Reduction of Squalene Epoxidase by Cholesterol Accumulation Accelerates Colorectal Cancer Progression and Metastasis
Reduction of Squalene Epoxidase by Cholesterol Accumulation Accelerates Colorectal Cancer Progression and Metastasis
复制标题
DOI：
10.1053/j.gastro.2020.09.009
复制
发表时间：
2021-03-09
期刊：
影响因子：
29.4
通讯作者：
Kim, Nam-Soon
中科院分区：
文献类型：
--
作者：
Jun, Soo Young;Brown, Andrew J.;Kim, Nam-Soon
背景与目的：角鲨烯环氧酶(Sqle)是胆固醇生物合成的限速酶，被认为是原癌基因。矛盾的是，SQLE会被过高的胆固醇降解，而低SQLE与侵袭性结直肠癌(CRC)有关。因此，我们研究了SQLE减少在CRC进展中的功能后果。方法：从公共数据库和293例人类组织中获取癌基因和蛋白表达数据及临床特征，并进行免疫组织化学分析。体外研究揭示了Sqle减少介导的结直肠癌进展的潜在机制。小鼠在盲肠移植Sqle基因敲除/对照CRC细胞前后分别喂以2%的高胆固醇或对照饲料。体内示踪和流式细胞仪分析分别证实了肿瘤干细胞的转移和循环。结果：体外研究表明，SQLE的减少通过诱导产生癌症干细胞所需的上皮-间充质转化来帮助癌细胞克服限制。令人惊讶的是，Sqle与GSK3β和P53相互作用。激活的GSK3β有助于Sqle的稳定，从而增加细胞胆固醇含量，而Sqle的缺失破坏了GSK3β/P53复合体，导致转移表型。这一点在自发转移的结直肠癌小鼠模型中得到了证实，在该模型中，通过高胆固醇方案或基因敲除的Sqle减少，通过产生迁移性癌症干细胞显著促进了结直肠癌的侵袭性。结论：我们发现，胆固醇积聚导致的SQLE减少通过激活β-连环蛋白致癌通路和失活P53抑癌通路来加速结直肠癌的进展。我们的发现为胆固醇和结直肠癌之间的联系提供了新的见解，确定Sqle是结直肠癌侵袭性的关键调节因素和预后的生物标记物。
BACKGROUND & AIMS: Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is suggested as a proto-oncogene. Paradoxically, SQLE is degraded by excess cholesterol, and low SQLE is associated with aggressive colorectal cancer (CRC). Therefore, we studied the functional consequences of SQLE reduction in CRC progression. METHODS: Gene and protein expression data and clinical features of CRCs were obtained from public databases and 293 human tissues, analyzed by immunohistochemistry. In vitro studies showed underlying mechanisms of CRC progression mediated by SQLE reduction. Mice were fed a 2% high-cholesterol or a control diet before and after cecum implantation of SQLE genetic knock-down/control CRC cells. Metastatic dissemination and circulating cancer stem cells were demonstrated by in vivo tracking and flow cytometry analysis, respectively. RESULTS: In vitro studies showed that SQLE reduction helped cancer cells overcome constraints by inducing the epithelial-mesenchymal transition required to generate cancer stem cells. Surprisingly, SQLE interacted with GSK3 beta and p53. Active GSK3 beta contributes to the stability of SQLE, thereby increasing cell cholesterol content, whereas SQLE depletion disrupted the GSK3 beta/p53 complex, resulting in a metastatic phenotype. This was confirmed in a spontaneous CRC metastasis mice model, where SQLE reduction, by a high-cholesterol regimen or genetic knockdown, strikingly promoted CRC aggressiveness through the production of migratory cancer stem cells. CONCLUSIONS: We showed that SQLE reduction caused by cholesterol accumulation aggravates CRC progression via the activation of the beta-catenin oncogenic pathway and deactivation of the p53 tumor suppressor pathway. Our findings provide new insights into the link between cholesterol and CRC, identifying SQLE as a key regulator in CRC aggressiveness and a prognostic biomarker.