7-脱氢胆固醇还原酶通过调节胆固醇激活Hedgehog通路促进三阴性乳腺癌的发展

IF 2.3 4区 医学 Q3 ONCOLOGY
Jianwei Sun, Shuang Qiu, Yu Sun, Yuanyuan Liu, Jinyu Yang, Xin Chen, Di Wu, Li Li
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引用次数: 0

摘要

背景:胆固醇已被证明是乳腺癌发生和发展的潜在危险因素。本研究旨在探讨DHCR7在胆固醇合成中的调控作用及其在Hedgehog (Hh)信号通路激活中的作用,以及对三阴性乳腺癌(TNBC)进展的影响。方法:采用生物信息学分析方法,对GSE76275数据集中的基因表达数据进行分析,确定三阴性乳腺癌中胆固醇相关基因的表达。在包括BT-549和MDA-MB-231在内的三阴性乳腺癌细胞系中,采用RNA干扰基因敲除来评估DHCR7的功能影响。此外,引入具有抗胆固醇结合抑制作用的SMO突变体(SMOV329F),以确定其与DHCR7介导的通路变化的相互作用。通过Western blotting、CCK-8实验、transwell迁移实验和qPCR评估细胞增殖、迁移和信号通路激活。结果:DHCR7在TNBC组织和细胞系中表达显著升高,通过胆固醇调节增强Hh通路活性。敲除DHCR7和SMOV329F突变均可降低刺猬相关蛋白的表达,抑制细胞增殖和迁移能力。然而,SMOV329F突变逆转了敲低DHCR7对TNBC细胞的抑制作用。结论:DHCR7通过调节胆固醇激活Hedgehog通路,促进TNBC的发展。这些发现提供了DHCR7在TNBC细胞中胆固醇相关通路和Hh信号传导中的调节作用,为TNBC治疗提供了潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
7-Dehydrocholesterol Reductase Activates the Hedgehog Pathway by Regulating Cholesterol to Promote the Development of Triple-Negative Breast Cancer.

Background: Cholesterol has been shown to be a potential risk factor for the occurrence and progression of breast cancer. This study aimed to investigate the regulation of DHCR7 in cholesterol synthesis and its role in Hedgehog (Hh) signaling pathway activation, as well as its impact on the progression of triple-negative breast cancer (TNBC).

Methods: We analyzed the gene expression data from the GSE76275 data set by bioinformatics analysis to determine the expression of cholesterol-related genes in triple-negative breast cancer. In the triple-negative breast cancer cell lines, including BT-549 and MDA-MB-231, RNA interference gene knockout was used to evaluate the functional impact of DHCR7. In addition, the SMO mutant (SMOV329F) with anti-cholesterol binding inhibition was introduced to determine its interaction with the pathway changes mediated by DHCR7. Cell proliferation, migration, and signaling pathway activation were assessed through Western blotting, CCK-8 assay, transwell migration assay, and qPCR.

Results: DHCR7 expression was significantly elevated in TNBC tissues and cell lines, enhancing the Hh pathway activity through cholesterol modulation. Knocking down DHCR7 and the SMOV329F mutation both reduced the expression of Hedgehog-related proteins and inhibited cell proliferation and migration abilities. However, the SMOV329F mutation re-versed the inhibitory effect of knocking down DHCR7 on TNBC cells.

Conclusion: DHCR7 activates the Hedgehog pathway by regulating cholesterol to promote the development of TNBC. These findings provide insights into the regulatory roles of DHCR7 in cholesterol-related pathways and Hh signaling in TNBC cells, offering potential therapeutic targets for TNBC treatment.

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来源期刊
Current cancer drug targets
Current cancer drug targets 医学-肿瘤学
CiteScore
5.40
自引率
0.00%
发文量
105
审稿时长
1 months
期刊介绍: Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes. Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer. As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
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