El-Sherif A M, Seth R, Tighe P J, Jenkins D
Division of Pathology, Queens Medical Centre, University Hospital, Nottingham, UK.
J Pathol. 2000 Dec;192(4):494-501. doi: 10.1002/1096-9896(200012)192:4<494::AID-PATH760>3.0.CO;2-W.
Cervical carcinogenesis is a multistep process initiated by 'high-risk' human papillomaviruses (HR-HPVs), most commonly HPV 16. Transforming growth factor-beta (TGF-beta) inhibits epithelial proliferation and down-regulates transcription of E6/E7 genes of HPV. Altered TGF-beta expression may be important in carcinogenesis. Quantitative RT-PCR was used to investigate TGF-beta1, beta2, and beta3 mRNA levels in nine specimens of normal cervix and 15 cervical precancers (eight HPV-positive, including five HPV 16-positive). Immunocytochemical expression of TGF-beta1, beta2, and beta3 was examined in cervical intraepithelial neoplasia (CIN) positive for HPV 16 (26), and in HPV-negative, normal ectocervical epithelium (9); reserve cell hyperplasia (12); and immature (7) and mature (15) squamous metaplasia. The intensity of staining for TGF-beta1 was measured using grey-scale image analysis. Microdissection was used to investigate epithelial and stromal (excluding crypts) levels of TGF-beta1 mRNA in HPV 16-positive cervical precancer. Normal cervix, including reserve cells and immature and mature metaplasia, showed strong immunocytochemical expression of all TGF-beta isoforms. Expression was decreased in the basal third of the epithelium in CIN 1, in the basal and middle thirds in CIN 2, and in all layers in CIN 3. Quantitative analysis of TGF-beta1 expression showed that the changes in CIN compared with normal ectocervix and mature metaplasia were statistically highly significant (p<0.001, ANOVA). TGF-beta1, beta2, and beta3 mRNA levels showed a significant decrease only in the five HPV 16-positive CIN samples when compared with normal (p=0. 0034, 0.0033, and 0.029, respectively). TGF-beta mRNA levels in HPV 16-positive epithelium also decreased from normal through low-grade to high-grade precancer. Stromal TGF-beta1 was absent or very low compared with epithelial production and was not altered in HPV 16 precancer. Progressive loss of epithelial TGF-beta expression and synthesis may be important in HPV 16-associated human cervical carcinogenesis.
宫颈癌发生是一个由“高危”人乳头瘤病毒（HR - HPV）启动的多步骤过程，最常见的是HPV 16。转化生长因子 - β（TGF - β）抑制上皮细胞增殖并下调HPV的E6/E7基因转录。TGF - β表达改变在致癌过程中可能很重要。采用定量逆转录 - 聚合酶链反应（qRT - PCR）研究9例正常宫颈标本和15例宫颈上皮内瘤变（8例HPV阳性，包括5例HPV 16阳性）中TGF - β1、β2和β3的mRNA水平。在16例HPV阳性的宫颈上皮内瘤变（CIN）、9例HPV阴性的正常宫颈外膜上皮、12例储备细胞增生、7例未成熟和15例成熟鳞状化生中检测TGF - β1、β2和β3的免疫细胞化学表达。使用灰度图像分析测量TGF - β1的染色强度。采用显微切割术研究HPV 16阳性宫颈上皮内瘤变中上皮和基质（不包括腺管）的TGF - β1 mRNA水平。正常宫颈包括储备细胞、未成熟和成熟化生，均显示所有TGF - β亚型的强免疫细胞化学表达。在CIN 1中上皮基底部三分之一处表达降低，在CIN 2中基底部和中间三分之一处降低，在CIN 3中所有层均降低。TGF - β1表达的定量分析表明，与正常宫颈外膜和成熟化生相比，CIN中的变化具有高度统计学意义（p<0.001，方差分析）。与正常相比，仅在5例HPV 16阳性的CIN样本中TGF - β1、β2和β3的mRNA水平显著降低（分别为p = 0.0034、0.0033和0.029）。HPV 16阳性上皮中的TGF - β mRNA水平也从正常通过低级别到高级别上皮内瘤变逐渐降低。与上皮产生相比，基质TGF - β1不存在或非常低，且在HPV 16上皮内瘤变中未改变。上皮TGF - β表达和合成的逐渐丧失在HPV 16相关的人类宫颈癌发生中可能很重要。
