Nerusch Julia, Schicht Gerda, Herzog Natalie, Küpper Jan-Heiner, Seehofer Daniel, Damm Georg
Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany.
Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany.
Cells. 2025 Aug 14;14(16):1254. doi: 10.3390/cells14161254.
Metabolic rewiring is a hallmark of both hepatic regeneration and malignant transformation, complicating the identification of cancer-specific traits. This study aimed to distinguish the metabolic profiles of proliferating hepatocytes and hepatocellular carcinoma (HCC) cells through integrated analyses of mRNA and protein expression, along with functional characterization. We compared non-malignant Upcyte hepatocytes (HepaFH3) cultured under proliferative and confluent conditions with primary human hepatocytes, primary human hepatoma cells, and hepatoma cell lines. Proliferating HepaFH3 cells exhibited features of metabolic reprogramming, including elevated glycolysis, increased expression, and ketone body accumulation, while maintaining low c-MYC expression and reduced levels, distinguishing them from malignant models. In contrast, HCC cells showed upregulation of HK2, c-MYC, and , reflecting a shift toward aggressive glycolytic and ketolytic metabolism. Functional assays supported the transcript and protein expression data, demonstrating increased glucose uptake, elevated lactate secretion, and reduced glycogen storage in both proliferating and malignant cells. These findings reveal that cancer-like metabolic changes also occur during hepatic regeneration, limiting the diagnostic utility of individual metabolic markers. HepaFH3 cells thus provide a physiologically relevant in vitro model to study regeneration-associated metabolic adaptation and may offer insights that contribute to distinguishing regenerative from malignant processes. Our findings highlight the potential of integrated metabolic profiling in differentiating proliferation from tumorigenesis.
代谢重编程是肝脏再生和恶性转化的一个标志，这使得癌症特异性特征的识别变得复杂。本研究旨在通过对mRNA和蛋白质表达的综合分析以及功能表征，区分增殖肝细胞和肝细胞癌（HCC）细胞的代谢谱。我们将在增殖和汇合条件下培养的非恶性Upcyte肝细胞（HepaFH3）与原代人肝细胞、原代人肝癌细胞和肝癌细胞系进行了比较。增殖的HepaFH3细胞表现出代谢重编程的特征，包括糖酵解增加、表达增加和酮体积累，同时保持低c-MYC表达和降低水平，这使它们与恶性模型区分开来。相比之下，HCC细胞显示HK2、c-MYC和上调，反映出向侵袭性糖酵解和酮解代谢的转变。功能分析支持转录和蛋白质表达数据，表明增殖细胞和恶性细胞中葡萄糖摄取增加、乳酸分泌升高和糖原储存减少。这些发现揭示，类似癌症的代谢变化在肝脏再生过程中也会发生，限制了单个代谢标志物的诊断效用。因此，HepaFH3细胞提供了一个生理相关的体外模型来研究与再生相关的代谢适应，并可能提供有助于区分再生过程和恶性过程的见解。我们的发现突出了综合代谢谱在区分增殖和肿瘤发生方面的潜力。
