Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
The Nursing Department, Shanghai Public Health Clinical Center, Shanghai, China.
Cancer Res Treat. 2020 Apr;52(2):604-621. doi: 10.4143/crt.2019.444. Epub 2019 Dec 27.
Cancer stem cells (CSCs) are naturally resistant to chemotherapy, explaining why tumor relapse frequently occurs after initial regression upon administration of chemotherapeutic agents in most cases. A CSC population characterized by CD13 expression has been identified in hepatocellular carcinoma (HCC). In the current study, we aimed to clarify the molecular mechanism by which it escapes conventional therapies.
Here, we used flow cytometry to examine the percentage of CD13+ CSCs in HepG2 and HuH7 cells after chemotherapy. Using in vitro isotope labeling technique, we compared metabolic pathways between CD13+ and CD13- subpopulations. Using co-immunoprecipitation and western blotting, we determined the target expressions in protein levels under different conditions. We also performed immunohistochemistry to detect the target proteins under different conditions. Animal models were constructed to verify the potential role of tyrosine metabolism in post-chemotherapeutic relapse in vivo.
We observed that quiescent CD13+ CSCs are enriched after chemotherapy in HCCs, and serve as a reservoir for recurrence. Mechanistically, CD13+ CSCs were dependent on aerobic metabolism of tyrosine rather than glucose as energy source. Tyrosine metabolism also generated nuclear acetyl-CoA to acetylate and stabilize Foxd3, thereby allowing CD13+ CSCs cells to sustain quiescence and resistance to chemotherapeutic agents.
These findings encourage further exploration of eliminating CD13+ cells by targeting specific metabolic pathways to prevent recurrence in HCCs.
癌症干细胞（CSC）对化疗具有天然抗性，这解释了为什么在大多数情况下，肿瘤在初始消退后接受化疗药物治疗，仍会经常复发。在肝癌（HCC）中已经鉴定出表达 CD13 的 CSC 群体。在本研究中，我们旨在阐明其逃避常规治疗的分子机制。
我们使用流式细胞术检查化疗后 HepG2 和 HuH7 细胞中 CD13+ CSC 的百分比。我们使用体外同位素标记技术比较了 CD13+和 CD13-亚群之间的代谢途径。通过共免疫沉淀和 Western blot 检测不同条件下的靶蛋白表达。我们还在不同条件下进行了免疫组织化学检测以检测靶蛋白。构建动物模型以验证酪氨酸代谢在体内化疗后复发中的潜在作用。
我们观察到 HCC 中化疗后静止的 CD13+ CSC 会被富集，成为复发的储备库。从机制上讲，CD13+ CSC 依赖于有氧代谢酪氨酸而不是葡萄糖作为能量来源。酪氨酸代谢还产生核乙酰辅酶 A 以乙酰化并稳定 Foxd3，从而使 CD13+ CSC 细胞能够维持静止和对化疗药物的抗性。
这些发现鼓励进一步探索通过靶向特定代谢途径来消除 CD13+细胞，以预防 HCC 的复发。
