TGF-β1和TβRⅠ在胆囊癌发病及预后中的作用

Effects on TGF-β1 and TβRⅠ in Carcinogenesis and Prognosis of Gallbladder Carcinomas

目的探讨转化生长因子-β1(TGF-β1)和转化生长因子βⅠ型受体(TβRⅠ)与胆囊癌细胞增殖和细胞周期的关系,分析其在胆囊癌发病中的机理,评价其对胆囊癌预后的价值。方法用免疫组化方法检测原发性胆囊癌、胆囊腺瘤及慢性胆囊炎组织中TGF-β1、TβRⅠ、增殖细胞核抗原(PCNA)及细胞周期素E(cyclinE)的表达,对胆囊癌患者进行随访。结果胆囊癌TGF-β1表达阳性率为57.14%(20/35),显著高于胆囊腺瘤〔20.00%(2/10)〕和胆囊炎〔10.00%(1/10)〕,P<0.01,TGF-β1表达阳性率在Nevin各分期间和是否伴淋巴结及远处转移患者中差异有统计学意义(P<0.05,P<0.01),TGF-β1表达阳性率与PCNALI和cyclinE表达阳性率呈正相关(r=0.5232,P=0.0013;r=0.4065,P=0.0154)。胆囊癌中TβRⅠ表达阳性率为34.29%(12/35),显著低于胆囊腺瘤〔70.00%(7/10)〕和胆囊炎〔70.00%(7/10)〕,P<0.05,伴淋巴结和远处转移者TβRⅠ表达阳性率明显低于无转移者(P<0.05),TβRⅠ表达阳性率与PCNALI呈负相关(r=-0.4024,P=0.0166)。TGF-β1和TβRⅠ表达与胆囊癌预后密切相关,TGF-β1阳性表达者预后比阴性者差(P<0.01),TβRⅠ阳性表达者预后比阴性者好(P<0.05)。结论TGF-β1和TβRⅠ表达与胆囊癌细胞增殖和细胞周期关系密切,是判断胆囊癌发生、发展的重要生物学标志。TβRⅠ低表达而导致TGF-β1负性生长调控作用的逃逸,以及TGF-β1的促肿瘤形成作用,可能是胆囊癌变过程中的重要机理。TGF-β1和TβRⅠ是判断胆囊癌预后的良好指标。

Objective To study the relation between expressions of transforming growth factor β1 （TGF-β1）, transforming growth factor receptor type Ⅰ （TβR Ⅰ ） and cell proliferation, cell cycle in gallbladder carcinomas, to disclose the mechanism of TGF-β1 and TβR Ⅰ in the gallbladder carcinogenesis, and to evaluate their values in the prognosis of gallbladder carcinomas. Methods Thirty five gallbladder carcinomas [age （57.94±4.61） years, 14 male cases and 21 female cases] comprised 32 adenocarcinomas, 2 adenosquamous carcinoma and 1 squamous cell carcinomas. Formalin fixed, paraffin embedded sections from gallbladder carcinomas were immunostained with TGF-β1, TβR Ⅰ , PCNA, cyclin E antibodies by immunochemical assays. Gallbladder adenoma and chronic cholecystitis were collected as non-malignant controls. Patients of gallbladder carcinomas were followed up. Results Positive immunostaining rate of TGF-β1 was 57.14 % in gallbladder carcinomas, which was significantly higher than that in gallbladder adenomas and chronic cholecystitis （P〈0.01, respectively）. Expression of TGF-β1 was associated with Nevin stage, lymph nodes and distant metastasis （P〈0.05, P〈0.01, respectively）. Expression of TGF-β1 was positively correlated with expression of PCNA LI and cyclin E （r=0.523 2, P=0.001 3; r=0.406 5, P= 0. 015 4）, and 34.29% of gallbladder carcinomas were immunostained positively for TβR Ⅰ . Expression of TβR Ⅰ was significantly lower in gallbladder carcinomas than that in gallbladder adenomas and cholecystitis （P〈0.05 , respectively）. It was significantly lower in gallbladder carcinomas patients with lymph nodes and distant metastases than in those without （P 〈 0. 05 ）. Expression of TβR Ⅰ was negatively correlated with PCNA LI （r=-0. 402 4, P=0. 016 6）. Patients with negative expression of TGF-β1 and/or positive expression of TβR Ⅰ had significant longer survival rates than those with positive expression of TGF-β1 and/or negative expression of TβR Ⅰ（P〈0.01, P〈0.05, respectively）. Expressions of TGF-βI and TβR Ⅰ correlated with prognosis of gallbladder carcinomas closely. Conclusion TGF-β1 and TβR Ⅰ have close correlation with cell proliferation, cell cycle of gallbladder carcinomas and are important biological markers of carcinogenesis and progress of gallbladder carcinomas. The escape of growth inhibition of TGF-β1 due to low expression of TβR Ⅰ and carcinogenesis of TGF-β1 may play an important role in gallbladder carcinogenesis. TGF-β1 and TβR Ⅰ are valuable indices for judging the prognosis of gallbladder carcinoma.