Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
Oncogene. 2020 Dec;39(50):7265-7278. doi: 10.1038/s41388-020-01492-9. Epub 2020 Oct 12.
5-FU is one of the key drugs in the treatment of gastric cancer (GC). Much evidence has shown that cancer stem cells (CSCs) play a key role in the acquisition of drug resistance. The organoid is a novel 3D cell culture system technology that sustains stem-cell-driven formation of near-physiological, self-renewing tissues using specific niche factors in a dish. In this study, we established GC organoids (GCOs) and gradually treated them with higher concentrations of 5-FU. We successfully harvested four 5-FU-resistant GCOs, which were supported by significant changes in the expression of molecules related to 5-FU metabolism. We then performed microarray analysis using three normal gastric organoids and three pairs of 5-FU-resistant and parental GCOs. Through the comparison of expression profiles and further validation, we chose KHDRBS3 as a target gene. We found KHDRBS3 to be an independent prognostic factor in GC patients, especially in GC patients treated with 5-FU chemotherapy. We also determined that KHDRBS3 might play an important role in the acquisition of stem cell-like features, such as multi-drug resistance and organoid formation, by regulating CD44 variant expression. We found KHDRBS3, which is thought to play an important role in the acquisition of characteristics of CSCs in GC, to be a promising candidate marker for predicting therapeutic effect and prognosis in GC patients.
5-FU 是胃癌（GC）治疗的关键药物之一。大量证据表明，癌症干细胞（CSC）在获得耐药性方面起着关键作用。类器官是一种新型的 3D 细胞培养系统技术，它使用特定的龛位因子在培养皿中维持干细胞驱动的近生理、自我更新组织的形成。在这项研究中，我们建立了 GC 类器官（GCO），并逐渐用更高浓度的 5-FU 对其进行处理。我们成功地收获了四个 5-FU 耐药的 GCO，这与与 5-FU 代谢相关的分子表达的显著变化有关。然后，我们使用三个正常胃类器官和三对 5-FU 耐药和亲本 GCO 进行了微阵列分析。通过表达谱的比较和进一步验证，我们选择 KHDRBS3 作为靶基因。我们发现 KHDRBS3 是 GC 患者的独立预后因素，特别是在接受 5-FU 化疗的 GC 患者中。我们还确定 KHDRBS3 可能通过调节 CD44 变体表达在获得干细胞样特征（如多药耐药和类器官形成）方面发挥重要作用。我们发现 KHDRBS3 被认为在 GC 中获得 CSC 特征方面发挥重要作用，是预测 GC 患者治疗效果和预后的有前途的候选标志物。
