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首页> 外文期刊>Journal of experimental & clinical cancer research : >FOXC1 promotes HCC proliferation and metastasis by Upregulating DNMT3B to induce DNA Hypermethylation of CTH promoter
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FOXC1 promotes HCC proliferation and metastasis by Upregulating DNMT3B to induce DNA Hypermethylation of CTH promoter

机译：FoxC1通过上调DNMT3B来促进HCC增殖和转移，诱导CTH启动子的DNA高甲基化

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Forkhead box C1 (FOXC1), as a member of the FOX family, is important for promote HCC invasion and metastasis. FOX family protein lays a pivotal role in metabolism. ROS is involved in tumor progression and is associated with the expression of lots of transcription factors. We next explored the mechanism underlying FOXC1 modulating the metabolism and ROS hemostasis in HCC. We used amino acids arrays to verify which metabolism is involved in FOXC1-induced HCC. The kits were used to detect the ROS levels in HCC cells with over-expression or down-expression of FOXC1. After identified the downstream target genes and candidate pathway which regulated by FOXC1 during HCC progression in vitro and in vivo, we used western blot, immunohistochemistry, bisulfite genomic sequencing, methylation-specific PCR, chromatin immunoprecipitation analysis and luciferase reporter assays to explore the relationship of FOXC1 and downstream genes. Moreover, the correlation between FOXC1 and target genes and the correlation between target genes and the recurrence and overall survival were analyzed in two independent human HCC cohorts. Here, we reported that FOXC1 could inhibit the cysteine metabolism and increase reactive oxygen species (ROS) levels by regulating cysteine metabolism-related genes, cystathionine γ-lyase (CTH). Overexpression of CTH significantly suppressed FOXC1-induced HCC proliferation, invasion and metastasis, while the reduction in cell proliferation, invasion and metastasis caused by the inhibition of FOXC1 could be reversed by knockdown of CTH. Meanwhile, FOXC1 upregulated de novo DNA methylase 3B (DNMT3B) expression to induce DNA hypermethylation of CTH promoter, which resulted in low expression of CTH in HCC cells. Moreover, low levels of ROS induced by N-acetylcysteine (NAC) which is an antioxidant inhibited the cell proliferation, migration, and invasion abilities mediated by FOXC1 overexpression, whereas high levels of ROS induced by L-Buthionine-sulfoximine (BSO) rescued the suppression results mediated by FOXC1 knockdown. Our study demonstrated that the overexpression of FOXC1 that was induced by the ROS dependent on the extracellular regulated protein kinases 1 and 2 (ERK1/2)- phospho-ETS Transcription Factor 1 (p-ELK1) pathway. In human HCC tissues, FOXC1 expression was positively correlated with oxidative damage marker 8-hydroxy-2′-deoxyguanosine (8-OHdG), p-ELK1 and DNMT3B expression, but negatively correlated with CTH expression. HCC patients with positive co-expression of 8-OHdG/FOXC1 or p-ELK1/FOXC1 or FOXC1/DNMT3B had the worst prognosis, whereas HCC patients who had positive FOXC1 and negative CTH expression exhibited the worst prognosis. In a word, we clarify that the positive feedback loop of ROS-FOXC1-cysteine metabolism-ROS is important for promoting liver cancer proliferation and metastasis, and this pathway may provide a prospective clinical treatment approach for HCC.
机译：FORKHEAD盒C1（FOXC1）作为狐狸家族的成员，对于促进HCC入侵和转移至关重要。福克斯家族蛋白在新陈代谢中占枢轴作用。 ROS参与肿瘤进展，与大量转录因子的表达有关。我们接下来探讨了FoxC1潜在的机制调节了HCC中的新陈代谢和ROS止血。我们使用氨基酸阵列来验证哪种新陈代谢参与FoxC1诱导的HCC。该试剂盒用于检测HCC细胞中的ROS水平，具有FOXC1的过表达或下表达。在鉴定在体外和体内的FOXC1期间由FOXC1调节的下游靶基因和候选途径，我们使用Western印迹，免疫组化，亚硫酸氢盐，染色体免疫沉淀分析和荧光素酶报告分析来探索关系FOXC1和下游基因。此外，在两个独立的人HCC队列中分析了FoxC1与靶基因与靶基因之间的相关性和靶基因与复发和整体存活之间的相关性。在这里，我们报道了FoxC1可以通过调节半胱氨酸代谢相关基因，半胱氨酸γγ-裂解酶（CTH）来抑制半胱氨酸代谢和增加反应性氧物种（ROS）水平。 CTH的CTH过表达显着抑制了FoxC1诱导的HCC增殖，侵袭和转移，而通过抑制FOXC1引起的细胞增殖，侵袭和转移的降低可以通过敲低的CTH逆转。同时，FoxC1上调的De Novo DNA甲基酶3B（DNMT3B）表达，以诱导CTH启动子的DNA高甲基化，从而导致HCC细胞中的CTH的表达低。此外，由N-乙酰半胱氨酸（NAC）诱导的低水平的RO，其是抗氧化剂的细胞增殖，迁移和侵袭能力，而L-BATHIONINININE-磺酰胺（BSO）诱导的高水平ROS诱导FoxC1敲低介导的抑制结果。我们的研究证明，由ROS依赖于细胞外调节蛋白激酶1和2（ERK1 / 2） - 磷酸-ETS转录因子1（P-ELK1）途径的ROS诱导的FOXC1过表达。在人HCC组织中，FoxC1表达与氧化损伤标记8-羟基-2'-脱氧核苷酸（8-OHDG），P-ELK1和DNMT3B表达呈正相关，但与第四次表达呈负相关。 HCC患有8-OHDG / FOXC1或P-ELK1 / FOXC1或FOXC1 / DNMT3B的患者预后最差，而患有阳性FOXC1和阴性CTH表达的HCC患者表现出最糟​​糕的预后。总之，我们阐明了ROS-FOXC1-半胱氨酸代谢-ROS的阳性反馈环 - 对于促进肝癌增殖和转移至关重要，并且该途径可以为HCC提供前瞻性临床治疗方法。

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