Loss of FBP1 facilitates aggressive features of hepatocellular carcinoma cells through the Warburg effect
Loss of FBP1 facilitates aggressive features of hepatocellular carcinoma cells through the Warburg effect
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FBP1 的缺失通过 Warburg 效应促进肝细胞癌细胞的侵袭性特征
DOI：
10.1093/carcin/bgw109
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发表时间：
2017-02-01
期刊：
影响因子：
4.7
通讯作者：
Qin, Wenxin
中科院分区：
文献类型：
--
作者：
Yang, Juan;Wang, Cun;Qin, Wenxin
重编程代谢已被确定为癌细胞中出现的标志。果糖-1，6-二磷酸酶1（fructose-1，6-bisphosphatase 1，FBP 1）作为肿瘤发生的限速酶，在多种肿瘤的发生、发展中起着重要作用。然而，FBP 1在肝细胞癌（HCC）中的作用尚不清楚。在本研究中，我们观察到FBP 1在肝癌细胞系和组织中的表达明显下调。肝癌组织中FBP 1的下调与较低的总生存率相关，并且具有相对较高的肿瘤复发倾向（n = 224）。FBP 1基因沉默可显著促进肝癌细胞集落形成、增殖和转移，而FBP 1基因的异位过表达则导致肝癌细胞集落形成、增殖和转移能力的降低。从机制上讲，沉默FBP 1促进HCC细胞系中的糖酵解，这可能是HCC细胞侵袭性的原因。我们进一步发现，使用特异性抑制剂FX 11靶向瓦尔堡效应可以抑制由FBP 1缺失介导的HCC细胞的侵袭性。这些发现表明FBP 1似乎是HCC中的肿瘤抑制因子。恢复FBP 1水平和活性的策略可能被开发用于治疗HCC患者。
Reprogrammed metabolism has been identified as an emerging hallmark in cancer cells. It has been demonstrated that fructose-1, 6-bisphosphatase 1 (FBP1) as a rate-limiting enzyme in gluconeogenesis plays critical roles in tumor initiation and progression in several cancer types. However, function of FBP1 in hepatocellular carcinoma (HCC) is still not clear. In this study, we observed that the expression of FBP1 was obviously downregulated in the cell lines and tissues of HCC. Downregulation of FBP1 in HCC tissues was correlated with a lower overall survival rate and had a relatively higher tendency of tumor recurrence (n = 224). Silencing FBP1 could significantly promote colony formation, proliferation and metastasis of HCC cells, while ectopic overexpression of FBP1 resulted in impaired abilities of colony formation, proliferation and metastasis in vitro and in vivo. Mechanistically, silencing FBP1 facilitated glycolysis in HCC cell lines, which may be responsible for aggressiveness of HCC cells. We further found that targeting the Warburg effect using the specific inhibitor FX11 could suppress the aggressiveness of HCC cells which was mediated by loss of FBP1. These findings indicate that FBP1 appears to be a tumor suppressor in HCC. Strategies to restore the levels and activities of FBP1 might be developed to treat patients with HCC.