Medical Genomics Research Center, Daejon, Korea; Functional Genomics, University of Science and Technology, Daejeon, Korea.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
Gastroenterology. 2021 Mar;160(4):1194-1207.e28. doi: 10.1053/j.gastro.2020.09.009. Epub 2020 Sep 15.
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.
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 knockdown/control CRC cells. Metastatic dissemination and circulating cancer stem cells were demonstrated by in vivo tracking and flow cytometry analysis, respectively.
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 GSK3β and p53. Active GSK3β contributes to the stability of SQLE, thereby increasing cell cholesterol content, whereas SQLE depletion disrupted the GSK3β/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.
We showed that SQLE reduction caused by cholesterol accumulation aggravates CRC progression via the activation of the β-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.
角鲨烯环氧化酶（SQLE）是胆固醇生物合成中的限速酶，被认为是原癌基因。矛盾的是，SQLE 会被过量胆固醇降解，而低水平的 SQLE 与侵袭性结直肠癌（CRC）相关。因此，我们研究了 SQLE 减少在 CRC 进展中的功能后果。
从公共数据库和 293 个人体组织中获取 CRC 的基因和蛋白表达数据及临床特征，并通过免疫组织化学进行分析。体外研究显示了 SQLE 减少介导 CRC 进展的潜在机制。在 Cecum 植入 SQLE 基因敲低/对照 CRC 细胞前后，用 2%高胆固醇或对照饮食喂养小鼠。通过体内追踪和流式细胞术分析分别证明了转移扩散和循环肿瘤干细胞。
体外研究表明，SQLE 减少通过诱导产生肿瘤干细胞所需的上皮-间充质转化，帮助癌细胞克服限制。令人惊讶的是，SQLE 与 GSK3β 和 p53 相互作用。活性 GSK3β 有助于 SQLE 的稳定性，从而增加细胞胆固醇含量，而 SQLE 耗竭破坏了 GSK3β/p53 复合物，导致转移表型。在自发 CRC 转移小鼠模型中得到了证实，其中通过高胆固醇方案或基因敲低减少 SQLE 水平，通过产生迁移性肿瘤干细胞，显著促进了 CRC 的侵袭性。
我们表明，胆固醇积累导致的 SQLE 减少通过激活β-catenin 致癌途径和失活 p53 肿瘤抑制途径加重 CRC 进展。我们的发现为胆固醇与 CRC 之间的联系提供了新的见解，确定 SQLE 是 CRC 侵袭性的关键调节因子和预后生物标志物。
