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缺氧和氧化应激对 3D 胆管癌细胞模型的蛋白质代谢组学改变的影响。

The impact of hypoxia and oxidative stress on proteo-metabolomic alterations of 3D cholangiocarcinoma models.

机构信息

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.

Khon Kaen University Phenome Centre, Khon Kaen, 40002, Thailand.

出版信息

Sci Rep. 2023 Feb 21;13(1):3072. doi: 10.1038/s41598-023-30204-y.

DOI:10.1038/s41598-023-30204-y
PMID:36810897
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9944917/
Abstract

The three-dimensional multicellular spheroid (3D MCS) model has been employed in cholangiocarcinoma research as it generates 3D architecture and includes more physiological relevance with the multicellular arrangement. However, it is also essential to explain the molecular signature in this microenvironment and its structural complexity. The results indicated that poorly differentiated CCA cell lines were unable to form 3D MCS due to the lack of cell adhesion molecules with more mesenchymal marker expression. The well-differentiated CCA and cholangiocyte cell lines were able to develop 3D MCSs with round shapes, smooth perimeter, and cell adhesion molecules that led to the hypoxic and oxidative microenvironment detected. For MMNK-1, KKU-213C, and KKU-213A MCSs, the proteo-metabolomic analysis showed proteins and metabolic products altered compared to 2D cultures, including cell-cell adhesion molecules, energy metabolism-related enzymes and metabolites, and oxidative-related metabolites. Therefore, the 3D MCSs provide different physiological states with different phenotypic signatures compared to 2D cultures. Considering the 3D model mimics more physiological relevance, it might lead to an alternate biochemical pathway, targeting to improve drug sensitivity for CCA treatment.

摘要

三维多细胞球体（3D MCS）模型已被应用于胆管癌研究，因为它生成了 3D 结构，并且具有更多的与多细胞排列相关的生理相关性。然而，解释微环境中的分子特征及其结构复杂性也同样重要。结果表明，由于缺乏具有更多间充质标志物表达的细胞黏附分子，低分化 CCA 细胞系无法形成 3D MCS。分化良好的 CCA 和胆管细胞系能够形成 3D MCS，其形状为圆形，轮廓光滑，细胞黏附分子导致检测到缺氧和氧化微环境。对于 MMNK-1、KKU-213C 和 KKU-213A 的 3D MCS，蛋白质组代谢组学分析显示与 2D 培养相比，蛋白质和代谢产物发生了改变，包括细胞-细胞黏附分子、与能量代谢相关的酶和代谢物以及与氧化相关的代谢物。因此，与 2D 培养相比，3D MCS 提供了不同的生理状态和不同的表型特征。考虑到 3D 模型更能模拟生理相关性，它可能会导致替代的生化途径，以提高 CCA 治疗的药物敏感性。

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