NSDHL 通过 TGFβ 信号通路和胆固醇生物合成促进三阴性乳腺癌转移。,Breast Cancer Research and Treatment

当前位置： X-MOL 学术 › Breast Cancer Res. Treat. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

NSDHL 通过 TGFβ 信号通路和胆固醇生物合成促进三阴性乳腺癌转移。
Breast Cancer Research and Treatment ( IF 3.0 ) Pub Date : 2021-04-16 , DOI: 10.1007/s10549-021-06213-8
Mengting Chen _{1,

2} , Yang Zhao _{1,

2} , Xueli Yang ₁ , Yuanyuan Zhao _{1,

2} , Qiqi Liu _{1,

2} , Yang Liu _{1,

2} , Yifeng Hou _{1,

2} , Hefen Sun ₁ , Wei Jin _{1,

2}

Affiliation

目的转移是乳腺癌死亡的主要原因。最近的研究证明，脂质代谢重编程在乳腺癌的发生和转移中起关键作用。我们的目标是确定乳腺癌转移中的关键脂质代谢基因。方法我们设计并克隆了一个包含脂质代谢基因指导 RNA 的 CRISPR 池库，并在体内进行了遗传筛选。Transwell 试验和动物实验分别用于评估体外或体内细胞转移能力。我们用乳腺癌组织微阵列进行了免疫组织化学，以研究 NSDHL 的临床意义。结果我们确定了一种胆固醇代谢酶 NSDHL，它是三阴性乳腺癌的潜在转移驱动因子。NSDHL 在乳腺癌组织中高表达，预示预后不良。NSDHL 敲低显着抑制细胞增殖和迁移。从机制上讲，NSDHL 通过抑制 TGFβR2 的内体降解来激活 TGFβ 信号通路。此外，用酮康唑阻断 NSDHL 的上游代谢可挽救癌症转移和 TGFβR2 降解。然而，NSDHL (Y151X) 的失活并没有挽救迁移能力和 TGFβR2 蛋白表达。结论综上所述，我们的研究结果确定 NSDHL 作为转移驱动因子，其功能取决于其在胆固醇生物合成中的酶活性，并由 NSDHL-TGFβR2 信号通路介导。我们的研究表明，NSDHL 和类固醇生物合成可作为晚期乳腺癌患者的新药靶点。

"点击查看英文标题和摘要"

NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis.

PURPOSE Metastasis is the main cause of breast cancer mortality. Recent studies have proved that lipid metabolic reprogramming plays critical roles in breast cancer carcinogenesis and metastasis. We aim to identify critical lipid metabolism genes in breast cancer metastasis. METHODS We designed and cloned a CRISPR pooled library containing lipid metabolic gene guide RNAs and performed a genetic screen in vivo. Transwell assay and animal experiments were used to evaluate cell metastatic ability in vitro or in vivo, respectively. We performed immunohistochemistry with breast cancer tissue microarray to study the clinical significance of NSDHL. FINDINGS We identified a cholesterol metabolic enzyme, NSDHL, as a potential metastatic driver in triple-negative breast cancer. NSDHL was highly expressed in breast cancer tissues and predicted a poor prognosis. NSDHL knockdown significantly suppressed cell proliferation and migration. Mechanistically, NSDHL activated the TGFβ signaling pathway by inhibiting the endosomal degradation of TGFβR2. In addition, blocking the upstream metabolism of NSDHL with ketoconazole rescued cancer metastasis and TGFβR2 degradation. However, the inactivation of NSDHL (Y151X) did not rescue the migration ability and the TGFβR2 protein expression. CONCLUSION Taken together, our findings established that NSDHL serves as a metastatic driver, and its function depends on its enzyme activity in cholesterol biosynthesis and is mediated by the NSDHL-TGFβR2 signal pathway. Our study indicated that NSDHL and steroid biosynthesis may serve as new drug targets for patients with advanced breast cancer.

更新日期：2021-04-16

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南