乳腺癌中高迁移率族蛋白B1和表皮生长因子受体1的表达及相关性研究

doi:10.3760/cma.j.cn101202-20191008-00303

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摘要目的探讨乳腺癌组织中高迁移率族蛋白B1(HMGB1)和表皮生长因子受体1(EGFR)的表达情况、相关性,及其对患者预后的影响。方法纳入2007年1月—2018年12月东阳市人民医院病理科浸润性乳腺癌石蜡标本392例。患者均为女性;年龄26～90岁,中位年龄52岁。采用免疫组织化学EnVision法,检测标本中HMGB1蛋白在细胞核、细胞质的表达情况以及EGFR蛋白在细胞膜的表达情况,分析HMGB1蛋白与EGFR蛋白表达的相关性。根据HMGB1蛋白在细胞核及细胞质表达状态分为细胞核低表达且细胞质阴性组、细胞核高表达且细胞质阴性组、细胞核低表达且细胞质阳性组、细胞核高表达且细胞质阳性组,比较4组间EGFR蛋白的表达情况。分别观察细胞核HMGB1蛋白高表达+EGFR蛋白阳性、细胞质HMGB1蛋白阳性+EGFR蛋白阳性时对患者预后的影响。结果 (1)乳腺癌中,HMGB1蛋白在细胞核和细胞质阳性表达率分别为80.1%(314/392)和15.1%(59/392),EGFR蛋白在细胞膜阳性表达率为53.6%(210/392)。(2)细胞核HMGB1蛋白高表达患者的EGFR蛋白阳性率56.1%(176/314),高于细胞核HMGB1蛋白低表达的EGFR蛋白阳性率43.6%(34/78),差异有统计学意义(χ²=3.901, P<0.05);Spearman相关分析显示细胞核HMGB1蛋白高表达和EGFR蛋白阳性呈正相关(r=0.100, P<0.05)。细胞质HMGB1蛋白阳性患者的EGFR蛋白阳性率(66.1%,39/59),高于细胞质HMGB1蛋白阴性的EGFR蛋白阳性率(51.4%,171/333),差异有统计学意义(χ²=4.384, P<0.05);Spearman相关分析显示细胞质HMGB1蛋白阳性和EGFR蛋白阳性表达亦呈正相关(r=0.106, P<0.05)。(3)HMGB1蛋白细胞核低表达且细胞质阴性68例、细胞核高表达且细胞质阴性265例、细胞核低表达且细胞质阳性10例、细胞核高表达且细胞质阳性49例,4组中EGFR蛋白阳性率分别为42.6%(29/68)、53.6%(142/265)、50.0%(5/10)、69.4%(34/49),组间比较差异有统计学意义(χ²=8.242, P<0.05)。(4)392例乳腺癌病例中,235例获得了预后生存分析资料。患者术后随访时间为3～80个月,平均60个月。生存分析显示,在235例患者中,5年累积生存率为90.6%,5年无复发累积生存率为81.3%。细胞核HMGB1蛋白高表达且EGFR阳性的患者5年无复发累积生存率为75.2%,低于其他患者的85.8%,差异有统计学意义(χ²=4.171、P<0.05)。细胞核HMGB1蛋白高表达+EGFR阳性的患者5年累积生存率为89.1%,与其他患者的91.8%比较,差异无统计学意义(χ²=0.557、P＞0.05)。细胞质HMGB1蛋白阳性+EGFR阳性的患者5年无复发累积生存率为72.2%,5年累积生存率为83.3%,分别低于其他患者的82.0%、91.2%,但差异均无统计学意义(χ²=1.070、1.307,P值均＞0.05)。结论细胞核及细胞质HMGB1蛋白的表达均与EGFR蛋白表达正相关,并且细胞核或细胞质HMGB1蛋白与EGFR蛋白同时高表达的患者有更低的5年无复发累积生存率和5年累积生存率。同时抑制HMGB1和EGFR可能成为抗乳腺癌治疗的新策略。

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关键词 ：乳腺肿瘤, 高迁移率族蛋白B1, 表皮生长因子受体1, 预后, 生存率

Abstract：Objective To investigate the expression and correlation of high-mobility group box protein B1 (HMGB1) and epidermal growth factor receptor(EGFR) in breast cancer tissues and their effect on the prognosis of patients.Methods A total of 392 paraffin-embedded specimens of invasive breast cancer were collected from the Department of Pathology, Dongyang People's Hospital from 2007 to 2018. The patients were all female aged 26-90 years, with a median age of 52 years. The EnVision method was used to detect the expression of HMGB1 in the nucleus and cytoplasm and the expression of EGFR in the cell membrane. This immunohistochemistry technique was also used to observe the correlation between the expression of both proteins. In accordance with the nuclear and cytoplasmic HMGB1 status, breast cancer was categorized into four subtypes: nuclear low expression and cytoplasmic negative, nuclear high expression and cytoplasmic negative, nuclear low expression and cytoplasmic positive, and nuclear high expression and cytoplasmic positive. The expression of EGFR among the four groups was observed. The effects of the high expression levels of nuclear HMGB1 and positive EGFR and the positive rates of cytoplasmic HMGB1 and EGFR on the prognosis of patients were also observed.Results The high expression of nuclear HMGB1, the positive rate of cytoplasmic HMGB1, and the positive rate of EGFR were 80.1% (314/392), 15.1% (59/392), and 53.6% (210/392), respectively. The expression of EGFR was significantly higher in nuclear HMGB1 high-expression cases (56.1%, 176/314) than in nuclear low-expression cases (43.6%, 34/78, χ² = 3.901, P<0.05). Spearman correlation analysis showed a significant positive correlation between the nuclear HMGB1 high expression and the expression of EGFR (r= 0.100, P<0.05). The expression of EGFR was significantly higher in the cytoplasmic HMGB1 positive cases (66.1%, 39/59) than in the cytoplasmic negative cases (51.4%, 171/333, χ²=4.384, P<0.05). Spearman correlation analysis showed that the HMGB1 cytoplasmic positive and the expression of EGFR were also significantly positively correlated (r=0.106, P<0.05). A total of 68, 265, 10, and 49 cases exhibited HMGB1 nuclear low expression/cytoplasmic negative, nuclear high expression and cytoplasmic negative, nuclear low expression and cytoplasmic positive, and nuclear high expression and cytoplasmic positive, respectively. The positive rates of EGFR in the four groups were 42.6% (29/68), 53.6% (142/265), 50.0% (5/10), and 69.4% (34/49), and the differences between the groups were statistically significant (χ²=8.242, P<0.05). Prognostic survival data were obtained in 235 of 392 breast cancer cases. The patients were followed up for 3-80 months, with an average of 60 months. Survival analysis showed that among the 235 patients, the 5-year cumulative survival rate was 90.6%, and the 5-year relapse-free cumulative survival rate was 81.3%. The 5-year relapse-free cumulative survival rate of patients with high expression of nuclear HMGB1 and positive EGFR was 75.2%, which was lower than that of other patients at 85.8%, and the difference was statistically significant (χ²=4.171, P<0.05). The 5-year cumulative survival rate of patients with high expression of nuclear HMGB1 and positive EGFR was 89.1% compared with that of the other patients at 91.8%, and the difference was not statistically significant (χ²=0.557, P>0.05). The 5-year cumulative and relapse-free cumulative survival rates of patients with positive cytoplasmic HMGB1 and EGFR were 72.2% and 83.3%, which were lower than those of the other patients at 82.0% and 91.2%, respectively. However, the differences were not statistically significant (χ²=1.070 and 1.307, respectively, all P values>0.05).Conclusions Nuclear and cytoplasmic HMGB1 were significantly positively correlated with the expression of EGFR, and the patients with high expression of nuclear or cytoplasmic HMGB1 and EGFR had lower 5-year relapse-free survival and overall survival than the other patients. Therefore, simultaneously inhibiting HMGB1 and EGFR may be a new potential strategy for breast cancer treatment.

Key words： Breast neoplasms High mobility group box protein B1 Epidermal growth factor receptor Prognosis Survival Rate

收稿日期: 2019-10-08

基金资助:国家自然科学基金项目(81802660)

通讯作者: 王超群,Email:chaoqunw869@163.com

引用本文:

王超群, 黄必飞, 王艳, 李晓妮, 胡桂女, 王倩, 邵俊康. 乳腺癌中高迁移率族蛋白B1和表皮生长因子受体1的表达及相关性研究[J]. 中华解剖与临床杂志, 2020, 25(5): 542-547.
Wang Chaoqun, Huang Bifei, Wang Yan, Li Xiaoni, Hu Guinv, Wang Qian, Shao Junkang. Expression and correlation of high-mobility group box protein B1 and epidermal growth factor receptor in breast cancer. Chinese Journal of Anatomy and Clinics, 2020, 25(5): 542-547.

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http://www.cjac.com.cn/CN/10.3760/cma.j.cn101202-20191008-00303 或 http://www.cjac.com.cn/CN/Y2020/V25/I5/542

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