HER2信号对E3泛素连接酶NEDD4L的调控及其在乳腺癌转移中的作用

HER2 signal pathway is a key driver of breast cancer progression. However, it remains to be fully understood how HER2 signaling elicits breast cancer metastasis. The E3 ubiquitin ligase NEDD4L functions as a negative regulator of TGF-β signaling via mediating proteasomal degradation of TGF-β receptor I and Smad2. Nonetheless, the involvement of NEDD4L, e.g. its inhibitory role in TGF-β signaling, is largely uncharacterized in HER2-overexpressing breast cancer. We found previously that the NEDD4L gene was silenced due to histone hypoacetylation on the promoter region, which was determined by HER2 and the downstream transcription factor Sp1. After referring to recent reports on this area, we propose that HER2 signaling phosphorylates Sp1 to increase its affinity for the histone deacetylase HDAC1, recruits HDAC1 to NEDD4L promoter, and induces epigenetic silencing of NEDD4L, which culminates in the activation of TGF-β signaling, epithelial-mesenchymal transition of malignant cells and the metastasis of breast cancer. In the present study, cultured breast cancer cells, transgenic mice that spontaneously develop breast cancer, and clinical specimens will be combinatorially utilized to decipher the regulation of NEDD4L and its outcome in HER2-positive breast cancer. This study holds out promise to provide novel insights into the mechanisms underlying the metastasis of HER2-positive breast cancer, and thereby has implications for clinical treatment of these malignancies by targeting the aforementioned pathways.

HER2信号通路在乳腺癌进展中发挥关键驱动作用，但其促进乳腺癌转移的分子机制尚未完全阐明。转化生长因子β（TGF-β）通过多种机制介导乳腺癌转移，E3泛素连接酶NEDD4L通过靶向降解TβRI和下游Smad2蛋白而抑制TGF-β通路，但其在HER2阳性乳腺癌中的作用仍有待深入研究。我们发现，乳腺癌细胞中NEDD4L由于启动子区组蛋白去乙酰化而发生沉默，HER2信号及其下游转录因子Sp1调控这一过程。结合文献报道，我们提出HER2信号通过磷酸化Sp1，使之募集组蛋白去乙酰化酶HDAC1，诱导NEDD4L基因沉默，从而活化TGF-β通路，促进细胞发生上皮-间质转化和乳腺癌转移。本研究以乳腺癌细胞、转基因小鼠和临床样本为模型，揭示NEDD4L在HER2阳性乳腺癌转移中的作用及其自身表达调控机制，以期为认识HER2阳性乳腺癌转移的机制提供新思路，并为乳腺癌的治疗提供新的候选靶点。

NEDD4L在多种肿瘤的发生和发展中起着至关重要的作用，但其在乳腺癌中的作用仍不清楚。本研究的目的是揭示乳腺癌中NEDD4L的表达机制及其对预后的影响。生物信息学分析显示，NEDD4L在乳腺癌中表达显著下调，且与患者不良预后相关。CCK-8实验、平板克隆形成实验和transwell实验证实NEDD4L可以抑制乳腺癌细胞的增殖和迁移。生物信息学分析、细胞学实验和乳腺癌临床样本检测的结果表明，SP1促进NEDD4L表达，导致乳腺癌中SNAI2下调。风险评分和临床指标建立诺模图，以定量评估乳腺癌患者的预后。本研究首次揭示了SP1/NEDD4L/SNAI2信号轴在乳腺癌中的作用机制，并建立了可靠的预后模型，为乳腺癌的治疗提供了新的靶点。