Laboratorio de Células Madre/Stem Cells Lab (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, CP 1428, Ciudad Autónoma de Buenos Aires, Argentina.
Instituto de Ciencias Básicas y Medicina Experimental, Instituto Universitario del Hospital Italiano, Potosí 4265, C1199ACL, Buenos Aires, Argentina.
J Cancer Res Clin Oncol. 2024 Feb 28;150(2):106. doi: 10.1007/s00432-024-05607-7.
De novo synthesis of cholesterol and its rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR), is deregulated in tumors and critical for tumor cell survival and proliferation. However, the role of HMGCR in the induction and maintenance of stem-like states in tumors remains unclear.
A compiled public database from breast cancer (BC) patients was analyzed with the web application SurvExpress. Cell Miner was used for the analysis of HMGCR expression and statin sensitivity of the NCI-60 cell lines panel. A CRISPRon system was used to induce HMGCR overexpression in the luminal BC cell line MCF-7 and a lentiviral pLM-OSKM system for the reprogramming of MCF-7 cells. Comparisons were performed by two-tailed unpaired t-test for two groups and one- or two-way ANOVA.
Data from BC patients showed that high expression of several members of the cholesterol synthesis pathway were associated with lower recurrence-free survival, particularly in hormone-receptor-positive BC. In silico and in vitro analysis showed that HMGCR is expressed in several BC cancer cell lines, which exhibit a subtype-dependent response to statins in silico and in vitro. A stem-like phenotype was demonstrated upon HMGCR expression in MCF-7 cells, characterized by expression of the pluripotency markers NANOG, SOX2, increased CD44 +/CD24low/ -, CD133 + populations, and increased mammosphere formation ability. Pluripotent and cancer stem cell lines showed high expression of HMGCR, whereas cell reprogramming of MCF-7 cells did not increase HMGCR expression.
HMGCR induces a stem-like phenotype in BC cells of epithelial nature, thus affecting tumor initiation, progression and statin sensitivity.
胆固醇及其限速酶 3-羟-3-甲基戊二酰基辅酶 A 还原酶（HMGCR）的从头合成在肿瘤中失调，对肿瘤细胞的存活和增殖至关重要。然而，HMGCR 在肿瘤中诱导和维持干细胞样状态中的作用尚不清楚。
使用网络应用程序 SurvExpress 分析来自乳腺癌（BC）患者的综合公共数据库。使用 Cell Miner 分析 NCI-60 细胞系面板中 HMGCR 的表达和他汀类药物敏感性。CRISPRon 系统用于诱导腔型 BC 细胞系 MCF-7 中 HMGCR 的过表达，以及慢病毒 pLM-OSKM 系统用于 MCF-7 细胞的重编程。两组比较采用双尾无配对 t 检验，多组比较采用单因素或双因素方差分析。
来自 BC 患者的数据表明，胆固醇合成途径的几个成员的高表达与无复发生存率降低相关，尤其是在激素受体阳性的 BC 中。计算机模拟和体外分析表明，HMGCR 在几种 BC 癌细胞系中表达，这些细胞系在计算机模拟和体外对他汀类药物表现出亚型依赖性反应。在 MCF-7 细胞中表达 HMGCR 后，表现出干细胞样表型，其特征是多能性标记物 NANOG、SOX2 的表达、增加的 CD44+/CD24low/-、CD133+/细胞群和增加的乳腺球体形成能力。多能性和癌症干细胞系表现出 HMGCR 的高表达，而 MCF-7 细胞的细胞重编程并未增加 HMGCR 的表达。
HMGCR 在具有上皮性质的 BC 细胞中诱导干细胞样表型，从而影响肿瘤的起始、进展和他汀类药物敏感性。
