Abstract：
BACKGROUND: The metastasis accounts for most deaths from breast cancer (BRCA). Understanding the molecular mechanisms of BRCA metastasis is urgently demanded. Flap Endonuclease 1 (FEN1), a pivotal factor in DNA metabolic pathways, contributes to tumor growth and drug resistance, however, little is known about the role of FEN1 in BRCA metastasis.
RESULTS: In this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α).
CONCLUSIONS: These results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.
RESULTS: In this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α).
CONCLUSIONS: These results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.
摘要：
背景：转移是乳腺癌（BRCA）死亡的主要原因。迫切需要了解BRCA转移的分子机制。皮瓣核酸内切酶1(FEN1),DNA代谢途径中的一个关键因素，有助于肿瘤生长和耐药性，然而,关于FEN1在BRCA转移中的作用知之甚少。
结果：在这项研究中，FEN1在BRCA中的表达及其临床相关性进行了生物信息学研究，显示在BRCA样本中上调，与肿瘤分期有显著关系，淋巴结转移，和预后。局部BRCA队列的免疫组织化学（IHC）染色表明，转移性BRCA组织中FEN1高表达的比例高于非转移性组织。功能丧失和功能获得的测定显示FEN1增强BRCA细胞增殖,迁移,入侵,异种移植生长以及肺转移。进一步发现，FEN1通过信号转导和转录激活因子3（STAT3）激活促进BRCA细胞的攻击行为。具体来说,STAT3抑制剂Stattic阻止了FEN1诱导的迁移和侵袭增强，而激活剂IL-6拯救了FEN1敲低引起的迁移和侵袭减少。此外,FEN1的过表达挽救了核因子-κB（NF-κB）抑制剂BAY117082对磷酸化STAT3的抑制作用。同时,FEN1的敲减减弱了NF-κB激活剂肿瘤坏死因子α（TNF-α）促进的STAT3的磷酸化。
结论：这些结果表明NF-κB驱动的FEN1通过STAT3激活促进BRCA生长和转移的新机制。
结果：在这项研究中，FEN1在BRCA中的表达及其临床相关性进行了生物信息学研究，显示在BRCA样本中上调，与肿瘤分期有显著关系，淋巴结转移，和预后。局部BRCA队列的免疫组织化学（IHC）染色表明，转移性BRCA组织中FEN1高表达的比例高于非转移性组织。功能丧失和功能获得的测定显示FEN1增强BRCA细胞增殖,迁移,入侵,异种移植生长以及肺转移。进一步发现，FEN1通过信号转导和转录激活因子3（STAT3）激活促进BRCA细胞的攻击行为。具体来说,STAT3抑制剂Stattic阻止了FEN1诱导的迁移和侵袭增强，而激活剂IL-6拯救了FEN1敲低引起的迁移和侵袭减少。此外,FEN1的过表达挽救了核因子-κB（NF-κB）抑制剂BAY117082对磷酸化STAT3的抑制作用。同时,FEN1的敲减减弱了NF-κB激活剂肿瘤坏死因子α（TNF-α）促进的STAT3的磷酸化。
结论：这些结果表明NF-κB驱动的FEN1通过STAT3激活促进BRCA生长和转移的新机制。
