Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell
Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell
复制标题
5-氟尿嘧啶耐药胃癌有机化合物的分子生物学研究KHDRBS3有助于获得肿瘤干细胞的特性
DOI：
10.1038/s41388-020-01492-9
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发表时间：
2020-10-12
期刊：
影响因子：
8
通讯作者：
Yasui, Wataru
中科院分区：
文献类型：
--
作者：
Ukai, Shoichi;Honma, Ririno;Yasui, Wataru
5-氟尿嘧啶(5-Fu)是治疗胃癌的关键药物之一。大量证据表明，肿瘤干细胞(CSCs)在获得耐药性中起着关键作用。类有机物是一种新型的3D细胞培养系统技术，它使用培养皿中特定的利基因子，支持干细胞驱动的近生理、自我更新组织的形成。在本研究中，我们建立了GC有机物(GCOS)，并逐渐用更高浓度的5-FU处理它们。我们成功地获得了四个5-FU耐药的GCOs，这是由于5-FU代谢相关分子的表达发生了显著变化。然后，我们使用三个正常的胃器官和三对5-FU耐药和亲本GCOS进行了微阵列分析。通过表达谱比较和进一步验证，我们选择KHDRBS3作为目的基因。我们发现KHDRBS3是GC患者，尤其是接受5-FU化疗的GC患者的独立预后因素。我们还确定，KHDRBS3可能通过调节CD44变异体的表达，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被认为在获取胃癌CSCs特征方面起着重要作用，有望成为预测胃癌患者疗效和预后的候选标记物。
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.