Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis
Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis
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DOI：
10.1038/sj.onc.1210403
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发表时间：
2007-08-30
期刊：
影响因子：
8
通讯作者：
Ito, Y.
中科院分区：
文献类型：
--
作者：
Sakakura, C.;Miyagawa, K.;Ito, Y.
放疗是一些食管癌的有效治疗方法，但其放射敏感性的分子机制尚不清楚。RUNX3是一种新的胃癌肿瘤抑制因子，其作用于转化生长因子(TGF)- β依赖的细胞凋亡。我们从62例早期影像诊断为T3或T4的晚期食管癌患者中获得配对样本；一个样本来自术前放疗前的活检，另一个在放疗后的手术标本中切除。在67.7%的预处理活检样本和96.7%的辐照切除样本中，RUNX3被抑制。核表达RUNX3与放射敏感性相关，预后优于细胞质或不表达RUNX3 (P < 0.003)；细胞质RUNX3表达与放射线抗性密切相关。RUNX3在所有食管癌耐药细胞系中下调，其启动子高甲基化。用RUNX3稳定转染食管癌细胞，体外轻度抑制细胞增殖，增强tgf - β的抗增殖和凋亡作用，并结合Bim诱导提高放射敏感性。相反，转染带有RUNX3反义结构或bim特异性小干扰RNA的表达RUNX3的细胞可诱导辐射抗性。用5-aza-2'-脱氧胞苷处理后，对照组和放射耐药细胞中RUNX3的表达恢复，放射敏感性增加，并诱导了Bim。这些结果表明RUNX3沉默促进食管癌的放射耐药。检测预处理标本中RUNX3表达可预测放射敏感性，诱导RUNX3表达可增加肿瘤放射敏感性。
Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. RUNX3, a novel tumor suppressor of gastric cancer, functions in transforming growth factor ( TGF)-beta-dependent apoptosis. We obtained paired samples from 62 patients with advanced esophageal cancers diagnosed initially as T3 or T4 with image diagnosis; one sample was obtained from a biopsy before presurgical radiotherapy, and the other was resected in surgical specimens after radiotherapy. RUNX3 was repressed in 67.7% cases of the pretreatment biopsy samples and 96.7% cases of the irradiated, resected samples. The nuclear expression of RUNX3 was associated with radiosensitivity and a better prognosis than cytoplasmic or no RUNX3 expression ( P < 0.003); cytoplasmic RUNX3 expression was strictly associated with radioresistance. RUNX3 was downregulated and its promoter was hypermethylated in all radioresistant esophageal cancer cell lines examined. Stable transfection of esophageal cancer cells with RUNX3 slightly inhibited cell proliferation in vitro, enhanced the antiproliferative and apoptotic effects of TGF-beta and increased radiosensitivity in conjunction with Bim induction. In contrast, transfection of RUNX3-expressing cells with a RUNX3 antisense construct or a Bim-specific small interfering RNA induced radioresistance. Treatment with 5-aza-2'-deoxycytidine restored RUNX3 expression, increased radiosensitivity and induced Bim in both control and radioresistant cells. These results suggest that RUNX3 silencing promotes radioresistance in esophageal cancers. Examination of RUNX3 expression in pretreatment specimens may predict radiosensitivity, and induction of RUNX3 expression may increase tumor radiosensitivity.