Background and Aims: Hexokinases (HKs), a group of enzymes catalyzing the first step of glycolysis, have been shown to play important roles in liver metabolism and tumorigenesis. Our recent studies identified HKDC1 as a top candidate associated with liver cancer metastasis. We aimed to compare its cell type specificity with other HKs upregulated in liver cancer and investigate the molecular mechanisms underlying its involvement in liver cancer metastasis. Approach and Results: We found that, compared to HK1 and HK2, the other two commonly upregulated HKs in liver cancer, HKDC1 was most strongly associated with the metastasis potential of tumors and organoids derived from two liver cancer mouse models we previously established. RNA in situ hybridization and single-cell RNA-seq analysis revealed that HKDC1 was specifically upregulated in malignant cells in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patient tumors, whereas HK1 and HK2 were widespread across various tumor microenvironment lineages. An unbiased metabolomic profiling demonstrated that HKDC1 overexpression in HCC cells led to metabolic alterations distinct from those from HK1 and HK2 overexpression, with HKDC1 particularly impacting the tricarboxylic acid (TCA) cycle. HKDC1 was prometastatic in HCC orthotopic and tail vein injection mouse models. Molecularly, HKDC1 was induced by hypoxia and bound to glycogen synthase kinase 3β to stabilize β-catenin, leading to enhanced stemness of HCC cells. Conclusions: Overall, our findings underscore HKDC1 as a prometastatic HK specifically expressed in the malignant compartment of primary liver tumors, thereby providing a mechanistic basis for targeting this enzyme in advanced liver cancer.

中文翻译：

---

HKDC1 通过稳定 β-catenin 促进缺氧下肝癌干性


背景和目的： 己糖激酶 （HKs） 是一组催化糖酵解第一步的酶，已被证明在肝脏代谢和肿瘤发生中起重要作用。我们最近的研究发现 HKDC1 是与肝癌转移相关的首要候选基因。我们旨在将其细胞类型特异性与肝癌中上调的其他 HKs 进行比较，并探讨其参与肝癌转移的分子机制。方法和结果： 我们发现，与肝癌中其他两种通常上调的 HK1 和 HK2 相比，HKDC1 与我们之前建立的两种肝癌小鼠模型的肿瘤和类器官的转移潜力最密切相关。RNA 原位杂交和单细胞 RNA-seq 分析显示，HKDC1 在肝细胞癌 （HCC） 和胆管癌 （CCA） 患者肿瘤的恶性细胞中特异性上调，而 HK1 和 HK2 广泛存在于各种肿瘤微环境谱系中。无偏倚的代谢组学分析表明，HKDC1 在 HCC 细胞中的过表达导致不同于 HK1 和 HK2 过表达的代谢改变，其中 HKDC1 特别影响三羧酸 （TCA） 循环。HKDC1 在 HCC 原位和尾静脉注射小鼠模型中是促转移性的。在分子上，HKDC1 由缺氧诱导并与糖原合成酶激酶 3β 结合以稳定 β-catenin，导致 HCC 细胞的干性增强。结论： 总体而言，我们的研究结果强调 HKDC1 是一种在原发性肝肿瘤恶性隔室中特异性表达的前列腺癌，从而为在晚期肝癌中靶向该酶提供了机制基础。