Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan.
Division of Reconstructive Surgery for Oral and Maxillofacial Region, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan.
Int J Mol Sci. 2023 Mar 23;24(7):6035. doi: 10.3390/ijms24076035.
Cholesterol plays an important role in cancer progression, as it is utilized in membrane biogenesis and cell signaling. Cholesterol-lowering drugs have exhibited tumor-suppressive effects in oral squamous cell carcinoma (OSCC), suggesting that cholesterol is also essential in OSCC pathogenesis. However, the direct effects of cholesterol on OSCC cells remain unclear. Here, we investigated the role of cholesterol in OSCC with respect to caveolin-1 (CAV1), a cholesterol-binding protein involved in intracellular cholesterol transport. Cholesterol levels in OSCC cell lines were depleted using methyl-β-cyclodextrin and increased using the methyl-β-cyclodextrin-cholesterol complex. Functional analysis was performed using timelapse imaging, and CAV1 expression in cholesterol-manipulated cells was investigated using immunofluorescence and immunoblotting assays. CAV1 immunohistochemistry was performed on surgical OSCC samples. We observed that cholesterol addition induced polarized cell morphology, along with CAV1 localization at the trailing edge, and promoted cell migration. Moreover, CAV1 was upregulated in the lipid rafts and formed aggregates in the plasma membrane in cholesterol-added cells. High membranous CAV1 expression in tissue specimens was associated with OSCC recurrence. Therefore, cholesterol promotes the migration of OSCC cells by regulating cell polarity and CAV1 localization to the lipid raft. Furthermore, membranous CAV1 expression is a potential prognostic marker for OSCC patients.
胆固醇在癌症进展中起着重要作用，因为它被用于膜生物发生和细胞信号转导。降胆固醇药物在口腔鳞状细胞癌（OSCC）中表现出肿瘤抑制作用，这表明胆固醇在 OSCC 发病机制中也是必不可少的。然而，胆固醇对 OSCC 细胞的直接影响尚不清楚。在这里，我们研究了胆固醇在 OSCC 中的作用，特别是涉及胆固醇结合蛋白 Cav1 的作用，Cav1 参与细胞内胆固醇运输。使用甲基-β-环糊精耗竭 OSCC 细胞系中的胆固醇，并使用甲基-β-环糊精-胆固醇复合物增加胆固醇。使用延时成像进行功能分析，并使用免疫荧光和免疫印迹分析研究胆固醇处理细胞中的 Cav1 表达。对手术 OSCC 样本进行 Cav1 免疫组织化学染色。我们观察到添加胆固醇诱导极化的细胞形态，同时 Cav1 定位在尾部，并促进细胞迁移。此外，在添加胆固醇的细胞中，Cav1 在脂筏中上调并在质膜中形成聚集体。组织标本中高膜性 Cav1 表达与 OSCC 复发有关。因此，胆固醇通过调节细胞极性和 Cav1 向脂筏的定位来促进 OSCC 细胞的迁移。此外，膜性 Cav1 表达是 OSCC 患者的潜在预后标志物。
