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AKR1C1 Activates STAT3 to Promote the Metastasis of Non-Small Cell Lung Cancer
Theranostics ( IF 12.4 ) Pub Date : 2018-01-01 , DOI: 10.7150/thno.21463
Hong ZHU , Lin-Lin CHANG , Fang-Jie YAN , Yan HU , Chen-Ming ZENG , Tian-Yi ZHOU , Tao YUAN , Mei-Dan YING , Ji CAO , Qiao-Jun HE , Bo YANG

Metastasis is the leading cause of mortality for human non-small cell lung cancer (NSCLC). However, it is difficult to target tumor metastasis because the molecular mechanisms underlying NSCLC invasion and migration remain unclear. Methods: GEO data analyses and IHC analyses were performed to identify that the expression level of AKR1C1, a member of human aldo-keto reductase family, was highly elevated in patients with metastasis or metastatic foci of NSCLC patients. Functional analyses (in vitro and in vivo) and quantitative genomic analyses were preformed to confirm the pro-metastatic effects of AKR1C1 and the underlying mechanisms. The correlation of AKR1C1 with the prognosis of NSCLC patients was evaluated using Kaplan-Meier analyses. Results: in NSCLC patients, AKR1C1 expression was closely correlated with the metastatic potential of tumors. AKR1C1 overexpression in nonmetastatic cancer cells significantly promoted metastasis both in vitro and in vivo, whereas depletion of AKR1C1 in highly metastatic tumors potently alleviated these effects. Quantitative genomic and functional analyses revealed that AKR1C1 directly interacted with STAT3 and facilitated its phosphorylation—thus reinforcing the binding of STAT3 to the promoter regions of target genes—and then transactivated these genes, which ultimately promoted tumor metastasis. Further studies showed that AKR1C1 might facilitate the interaction of STAT3 with its upstream kinase JAK2. Intriguingly, AKR1C1 exerted these pro-metastatic effects in a catalytic-independent manner. In addition, a significant correlation between AKR1C1 and STAT3 pathway was observed in the metastatic foci of NSCLC patients, and the AKR1C1-STAT3 levels were highly correlated with a poor prognosis in NSCLC patients. Conclusions: taken together, we show that AKR1C1 is a potent inducer of NSCLC metastasis. Our study uncovers the active function of AKR1C1 as a key component of the STAT3 pathway, which promotes lung cancer metastasis, and highlights a candidate therapeutic target to potentially improve the survival of NSCLC patients with metastatic disease.

中文翻译:

AKR1C1激活STAT3促进非小细胞肺癌的转移

转移是人类非小细胞肺癌(NSCLC)死亡的主要原因。然而,由于靶向NSCLC侵袭和迁移的分子机制仍然不清楚,因此很难靶向肿瘤转移。方法:进行GEO数据分析和IHC分析,确定NSCLC转移或转移灶患者中人类醛酮还原酶家族成员AKR1C1的表达水平高。进行功能分析(体外和体内)和定量基因组分析,以确认AKR1C1的促转移作用及其潜在机制。使用Kaplan-Meier分析评估AKR1C1与NSCLC患者的预后的相关性。结果:在NSCLC患者中,AKR1C1的表达与肿瘤的转移潜力密切相关。AKR1C1在非转移性癌细胞中的过度表达在体外和体内均显着促进了转移,而在高度转移性肿瘤中消耗AKR1C1则有效地减轻了这些影响。定量的基因组和功能分析表明,AKR1C1直接与STAT3相互作用并促进其磷酸化(从而加强STAT3与靶基因启动子区域的结合),然后将这些基因反式激活,最终促进了肿瘤转移。进一步的研究表明,AKR1C1可能促进STAT3与其上游激酶JAK2的相互作用。有趣的是,AKR1C1以与催化无关的方式发挥了这些促转移作用。此外,结论:综上所述,我们显示AKR1C1是NSCLC转移的有效诱导剂。我们的研究揭示了AKR1C1作为STAT3通路的关键组成部分的活性功能,该通路可促进肺癌转移,并突出了潜在的治疗靶点,可潜在地改善NSCLC转移性疾病患者的生存率。
更新日期:2018-03-01
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