PFKFB3-mediated Pro-glycolytic Shift in Hepatocellular Carcinoma Proliferation.
PFKFB3-mediated Pro-glycolytic Shift in Hepatocellular Carcinoma Proliferation.
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DOI：
10.1016/j.jcmgh.2022.09.009
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发表时间：
2023
影响因子：
7.2
通讯作者：
Tsai, Leo L.
中科院分区：
文献类型：
--
作者：
Dou, Qianhui;Grant, Aaron K.;Callahan, Cody;de Souza, Patricia Coutinho;Mwin, David;Booth, Adam L.;Nasser, Imad;Moussa, Marwan;Ahmed, Muneeb;Tsai, Leo L.
代谢重编程，特别是糖酵解调节，支持肝细胞癌（HCC）的异常生存和生长，并可作为治疗靶点。在这项研究中，我们试图确定HCC中的糖酵解调节因子，这些调节因子可以被抑制以防止肿瘤进展，也可以在体内监测，目的是为现有治疗提供一种替代方案。采用原位肝细胞癌大鼠模型。使用脱靶肝消融术刺激肿瘤进入高增殖状态，并与低增殖对照进行比较。我们使用超极化13C磁共振成像（h13C MRI）测量了刺激前后肿瘤以及刺激肿瘤和对照肿瘤之间的体内代谢变化。我们将h13C MRI检测到的代谢变化与体外质谱检测到的代谢物水平、关键糖酵解调节因子的mRNA水平和组织病理学进行了比较。肝细胞癌肿瘤内糖酵解乳酸通量在肿瘤刺激后3天增加，通过Ki67检测与肿瘤增殖呈正相关。这与向有氧糖酵解的转变以及质谱检测到的戊糖磷酸途径的下调有关。mri测量的乳酸通量与PFKFB3表达最密切相关，并被PFK15直接抑制。抑制PFKFB3可阻止糖酵解介导的HCC增殖，可通过体内h13C MRI追踪。
Metabolic reprogramming, in particular, glycolytic regulation, supports abnormal survival and growth of hepatocellular carcinoma (HCC) and could serve as a therapeutic target. In this study, we sought to identify glycolytic regulators in HCC that could be inhibited to prevent tumor progression and could also be monitored in vivo, with the goal of providing a theragnostic alternative to existing therapies. An orthotopic HCC rat model was used. Tumors were stimulated into a high-proliferation state by use of off-target liver ablation and were compared with lower-proliferating controls. We measured in vivo metabolic alteration in tumors before and after stimulation, and between stimulated tumors and control tumors using hyperpolarized 13C magnetic resonance imaging (MRI) (h13C MRI). We compared metabolic alterations detected by h13C MRI to metabolite levels from ex vivo mass spectrometry, mRNA levels of key glycolytic regulators, and histopathology. Glycolytic lactate flux increased within HCC tumors 3 days after tumor stimulation, correlating positively with tumor proliferation as measured with Ki67. This was associated with a shift towards aerobic glycolysis and downregulation of the pentose phosphate pathway detected by mass spectrometry. MRI-measured lactate flux was most closely coupled with PFKFB3 expression and was suppressed with direct inhibition using PFK15. Inhibition of PFKFB3 prevents glycolytic-mediated HCC proliferation, trackable by in vivo h13C MRI.
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影响因子：
13.8
作者：
Patra, Krushna C.;Hay, Nissim
通讯作者：
Hay, Nissim
影响因子：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
影响因子：
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作者：
Ghouri YA;Mian I;Rowe JH
通讯作者：
Rowe JH
影响因子：
4.8
作者：
Minchenko, A;Leshchinsky, I;Caro, J
通讯作者：
Caro, J
影响因子：
19.7
作者：
Ahmed, Muneeb;Kumar, Gaurav;Goldberg, S. Nahum
通讯作者：
Goldberg, S. Nahum