Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Korea.
Department of Pathology, Korea Institute of Radiological and Medical Science, Seoul, Korea.
Mol Cancer Ther. 2020 Feb;19(2):479-489. doi: 10.1158/1535-7163.MCT-19-0265. Epub 2019 Oct 31.
Although chemo- or radiotherapy is usually performed in patients with colorectal cancer, the response is highly variable in locally rectal cancer. Therefore, additional studies are needed on predictable markers and the molecular mechanisms of chemo- and radiotherapy. Y box binding protein 1 (YB1) is an oncoprotein that is aberrantly expressed in many cancers, including colorectal cancer. However, to date there are no targeting agents or strategies to inhibit YB1 expression. Here, we investigate the oncogenic function of YB1 in colorectal cancer and methods to control its expression. We observed that YB1 expression level is correlated with colorectal cancer survival rate. Moreover, YB1 overexpression was associated with colorectal cancer lymph node metastasis and invasion. We also found that radiation exposure increased YB1 expression, which led to radioresistant colorectal cancer, mediated through the activation of cancer stem cell marker CD44 and PI3K/AKT/mTOR signaling. This study revealed, by both and assays, that depletion of YB1 could reduce cell proliferation and motility in colorectal cancer. We further demonstrated that the PI3K/mTOR inhibitor BEZ235 suppressed YB1 expression and enhanced the cytotoxicity of radiation. In addition, combined treatment with BEZ235 and radiation showed a significant antitumor response in an mouse xenograft model. Taken together, our results provide evidence that the activation of YB1 is a major factor in radioresistance and suggest that targeting YB1-mediated signaling is a promising therapeutic strategy for colorectal cancer.
虽然化疗或放疗通常用于结直肠癌患者，但局部直肠癌症的反应差异很大。因此，需要对可预测的标志物和化疗、放疗的分子机制进行更多的研究。Y 盒结合蛋白 1（YB1）是一种癌蛋白，在许多癌症中表达异常，包括结直肠癌。然而，迄今为止，还没有针对 YB1 表达的靶向药物或策略。在这里，我们研究了 YB1 在结直肠癌中的致癌功能及其表达控制方法。我们观察到 YB1 的表达水平与结直肠癌的存活率相关。此外，YB1 的过表达与结直肠癌的淋巴结转移和侵袭有关。我们还发现，辐射暴露会增加 YB1 的表达，从而导致结直肠癌细胞对辐射产生耐药性，这是通过激活癌症干细胞标志物 CD44 和 PI3K/AKT/mTOR 信号转导来实现的。本研究通过 和 实验表明，YB1 的耗竭可以减少结直肠癌细胞的增殖和迁移。我们进一步证明，PI3K/mTOR 抑制剂 BEZ235 可以抑制 YB1 的表达，并增强辐射的细胞毒性。此外，BEZ235 联合辐射治疗在结直肠癌细胞的异种移植模型中显示出显著的抗肿瘤反应。总之，我们的研究结果表明，YB1 的激活是辐射耐药的一个主要因素，并表明靶向 YB1 介导的信号通路是治疗结直肠癌的一种有前途的策略。
