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结肠癌是常见的恶性肿瘤之一,2018年全球新增180万例,死亡862 000例[1]。近年来结肠癌的发病率呈上升之势[1]。尽管根治性手术和辅助化疗可以提高结肠癌病人的生存率,但是肿瘤复发仍然是预后不良的主要原因[2]。寻找结肠癌潜在的分子生物学指标是临床和基础研究的重点。
肿瘤坏死因子受体相关因子(tumor necrosis factor receptor-associated factor,TRAF)是一类胞内接头蛋白,主要参与肿瘤坏死因子(tumor necrosis factor,TNF)受体家族信号通路的调控,具有影响细胞增殖、存活、凋亡、参与免疫炎症反应等多种功能[3]。TRAF家族共7个成员,分别为TRAF1、TRAF2、TRAF3、TRAF4、TRAF5、TRAF6、TRAF7,其中TRAF4作用较为独特,它能同时作为TNF受体家族和Toll样/白细胞介素1受体家族的接头分子[3]。TRAF4在人体各种组织中均有表达,既往研究显示TRAF4可能作为促癌基因在乳腺癌[4]、宫颈癌[5]和非小细胞肺癌[6]等肿瘤中发挥作用。TRAF4可表达于结肠组织[7],然而其在结肠癌中的表达及临床意义既往少有报道。本研究用免疫组织化学染色法检测结肠癌组织中TRAF4的表达,探讨其与结肠癌临床病理特征及预后的关系。
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TRAF4主要表达于细胞核中(见图 1)。结肠癌组织中TRAF4高表达率为73.21%(82/112),明显高于癌旁组织的33.04%(37/112),差异有统计学意义(χ2=38.81,P < 0.01)。
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低分化结肠癌病人的TRAF4高表达率明显高于高分化病人(P < 0.01),T分期越高,TRAF4高表达率越大(P < 0.01),M1期结肠癌病人的TRAF4高表达率明显高于M0期病人(P < 0.01)。不同年龄、性别、肿瘤部位、肿瘤直径、肉眼分型、组织学类型、N分期的TRAF4表达差异无统计学意义(P>0.05)(见表 1)。
项目 n 高表达
(n=82)低表达
(n=30)χ2 P 年龄/岁 ≥60 71 52(73.24) 19(26.76) 0.00 >0.05 < 60 41 30(73.17) 11(26.83) 性别 男 45 31(68.89) 14(31.11) 0.72 >0.05 女 67 51(76.12) 16(23.88) 肿瘤部位 升结肠 37 24(64.86) 13(35.14) 5.55 >0.05 横结肠 3 1(33.33) 2(66.67) 横结肠 10 7(70.00) 3(30.00) 乙状结肠 62 50(80.65) 12(19.35) 肿瘤直径/cm ≥4 50 39(78.00) 11(22.00) 1.05 >0.05 < 4 62 43(69.35) 19(30.65) 肉眼分型 肿块型 40 29(72.50) 11(27.50) 1.88 >0.05 浸润型 6 3(50.00) 3(50.00) 溃疡型 66 50(75.76) 16(24.24) 组织学类型 腺癌 101 75(74.26) 26(25.74) 1.93 >0.05 其他 11 6(54.44) 5(45.45) 分化程度 高中分化 30 16(53.33) 14(46.67) 8.26 < 0.01 低分化 82 66(80.49) 16(19.51) T分期 T1 7 1(14.29) 6(85.71) 3.25 < 0.01 T2 8 3(37.50) 5(62.50) T3 66 52(78.79) 8(12.12) T4 31 26(83.87) 5(16.13) N分期 N0 59 42(71.19) 17(28.81) 0.13 >0.05 N1 36 29(80.56) 7(19.44) N2 17 11(64.71) 6(35.29) M分期 M0 84 56(66.67) 26(30.95) 6.64 < 0.01 M1 28 26(92.86) 2(7.14) 表 1 TRAF4表达与结肠癌临床病理特征的关系[n; 百分率(%)]
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多因素分析结果显示,分化程度、T分期、N分期、M分期和TRAF4是结肠癌病人总体生存时间的独立影响因素(P < 0.05),分化程度、N分期、M分期和TRAF4是结肠癌病人无进展生存时间的独立影响因素(P < 0.05)(见表 2、3)。
因素 单因素 COX多因素 HR 95%CI P HR 95%CI P 年龄(≥60岁/ < 岁) 1.213 0.768~1.387 >0.05 — — — 性别(男/女) 0.574 0.267~1.105 >0.05 — — — 肿瘤部位(乙状结肠/其他) 1.008 0.897~1.269 >0.05 — — — 肿瘤直径(≥4 cm/ < 4 cm) 1.336 0.877~1.618 >0.05 — — — 肉眼分型(溃疡型/其他) 1.078 0.333~1.231 >0.05 — — — 组织学类型(腺癌/其他) 1.113 0.613~1.367 >0.05 — — — 分化程度(低/高中) 2.897 1.165~3.675 < 0.01 2.453 1.089~2.898 < 0.01 T分期(T3~T4/T1~T2) 2.676 1.555~4.786 < 0.01 2.108 1.316~3.336 < 0.05 N分期(N1~N2/N0) 2.887 1.898~4.009 < 0.01 2.137 1.465~3.009 < 0.05 M分期(M1/M0) 3.887 2.153~5.906 < 0.01 2.675 1.851~4.173 < 0.01 TRAF4(高表达/低表达) 3.152 1.851~4.878 < 0.01 3.014 1.574~4.427 < 0.01 表 2 结肠癌病人总生存时间的影响多因素分析
因素 单因素 COX多因素 HR 95%CI P HR 95%CI P 年龄(≥60岁/ < 岁) 1.089 0.267~1.067 >0.05 — — — 性别(男/女) 0.675 0.295~1.100 >0.05 — — — 肿瘤部位(乙状结肠/其他) 1.132 0.654~1.217 >0.05 — — — 肿瘤直径(≥4 cm/ < 4 cm) 1.182 1.001~1.343 < 0.05 1.017 0.819~1.276 >0.05 肉眼分型(溃疡型/其他) 1.009 0.789~1.135 >0.05 — — — 组织学类型(腺癌/其他) 0.989 0.756~1.134 >0.05 — — — 分化程度(低/高中) 2.787 1.445~3.387 < 0.01 2.110 1286~3.000 < 0.05 T分期(T3~T4/T1~T2) 2.787 0.605~4.080 >0.05 — — — N分期(N1~N2/N0) 5.023 2.605~10.502 < 0.01 6.323 1.298~13.342 < 0.01 M分期(M1/M0) 3.267 1.563~4.802 < 0.01 2.187 1.342~4.008 < 0.01 TRAF4(高表达/低表达) 2.459 1.177~5.192 < 0.05 1.785 1.207~4.510 < 0.05 表 3 结肠癌病人无进展生存时间的单因素和多因素分析
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高表达组总体生存率和无进展生存率分别为64.29%和69.64%,均低于低表达组的82.43%和90.18%(χ2=3.15、4.92,P < 0.05)。高表达组中位生存时间和无进展生存时间分别为70.92个月和72.55个月,均低于低表达组的84.81个月和89.66个月(uc=3.71、5.00, P < 0.05)。
肿瘤坏死因子受体相关因子4在结直肠癌中的表达及临床意义
Expression and clinical significance of tumor necrosis factor receptor-related factor 4 in colorectal cancer
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摘要:
目的探讨肿瘤坏死因子受体相关因子4(tumor necrosis factor receptor-associated factor 4,TRAF4)在结肠癌组织中的表达及临床意义。 方法用免疫组织化学染色法检测112例结肠癌组织标本及其配对的癌旁组织标本中TRAF4的表达。根据染色结果将病人分为高表达组和低表达组,比较2组临床病理学资料和生存预后。生存分析用Kaplan-Meier法,组间生存率比较用Log-rank检验;用COX比例风险回归模型分析结肠癌病人预后的影响因素。 结果TRAF4主要表达于细胞核中。结肠癌组织中TRAF4高表达率为73.21%(82/112),明显高于癌旁组织的33.04%(37/112)(P < 0.01)。低分化结肠癌病人的TRAF4高表达率明显高于高分化病人(P < 0.01),T分期越高,TRAF4高表达率越大(P < 0.01),M1期结肠癌病人的TRAF4高表达率明显高于M0期病人(P < 0.01)。分化程度、T分期、N分期、M分期和TRAF4均为结肠癌病人总体生存时间的独立影响因素(P < 0.05),分化程度、N分期、M分期和TRAF4均为结肠癌病人无进展生存时间的独立影响因素(P < 0.05)。高表达组总体生存率和无进展生存率分别为64.29%和69.64%,均低于低表达组的82.43%和90.18%(P < 0.05)。高表达组中位生存时间和无进展生存时间分别为70.92个月和72.55个月,均低于低表达组的84.81个月和89.66个月(P < 0.05)。 结论TRAF4与结肠癌分化程度、T分期、M分期有关,TRAF4高表达往往预示着结肠癌的不良生存预后。 -
关键词:
- 结直肠肿瘤 /
- 肿瘤坏死因子受体相关因子4 /
- 预后
Abstract:ObjectiveTo investigate the expression levels and clinical significance of tumor necrosis factor receptor-associated factor 4(TRAF4) in colon cancer. MethodsThe expression levels of TRAF4 in 112 colon cancer tissue specimens and their matched adjacent tissue specimens were detected using the immunohistochemical staining.According to the staining results, the patients were divided into the high expression group and low expression group, and the clinical pathology data and survival prognosis between two groups were compared.The Kaplan-Meier method was used for survival analysis, and the Log-rank test was used to compare the survival rates between groups.The COX proportional hazards regression model was used to analyze the prognostic factors of colon cancer patients. ResultsTRAF4 was mainly expressed in the nucleus.The high expression rate of TRAF4 in colon cancer tissue was 73.21%(82/112), which was significantly higher than that in the adjacent tissues[33.04%(37/112)](P < 0.01).The high expression rate of TRAF4 in patients with poorly differentiated colon cancer was significantly higher than that in patients with well differentiated patients(P < 0.01).The higher the T stage, the greater the high expression rate of TRAF4 was(P < 0.01).The high expression rate of TRAF4 in patients with stage M1 colon cancer was significantly higher than that in patients with M0 stage(P < 0.01).The degree of differentiation, T stage, N stage, M stage and TRAF4 were the independent factors affecting the overall survival time of colon cancer patients(P < 0.05), and the degree of differentiation, N stage, M stage and TRAF4 were the independent factors influencing the progression-free survival time of colon cancer patients(P < 0.05).The overall survival rate and progression-free survival rate in high expression group were 64.29% and 69.64%, respectively, which were lower than those in low expression group(82.43% and 90.18%)(P < 0.05).The median survival time and progression-free survival time in the high expression group were 70.92 months and 72.55 months, respectively, which were lower than those in low expression group(84.81 months and 89.66 months)(P < 0.05). ConclusionsTRAF4 is related to the degree of differentiation, T stage and M stage of colon cancer, and the high expression of TRAF4 predicts the poor survival prognosis of colon cancer. -
表 1 TRAF4表达与结肠癌临床病理特征的关系[n; 百分率(%)]
项目 n 高表达
(n=82)低表达
(n=30)χ2 P 年龄/岁 ≥60 71 52(73.24) 19(26.76) 0.00 >0.05 < 60 41 30(73.17) 11(26.83) 性别 男 45 31(68.89) 14(31.11) 0.72 >0.05 女 67 51(76.12) 16(23.88) 肿瘤部位 升结肠 37 24(64.86) 13(35.14) 5.55 >0.05 横结肠 3 1(33.33) 2(66.67) 横结肠 10 7(70.00) 3(30.00) 乙状结肠 62 50(80.65) 12(19.35) 肿瘤直径/cm ≥4 50 39(78.00) 11(22.00) 1.05 >0.05 < 4 62 43(69.35) 19(30.65) 肉眼分型 肿块型 40 29(72.50) 11(27.50) 1.88 >0.05 浸润型 6 3(50.00) 3(50.00) 溃疡型 66 50(75.76) 16(24.24) 组织学类型 腺癌 101 75(74.26) 26(25.74) 1.93 >0.05 其他 11 6(54.44) 5(45.45) 分化程度 高中分化 30 16(53.33) 14(46.67) 8.26 < 0.01 低分化 82 66(80.49) 16(19.51) T分期 T1 7 1(14.29) 6(85.71) 3.25 < 0.01 T2 8 3(37.50) 5(62.50) T3 66 52(78.79) 8(12.12) T4 31 26(83.87) 5(16.13) N分期 N0 59 42(71.19) 17(28.81) 0.13 >0.05 N1 36 29(80.56) 7(19.44) N2 17 11(64.71) 6(35.29) M分期 M0 84 56(66.67) 26(30.95) 6.64 < 0.01 M1 28 26(92.86) 2(7.14) 表 2 结肠癌病人总生存时间的影响多因素分析
因素 单因素 COX多因素 HR 95%CI P HR 95%CI P 年龄(≥60岁/ < 岁) 1.213 0.768~1.387 >0.05 — — — 性别(男/女) 0.574 0.267~1.105 >0.05 — — — 肿瘤部位(乙状结肠/其他) 1.008 0.897~1.269 >0.05 — — — 肿瘤直径(≥4 cm/ < 4 cm) 1.336 0.877~1.618 >0.05 — — — 肉眼分型(溃疡型/其他) 1.078 0.333~1.231 >0.05 — — — 组织学类型(腺癌/其他) 1.113 0.613~1.367 >0.05 — — — 分化程度(低/高中) 2.897 1.165~3.675 < 0.01 2.453 1.089~2.898 < 0.01 T分期(T3~T4/T1~T2) 2.676 1.555~4.786 < 0.01 2.108 1.316~3.336 < 0.05 N分期(N1~N2/N0) 2.887 1.898~4.009 < 0.01 2.137 1.465~3.009 < 0.05 M分期(M1/M0) 3.887 2.153~5.906 < 0.01 2.675 1.851~4.173 < 0.01 TRAF4(高表达/低表达) 3.152 1.851~4.878 < 0.01 3.014 1.574~4.427 < 0.01 表 3 结肠癌病人无进展生存时间的单因素和多因素分析
因素 单因素 COX多因素 HR 95%CI P HR 95%CI P 年龄(≥60岁/ < 岁) 1.089 0.267~1.067 >0.05 — — — 性别(男/女) 0.675 0.295~1.100 >0.05 — — — 肿瘤部位(乙状结肠/其他) 1.132 0.654~1.217 >0.05 — — — 肿瘤直径(≥4 cm/ < 4 cm) 1.182 1.001~1.343 < 0.05 1.017 0.819~1.276 >0.05 肉眼分型(溃疡型/其他) 1.009 0.789~1.135 >0.05 — — — 组织学类型(腺癌/其他) 0.989 0.756~1.134 >0.05 — — — 分化程度(低/高中) 2.787 1.445~3.387 < 0.01 2.110 1286~3.000 < 0.05 T分期(T3~T4/T1~T2) 2.787 0.605~4.080 >0.05 — — — N分期(N1~N2/N0) 5.023 2.605~10.502 < 0.01 6.323 1.298~13.342 < 0.01 M分期(M1/M0) 3.267 1.563~4.802 < 0.01 2.187 1.342~4.008 < 0.01 TRAF4(高表达/低表达) 2.459 1.177~5.192 < 0.05 1.785 1.207~4.510 < 0.05 -
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