IGF信号通路关键信号分子的表达与肝细胞恶性转化

Association between expression of key insulin-like growth factor signaling molecules and malignant transformation of hepatocytes

目的:研究肝细胞恶性转化过程中胰岛素样生长因子(insulin-like growth factor,IGF)轴中关键信号分子IGF-Ⅱ和IGF-Ⅰ受体(IGF-IR)的动态表达与改变特征.方法:采用以2-乙酰氨基芴(2-fluorenylacetam-ide,2-FAA)喂饲♂SD鼠诱发肝癌发生,以病理组织学观察肝细胞形态学改变、免疫组织化学法观察IGF-Ⅱ和IGF-IR表达与定位,以ELISA法定量肝组织及血IGF-Ⅱ和IGF-IR水平,以逆转录巢式PCR分析IGF-ⅡmRNA和IGF-IR mRNA的转录水平,扩增片段序列经DNA测序证实.结果:诱癌过程中,肝细胞在形态学上出现细胞颗粒样变性、不典型增生到肝癌的发展过程,伴随肝组织核酸代谢旺盛,肝总RNA、IGF-Ⅱ和IGF-IR在转录和蛋白水平上进行性升高;随肝病理组织学改变,组间差异显著(F=13.2,P<0.01).肝组织IGF-Ⅱ比浓度,癌变组明显升高,组间差异显著(F=48.1,P<0.01),癌变组明显高于对照组、变性组和癌前组(P<0.01);血IGF-Ⅱ浓度(nmol/L).与肝IGF-Ⅱ比浓度(nmol/mgwetliver)呈显著正相关(r=0.97,t=5.97,P<0.01).肝组织和血清IGF-IR浓度改变类似于IGF-Ⅱ,癌变组明显高于对照组、变性组和癌前组(P<0.01).结论:IGF-Ⅱ和IGF-IR参与肝细胞恶性转化过程,其过表达是肝癌发生的早期事件.

AIM：To investigate the dynamic expression of key insulin-like growth factor（IGF） signaling IGF-Ⅱ and IGF-Ⅰreceptor（IGF-IR） during ma-lignant transformation of rat hepatocytes.METHODS：Hepatoma was induced in maleSprague-Dawley rats with 2-uorenylacetamide（2-FAA）.Morphological changes of the liver were observed,and dynamic changes in the lev-els of IGF-Ⅱ and IGF-1R in the liver and serum were quantitatively analyzed.The expression and distribution of IGF-Ⅱ and IGF-1R proteins were analyzed by immunohistochemistry.Se-rum IGF-1R and IGF-II levels were detected by ELISA.Expression of IGF-Ⅱ and IGF-IR mRNAs in the liver was detected by nested RT-PCR and conf irmed by DNA sequencing.RESULTS：After induction with 2-FAA,rat hepatocytes showed granule-like degeneration,atypical hyperplasia,and malignant transforma-tion,and hepatic total RNA,IGF-1R,and IGF-Ⅱ levels signifi cantly increased.The levels of IGF-Ⅱ in the liver（F = 48.1,P 0.01） and serum（F = 13.2,P 0.01） were signif icantly higher in the hepatoma group than in any of other groups.There was a positive relationship（r = 0.97,t = 5.97,P 0.01） between liver IGF-II（nmol/mg wet liver） and serum IGF-Ⅱ（nmol/L）.Similar results were also obtained for IGF-IR in the liver and serum,and IGF-IR expression in the hepa-toma group was significantly higher（P 0.01） than that in any of other groups.CONCLUSION：IGF-1R and IGF-Ⅱ may partici-pate in hepatocyte canceration.Overexpression of IGF-1R and IGF-Ⅱ might be useful molecular markers for early diagnosis and prognosis of he-patocellular carcinoma.