HMGB1对食管癌患者预后生存及裸鼠移植瘤放射敏感性的影响

doi:10.3760/cma.j.cn113030-20210622-00235

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摘要目的探讨肿瘤组织标本中高迁移率族蛋白B1（HMGB1）表达水平与食管鳞癌患者接受放化疗后预后生存的关系以及对裸鼠移植瘤放射敏感性的影响。方法收集接受放化疗的食管鳞癌患者90例,取其内镜活检组织标本,免疫组织化学检测HMGB1蛋白表达水平,以细胞核染色阳性细胞比例50%为界,分为高表达组（48例）和低表达组（42例）,并对其生存信息进行回顾性统计分析。构建HMGB1低表达食管鳞癌ECA109细胞株,建立裸鼠移植瘤模型,放射线照射后记录肿瘤体积变化和重量,检测凋亡水平。通过Kaplan-Meier方法进行生存分析,log-rank法单因素预后分析,通过方差分析比较不同实验组数据之间的差异。结果 HMGB1表达水平与肿瘤体积、肿瘤最长径、T分期、远处转移显著相关（χ²=9.663、5.625、4.068、7.146,P值均<0.05）,并且HMGB1低表达患者的总生存（OS）（χ²=4.826,P=0.028）、无进展生存（PFS）（χ²=4.390,P=0.036）均优于高表达患者。进一步对HMGB1高表达患者进行分析发现,放化联合治疗、照射剂量对患者OS、PFS未见明显影响。动物实验显示,敲低HMGB1基因后裸鼠移植瘤生长速度减慢,肿瘤体积缩小,并且增加射线照射后凋亡水平。结论 HMGB1高表达食管鳞癌患者接受根治性放化疗后预后生存较差,改善此类患者预后的重要方法为改善其对放化疗的敏感性。敲低HMGB1基因能够提高裸鼠移植食管鳞癌的放射敏感性。

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	张雪原
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关键词 ：食管肿瘤/鳞癌, 高迁移率族蛋白B1, 裸鼠移植瘤, 放射敏感性

Abstract：Objective To evaluate the effects of high mobility group protein box 1 (HMGB1) on clinical prognosis of esophagus squamous cell carcinoma (ESCC) patients treated with chemoradiotherapy and the radiosensitivity of xenograft in nude mice. Methods A total of 90 endoscopic biopsy specimens were obtained from ESCC patients treated with chemoradiotherapy. The expression level of HMGB1 was determined by immunohistochemical staining. High expression level was defined when staining was observed on ≥50% of the tumor cells. All patients were divided into the high expression group (n=48) and low expression group (n=42), and their survival information was retrospectively analyzed. Cell transfection was performed with the plasmid carrying human HMGB1-shRNA to knockdown HMGB1 expression in ECA109 cells and xenograft mouse models were established. The tumor volume and mass were calculated after irradiation with a dose of 15 Gy. The cell apoptosis in xenograft tissues were detected. Survival analysis was performed using Kaplan-Meier method. Univariate prognostic analysis was conducted by log-rank test. Intergroup comparison was performed by analysis of variance (ANOVA). Results The expression level of HMGB1 was significantly associated with gross tumor volume, longest diameter of tumor, T staging and distant metastasis (χ²=9.663, 5.625, 4.068, 7.146, all P<0.05). In the low expression group, the overall survival (OS) (χ²=4.826, P=0.028), progression-free survival (PFS) (χ²=4.390, P=0.036) were longer compared with that in the high expression group. Further analysis of HMGB1-high expression patients showed that the radiation dose and the combination of chemoradiotherapy did not significantly affect the OS or PFS of ESCC patients. We observed that knockdown of HMGB1 slowed the growth rate of xenograft, decreased the tumor volume and increased the apoptosis rate after irradiation. Conclusions ESCC patients with high expression level of HMGB1 obtain poor prognosis after chemoradiotherapy, which can be enhanced by increasing the sensitivity to radiotherapy and chemotherapy. HMGB1 knockdown can effectively increase the radiosensitivity of xenograft in ESCC nude mice.

Key words： Esophageal squamous cell carcinoma HMGB1 Nude mouse xenograft Radiosensitivity

收稿日期: 2021-06-22

基金资助:国家自然科学基金（81872456）; 河北省自然科学基金（H2020206583）

通讯作者: 祝淑钗,Email：sczhu1965@163.com

引用本文:

张雪原,杨兴肖,邹乃祎等. HMGB1对食管癌患者预后生存及裸鼠移植瘤放射敏感性的影响[J]. 中华放射肿瘤学杂志, 2023, 32(1): 48-54.

Zhang Xueyuan,Yang Xingxiao,Zou Naiyi et al. Effects of HMGB1 on clinical prognosis of esophagus squamous cell carcinoma patients after chemoradiotherapy and the radiosensitivity of xenograft in nude mice[J]. Chinese Journal of Radiation Oncology, 2023, 32(1): 48-54.

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http://journal12.magtechjournal.com/Jweb_fszlx/CN/10.3760/cma.j.cn113030-20210622-00235 或 http://journal12.magtechjournal.com/Jweb_fszlx/CN/Y2023/V32/I1/48

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