FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism
FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism
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FABP5通过重编程脂肪酸代谢促进宫颈癌淋巴结转移
DOI：
10.7150/thno.44868
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Wang, Wei
中科院分区：
文献类型：
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作者：
Zhang, Chunyu;Liao, Yuandong;Wang, Wei
宫颈癌淋巴结转移患者预后极差。阐明LNM的分子机制可能为Cca的临床治疗提供策略。CCa肿瘤中脂肪酸结合蛋白5（FABP 5）表达的上调与LNM呈正相关。然而，FABP 5在Cca LNM中的确切作用和机制仍不清楚。方法：在CCa肿瘤样本中评估FABP 5作为CCa LNM预测因子的诊断价值。FABP 5及其上游和下游调控因子的功能作用通过体外和体内的功能获得和功能丧失试验进行了研究。使用LNM的小鼠模型来确定FABP 5对LNM的作用和FABP 5靶向的治疗价值。结果：我们发现FABP 5在伴有LNM的Cca中显著上调，并与不良预后相关。多因素Logistic回归分析显示FABP 5蛋白是LNM的独立预测因子。此外，FABP 5通过重编程脂肪酸（FA）代谢促进上皮-间质转化、淋巴管生成和LNM。从机制上讲，FABP 5促进脂肪分解和FA合成，导致细胞内脂肪酸（FA）增加，激活NF-κB信号传导，从而诱导LNM。重要的是，奥利司他的管理，削弱FA代谢重编程，抑制FABP 5诱导的LNM在CCa。FABP 5的促转移作用被miR-144- 3 p降低。此外，在低氧微环境中，miR-144- 3 p在CCa中显著下调，FABP 5在CCa中上调。结论：我们的研究结果强调了FA代谢依赖的机制FABP 5诱导LNM。此外，FABP 5的表达和生物学功能在缺氧条件下可通过miR-144- 3 p进行调控。我们的研究确定FABP 5作为一个潜在的诊断生物标志物和治疗靶点LNM在Cca。
Patients with cervical cancer (CCa) with lymph node metastasis (LNM) have an extremely poor prognosis. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa. Upregulation of fatty acid-binding protein 5 (FABP5) expression in CCa tumours was demonstrated to positively correlate with LNM. However, the precise role and mechanisms of FABP5 in the LNM of CCa remain unknown. Methods: The diagnostic value of FABP5 as a predictor of LNM in CCa was evaluated in CCa tumour samples. The functional role of FABP5 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. A mouse model of LNM was used to determine the effect of FABP5 on LNM and the therapeutic value of FABP5 targeting. Results: We demonstrated that FABP5 was markedly upregulated in CCa with LNM and correlated with poor prognosis. FABP5 protein was an independent predictor of LNM in a multivariate logistic analysis. Furthermore, FABP5 promoted epithelial-mesenchymal transition, lymphangiogenesis, and LNM by reprogramming fatty acid (FA) metabolism. Mechanistically, FABP5 promoted lipolysis and FA synthesis, which led to an increase in intracellular fatty acids (FAs) that activated NF-κB signalling, thus inducing LNM. Importantly, administration of orlistat, which attenuates FA metabolism reprogramming, inhibited FABP5-induced LNM in CCa. The pro-metastatic effect of FABP5 was reduced by miR-144-3p. Moreover, miR-144-3p was significantly downregulated and FABP5 was upregulated in CCa in a hypoxic microenvironment. Conclusion: Our findings highlight a FA metabolism-dependent mechanism of FABP5-induced LNM. Moreover, the expression and biological function of FABP5 can be regulated by miR-144-3p in hypoxia. Our study identifies FABP5 as a potential diagnostic biomarker and therapeutic target for LNM in CCa.