCCs, andserve as a reservoir for recurrence. Mechanistically, CD13+ CSCs were dependent on aerobicmetabolism of tyrosine rather than glucose as energy source. Tyrosine metabolism alsogenerated nuclear acetyl-CoA to acetylate and stabilize Foxd3, thereby allowing CD13+ CSCscells to sustain quiescence and resistance to chemotherapeutic agents. @*Conclusion@#These findings encourage further exploration of eliminating CD13+ cells by targeting specificmetabolic pathways to prevent recurrence in HCCs.