Wang Dawei, Jiao Chengbin, Zhu Yanli, Liang Deshen, Zao Ming, Meng Xiangyu, Gao Jianwei, He Yunlong, Liu Weixin, Hou Jie, Zhong Zhaohua, Cheng Zhuoxin
1 Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China.
2 Department of General Surgery, the First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
Exp Biol Med (Maywood). 2017 Feb;242(4):429-435. doi: 10.1177/1535370216675068. Epub 2016 Oct 23.
Colorectal cancer is the most common malignancy of the gastrointestinal tract. Surgical treatment combined with radiotherapy is the main treatment course for colorectal cancer; nevertheless, radio-resistance is commonly encountered during the treatment course and seriously influences the therapeutic efficacy. We tested the hypothesis that the CXCL12/CXCR4 axis is closely related to radiotherapy sensitivity in colorectal cancer cells. Here, we found that the decrease in cell viability and the increase in cell death induced by radiotherapy were attenuated by CXCL12 treatment, and the inhibition of CXCR4 promoted colorectal cancer cells to be more sensitive to radiotherapy. We also examined the critical roles of CXCL12/CXCR4 in cell survival and found that radiotherapy induced Bax expression and facilitated the activity of caspase-3 and caspase-9, which were reversed by CXCL12 treatment. Cell apoptosis was enhanced by the inhibition of CXCR4 under radiotherapy conditions. Furthermore, treatment with CXCL12 resulted in an increased expression of survivin, and the inhibitory roles of CXCL12 in radiotherapy-induced apoptosis were mitigated by survivin knockdown. These results indicate that CXCL12/CXCR4 protects colorectal cancer cells against radiotherapy via survivin, implying an important underlying mechanism of resistance to radiotherapy during colorectal cancer therapy.
结直肠癌是胃肠道最常见的恶性肿瘤。手术治疗联合放疗是结直肠癌的主要治疗方案；然而，治疗过程中常出现放射抗性，严重影响治疗效果。我们检验了CXCL12/CXCR4轴与结直肠癌细胞放疗敏感性密切相关的假设。在此，我们发现CXCL12处理减弱了放疗诱导的细胞活力降低和细胞死亡增加，并且抑制CXCR4可促进结直肠癌细胞对放疗更敏感。我们还研究了CXCL12/CXCR4在细胞存活中的关键作用，发现放疗诱导Bax表达并促进caspase-3和caspase-9的活性，而CXCL12处理可逆转这些作用。在放疗条件下，抑制CXCR4可增强细胞凋亡。此外，CXCL12处理导致survivin表达增加，而敲低survivin可减轻CXCL12对放疗诱导凋亡的抑制作用。这些结果表明，CXCL12/CXCR4通过survivin保护结直肠癌细胞免受放疗影响，这意味着结直肠癌治疗期间放疗抗性的一个重要潜在机制。
