Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Cancer Sci. 2021 Mar;112(3):1196-1208. doi: 10.1111/cas.14805. Epub 2021 Feb 2.
5-Fluorouracil (5-FU) is one of the most frequently used pharmacological agents in the treatment of colorectal cancer (CRC). Resistance to chemotherapy is a major cause of treatment failure of CRC, and it is a well known fact that cancer stem cells play a significant role in the acquisition of drug resistance. In this study, we focused on the KHDRBS3 gene that encodes KH RNA Binding Domain Containing, Signal Transduction Associated 3. We first clarified the relationship between KHDRBS3 and 5-FU resistance. We then observed higher expression levels of KHDRBS3 in KRAS-mutant organoids and cell lines in comparison with KRAS wild-type organoids and cell lines. Immunohistochemical analysis using CRC cases revealed that the prognosis of KHDRBS3-positive patients was significantly worse compared with that of KHDRBS3-negative patients. Univariate and multivariate Cox proportional hazards analyses showed that KHDRBS3 was an independent prognostic factor in patients with CRC. We determined that KHDRBS3 might play a crucial role in the acquisition of stem cell properties, such as drug resistance and spheroid/organoid formation, by regulating CD44 variant expression and the Wnt signaling pathway. In an immunodeficient mouse model, KHDRBS3-positive cells showed efficient tumor formation and formed metastatic lesions in the lungs. These results indicated that KHDRBS3 plays a crucial role in drug resistance and anchorage-independent growth by maintaining stem cell-like features in CRC cells. KHDRBS3 could be a promising candidate marker for predicting chemotherapeutic effect and prognosis in CRC patients.
5-氟尿嘧啶（5-FU）是治疗结直肠癌（CRC）最常用的药物之一。对化疗的耐药性是 CRC 治疗失败的主要原因，众所周知，癌症干细胞在获得耐药性方面起着重要作用。在本研究中，我们专注于编码 KH RNA 结合域包含、信号转导相关 3 的 KHDRBS3 基因。我们首先阐明了 KHDRBS3 与 5-FU 耐药性之间的关系。然后，我们观察到 KRAS 突变体类器官和细胞系中 KHDRBS3 的表达水平高于 KRAS 野生型类器官和细胞系。使用 CRC 病例进行的免疫组织化学分析表明，与 KHDRBS3 阴性患者相比，KHDRBS3 阳性患者的预后明显更差。单因素和多因素 Cox 比例风险分析表明，KHDRBS3 是 CRC 患者的独立预后因素。我们确定，KHDRBS3 通过调节 CD44 变体表达和 Wnt 信号通路，在获得耐药性和球体/类器官形成等干细胞特性方面发挥着关键作用。在免疫缺陷小鼠模型中，KHDRBS3 阳性细胞表现出有效的肿瘤形成能力，并在肺部形成转移性病变。这些结果表明，KHDRBS3 通过维持 CRC 细胞中的干细胞样特征，在药物耐药性和非锚定依赖性生长中发挥着关键作用。KHDRBS3 可能成为预测 CRC 患者化疗效果和预后的有前途的候选标志物。
